Chapter 16 - The Physical Basis of Vitality

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CHAPTER 16.
CONCLUSIONS REGAR DING CIRCULATORY FU NCTION IN PART 1.
An essential characteristic of living tissue is its ability to acquire and regulate energy in sufficient
quantity and direction of application, to exactly satisfy its functional requirements at a particular
instant in time. The energy necessary to preserve function may be obtained by direct transfer from
the environment, as for example light and heat from the sun, or it may require absorption of
material which can liberate energy by metabolic breakdown following absorption into its
substance. The appearance of liberated energy becomes manifested as movement of fluid, or
momentum, produced either immediately, or at some future time after an interval of energy
accumulation or storage. The amount of fluid movement may then be regarded as a measure of
the energy made available, and the metabolic activity which underlies it. Resulting physical
activity is related in this way to the momentum present in body fluid.
The implication is that energy production, tissue metabolism, and the momentum present in body
fluid are all dependent on each other, and production of fluid momentum becomes a critical factor
in maintenance of metabolic and physical activity. In order to understand these relationships,
attention must be focussed on the level of energy remaining within the cells where it is
developed, and the exchange with tissue fluid in which the cells are bathed.
The link between fluid momentum and generation, application, and maintenance of energy levels
within the mammalian circulation, depends on the size and shape of the effector cells (mainly
cells of striated muscle) from which fluid motion is initiated. The dimensions of these cells are
related in turn to the concentrations of the respiratory gases (
) and of the metabolic
substrate ([lactate]) directly available to them. The relationship between chemical concentrations
representing energy, and the physical dimensions of cells and organs, becomes the basis for an
algebraic model, expressed in terms of fluid volume, linear velocity of flow, vascular length, and
the resistance opposing fluid motion, which in a self perpetuating system, all need to be
maintained at a level which just balances the energy available at the cell membrane with that
provided by ventricular contraction.
Energy maintained within the effector cells is equivalent to that provided at the cell membranes
by the cardio-vascular system, and estimation of one indicates an equivalent value for the other,
while each is regulated by the physical dimensions of myocardial cells on one hand, and of the
effector cells on the other. The energy balance between myocardial and effector cells allows the
physical dimensions in each area to become related, and the ratios of these dimensions, represent
the ratios not only of total energy developed, but also the way in which energy is directed towards
external work capacity, energy exchanged with the surrounding media, and the developed or`free'
energy present in the cells, and indicated by the prevailing cell temperature.
The energy transported between different areas, serves as an indicator of the amount necessary
to preserve the balance, and energy production in each area varies accordingly in a corresponding
fashion. The cardio-vascular circulation behaves as an hydraulic system, where changes in one
area, are reflected in all other areas served by it, so that if the balance between areas is disturbed,
corresponding changes must occur elsewhere. Difficulty may arise when chemical reactions, and
cell dimensions become distorted so that the balance is altered, requiring adaptations to counter
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the changes. Such adaptations involve the concentrations of respiratory gases and lactate, and
may lead to the appearance of cardio-respiratory syndromes involving varying degrees of
disability. The emphasis laid on the relationships between cell dimensions, and energy
development and application, enlarges on the principle involved in `Starling's Law', viz. the work
capacity of cardiac muscle depends on the diastolic length of cardiac muscle fibres.Work capacity
also depends on oxidative metabolism, and the two may be related by the expression
`
', where `L' is cell length, '
sectional area), and `
i.e., `
' (where `a' represents the cell cross
' represents cell volume.
' (where `0 '
`Vs'
1/cross sectional area of cell), `length' times cross sectional
area = cell volume' In this expression `L' represents cell length and `stored ' energy as `ATP', ` '
represents `1/
' `
'
`[accumulated energy]' as `[creatine phosphate]', ,& `
'
represents cell volume, and `ATP'
`creatine phosphate'
`L'.
Distortions in these relationships occur from alteration of membrane permeability, which
changes the balance between systems. They appear because of inherent differences in
permeability, or because of chemical changes affecting permeability, which are related
particularly with respiratory enzymes, and the relative concentrations of oxygen, carbon dioxide,
and metabolic substrate (lactate) which then occur.
It follows that metabolic activity can only continue while the amount of fluid motion to and
from the cell is maintained.
Continuing metabolic activity in individual cells requires fluid motion in order to transfer energy
from these cells to other parts of the body, but requires fluid to be returned again through similar
activity of the cells constituting the myocardium. Because each of these activities is dependent
upon the other, neither effector organs or myocardium will continue to function in the intact
animal, in the absence of the contribution to fluid movement provided by the other. If the two are
separated, function may only continue in each area, if fluid movement is provided artificially by
some perfusion mechanism to maintain fluid flow .
The circulation and associated life processes may only continue if there is reciprocal activity of
effector cells and myocardial cells to support it. The size of the circulation is primarily dependent
on the activity of the `effector' cells (generally speaking those cells which maintain a potential
difference across the cell membrane, so that stimulation and temporary loss or reversal of the
potential difference initiates cell activity with loss of fluid to the extravascular space, and
performance of external work, e.g., muscle contraction, glandular secretion, nerve conduction,
etc.). The energy contained in the moving fluid determines the amount of the venous return, and
initiates a ventricular response which is of appropriate magnitude to maintain a fluctuating
balance between myocardial energy, and that produced by effector cells, e.g. ventricular stroke
volume directly equivalent to the volume exchanged with the effector cells per beat.
This relationship is maintained by alteration of circulatory length in proportion to the energy
available in the area, so that circulatory length becomes the yardstick which maintains the balance
between the relative amounts of activity in each area. The ratios that indicate length are
equivalent to each other, and each ratio may be designated the `circulatory ratio'. Equivalent ratios
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form the basis for a circulatory model, and the algebraic equivalents allow quantitative estimation
of each variable in terms of others, until a complete model has been constructed. The model
which is based on algebraic relationships between energy production and utilisation in the
mammalian circulation, seeks to increase understanding of the circulatory function initiated by
fluid movement between cells of effector organs, the myocardium, and the extra-vascular fluid
surrounding them.
By its nature, the circulatory model introduces concepts given little attention previously, but
which assume considerable importance in the regulation of function. For example, the internal
resistance to blood flow is determined by blood viscosity, which varies in the circulation
between one area and another, by virtue of the degree of oxygenation of haemoglobin in the blood
in each region Variation in resistance to blood flow from altered viscosity can be controlled by
changing external resistance, and change in the diameter of blood vessels in relationship to the
altered viscosity. It may occur particularly in those regions where blood is fully oxygenated, with
increased pressure necessary to move blood at optimal velocity Increasing velocity diminishes
the requirement for external resistance to flow, when vascular filling can be maintained simply
by changing linear velocity of flow. Although momentum may be unaltered, in one case it
requires increased blood pressure to move a smaller volume at high velocity, in the other a larger
volume moves at reduced linear velocity of flow, and negligible lateral pressure on the vessel
wall.
The change in resistance to flow from external resistance to internal resistance, has the effect of
increasing the volume of the vessel as oxygen concentration diminishes, and of reducing volume
as the concentration increases, i.e., it produces variation between linear velocity of flow, and
vascular volume. Variation of velocity and volume for a particular value of resistance per unit
volume per unit velocity, is the main regulating mechanism for circulatory function. It highlights
the equivalence of motion with respect to function, a principle first glimpsed by Harvey. One
result of this relationship is the maintenance of a relatively constant composition of extra-vascular
fluid (see Bernard), and a further one is the effect of function in effector organs on production
and regulation of venous return to the heart, and on cardiac output as described by Starling.
Enlarging on the ideas first put forward by Harvey, Bernard, and Starling, requires a relatively
small step to formulate mathematical relationships between volumes and linear velocities of flow
in order to describe movement of body fluids, and maintenance of fluid volumes as a result.The
underlying relationship that emerges is regulation of circulatory length by alteration of ratios
involving volume, linear velocity of flow, or by circulation time. It illustrates the importance of
time factors involved in tissue activity, both in the heart, and in effector organs Variations of
dimensions of space relative to time are represented by variation of volume, and/or speed of
moving blood. Nowhere is this more evident than in the venous system, and filling of the heart
chambers, which depends both as to volume and pulse rate on the momentum of the returning
blood. The manner in which blood distends ventricular walls in particular directions, controls the
mechanical response of the ventricle, and produces the characteristics of the ventricular output,
and consequently fluid distribution to individual cells, as well as the response of those cells to
activity.
Alteration of total resistance to flow (represented as `R') with respect to internal resistance to flow
(`l ') allows variation of the rigid requirements of the algebraic model which the circulation
follows in the absence of vasomotor activity from autonomic nerves, and from a variety of
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humoral factors that continually alter external resistance to flow. Altering the effective value of
`R' with respect to `l ' despite a fixed value for oxygen concentration, allows a variable
relationship between `R' and lactate concentration which gives flexibility to the system. Changing
[lactate],or L.
, in the cells, representing ` / Q' with respect to `R' representing ` ', alters
circulatory length with respect to the product of `increased linear velocity given to blood per beat'
times `mechanical efficiency' (representing changing dimensions of active cells) which are both
regulated by `R'. In order to maintain or alter circulatory length, lactate concentration has to vary
with the `artificial' or enhanced value of `R', produced by the activity of hormones or vasomotor
nerves.
This controlling mechanism distorts the algebraic model, because it may produce lactate
concentration well in excess of circulatory length. `Lactate concentration really represents
`l.
', and `artificial' alteration of `R' by imposed vasomotor activity, disturbs the amount of
lactate required, increasing myocardial activity, putting increased strain on vessel walls, and
resulting in reduced perfusion of tissues, leading to disturbed cardio-vascular function , and
possibly to cardio-vascular disorder.
Increased lactate concentration indicates disturbance of energy distribution between effector cells,
tissue fluid, and the intravascular circulation of the blood. It requires altered circulatory and
metabolic activity in each area, and for cardio-vascular function, with changed momentum
(volume and velocity) of fluid movement, and capacity for myocardial energy production. The
heart must vary the volume of ventricular output, together with the linear velocity of flow and
pressure changes associated with movement of blood and tissue fluid, and accumulation of energy
storage in tissue cells. Momentum provided by myocardial contraction is essential to maintain
the life process, and to overcome the peripheral resistance which regulates the size, shape, and
volume of the systemic blood vessels. A similar amount of energy produces blood movement and
blood pressure to fill the vessels with sufficient pressure to maintain flow, as well as energy
storage and/or accumulation in effector cells together with kinetic energy for perfusion of tissues,
and venous return to the heart for ventricular filling. Ventricular contraction expels blood volume
equivalent to the stroke volume, and increases blood pressure and linear velocity of blood flow
with energy to overcome peripheral resistance, to maintain the size and shape of the vascular
system, and also the flow and pressure energy to move blood along it.
Stroke volume and diastolic length of the ventricular muscle fibres provide the energy for
vascular filling, but ventricular contraction also produces kinetic energy proportional to 'Q.R'
times internal resistance to blood flow (
) increased by the 'contractility' of ventricular muscle
(
) which together produce kinetic energy proportional to the 'augmented stroke volume'
. This is equivalent to the increase in momentum given to the stroke volume as it moves
along the aorta at increased speed, so the volume of blood moved in a given time is greatly
'augmented', and this gives rise to the palpable pulse wave, transferring a large amount of energy
with the increased volume to distend the aorta, and allow the conversion of pressure energy into
flow energy in the arteries.
Regulation of energy generation and distribution is an essential element in biological cell
function. Energy generation is confined to individual cells, but distribution is more widespread,
with energy transfer to and from the extra-cellular fluid, and to more distant cells and organs. It
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influences the activity of those organs in turn, to coordinate bodily function. Without movement
of energy, continuing function could not occur, and activity must cease.
Transfer of both fluid and energy between different areas, and the association of fluid movement
with energy transfer, is fundamental to all biological function. It requires strict control of the
momentum available in body fluid to regulate volume and energy exchanges between regions.
A mechanism to accomplish the required motion becomes essential to cell activity, and the
collection of moving fluid within the cardio-vascular system has this function, with the
momentum of the contained blood becoming distributed to regulate motion elsewhere.
The energy that becomes available determines fluid movement, and this movement is then able
to modify any further energy development. Circulatory momentum becomes the measure of both
energy and volume in the fluid moved, and it presents as the most important parameter indicating
circulatory activity. Momentum contained in fluid leaving the cell, and that present in fluid
entering the cell as the result of energy developed elsewhere, together regulate cell activity. The
amount of energy produced by metabolic activity within the cell, together with that remaining as
a result of the exchange with tissue fluid, presents as `stored' energy and `accumulated' energy
retained by it, and together with 'free' or developed energy originating within the cell itself, to
accomplish the metabolic and external work the cell performs, at the same time as it contributes
energy to maintain the circulation. For its part the circulation needs to provide three separate
quantities of energy to preserve adequate cell function, consisting of `stored energy', `free energy'
and `exchanged energy'. The heart has to provide energy exactly equivalent to the total required
for each of these.
The emerging principle is that energy made available by ventricular contraction, must produce
an amount of motion in the circulating blood which in turn is able to initiate sufficient energy
production by other tissues to be equivalent to it. The cycle can be broken by transferring energy
to `storage' in the short term where it is removed from equivalence with motion. The variation
in the energy/motion equivalence is restored when `stored' energy is released again to perform
external work.
Energy is associated with motion leaving the cells, and is presented after passage through the
extra-vascular space and venous blood, to the right atrium. The momentum it retains determines
the energy produced by ventricular contraction through alteration of ventricular filling, and the
volume/velocity relationship of blood expelled to the aorta. `Stored' energy, no longer associated
with motion, remains in the cell initially, but is still able to influence the energy of motion by that
portion of the store made available for external work; e.g., muscle contraction.
The level of `free' energy present in the cell, may affect both `stored' energy and that available
for energy `exchange' and generation of momentum. Variation between them allows the level of
remaining `free' energy to persist which best suits the metabolic requirement of the cell. It
becomes proportional to the product of `stroke volume' (the volume exchanged per beat) and
systemic blood volume (or strength available in the cell to move that volume)
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(where Q is stroke volume; Vs is systemic blood volume, and lPR represents free energy level).
Energy is transferred to `store' by conversion to pyrophosphate bonds, which are either in the
form of adenosine triphosphate, and largely removed from immediate availability through
becoming associated with the `shape' and longitudinal extension of the cell, or they may remain
in the more labile form of creatine phosphate and able to transfer energy to `store' as `ATP', or
to expelled fluid to produce momentum in extra-cellular fluid, and contribute motion to the
`venous return'. When energy is produced either by myocardial cells or cells of `effector' organs,
the problem is to distribute the energy between the functions of storage, energy `exchange', and
`free' energy which best suits the requirements for adequate function. For the myocardium,
momentum present in venous blood entering the atrium, determines both cardiac output, and the
increase in linear velocity which blood must be given to maintain the necessary momentum at
the cell/extra-vascular fluid interface.
Fluid expelled from the cell contributes both volume and momentum to the venous return, and
initiates myocardial function, but the ventricular contraction which follows, replaces volume
equivalent to stroke volume, and energy equivalent to the average mean linear velocity of
systemic blood flow, to maintain both volume and energy in effector and myocardial cells before
the cycle is repeated again. This momentum alone is insufficient to produce adequate venous
return, until further energy equivalent to the internal resistance to blood flow is contributed from
glycolysis occurring within the cells. Momentum is kept proportional to `v .Vs', where `Vs' is
equivalent not only to systemic blood volume, but also to `strength' accumulated in the cell in the
form of `concentration of ATP', or `l /
' . The linear velocity, `v', is equivalent to energy
exchange, and `l ' is equivalent to internal resistance to flow &/or stroke volume. The pressure
equivalent needed for this purpose is `v lPR' , where `v' derives from circulatory momentum, and
`l PR' is developed in the cell from glycolysis, `l .vx', and `cell volume', `[ ]', to produce
`free' energy equivalent to `Q Vs' or `l PR'. Kinetic energy for venous return is maintained by
cell metabolism to be equivalent to pulse pressure, or proportional to `v lPR'. It provides kinetic
energy to maintain venous return, and overcome the internal resistance to flow, and leaves
momentum presented at the atrium as equivalent to `
', or `Q PR', after dissipation of
energy equivalent to `R Vs', representing internal resistance to flow, `l ', and the loss of linear
velocity proportional to vascular length, `l'. Without the energy contribution, `l PR', by cell
metabolism, venous return would not be possible. Circulation of blood requires energy from two
sources, the myocardial contraction, and `free' energy developed in the `effector' cells. The
product of energy from these two indicates the `power' needed to keep the circulation
functioning; i.e.,.
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The balance between the two sources; i.e., myocardial contraction, and cell `free' energy, is
maintained by circulatory momentum and energy storage which contribute to each other for a
given level of `free' energy, determined by the product of stroke volume and systemic blood
volume. Either excessive or inadequate `storage' can lead to syndromes representing circulatory
disturbance, appearing largely as disturbances of circulatory length and lactate concentration,
when the balance between glycolysis, oxidation, and oxidative phosphorylation alters. Energy
develops in the effector or myocardial cells from the combined effects of three processes,
glycolysis, oxidation, and oxidative phosphorylation. Increased direct oxidation produces an
increase in carbon dioxide concentration, while oxidative phosphorylation requires oxygen and
lactate concentrations to be elevated above that most suitable for direct oxidation, which occurs
more freely with lower oxygen concentrations.
Higher oxygen levels may inhibit respiratory enzymes and even lead to oxygen poisoning. The
circumstances under which it is produced by each process, becomes important for the
distribution of energy between cell activities and needs some further consideration. For glycolysis
to occur freely, requires an adequate supply of inorganic phosphate, preferably as
radicle, and the latter occurs more freely when carbon dioxide concentration is reduced with a
fall in local pH . Sufficient ATP is probably also necessary to produce glucose phosphate. When
the concentration of carbon dioxide is reduced, glycolysis is stimulated producing pyruvate,
which may be directly oxidised at the phospho-enol-pyruvate stage, by way of the Krebs cycle,
to carbon dioxide and water. These events can be inhibited by the effect of increased oxygen
concentration on respiratory enzymes, and glycolysis is blocked at the triose phosphate stage
through reduced concentration of coenzyme A, which acts as a hydrogen acceptor. Pyruvate is
then able to accept hydrogen from reduced coenzyme A, to produce lactate, and unblock the
glycolytic pathway. In the presence of lactate and increased oxygen partial pressure, oxidative
phosphorylation occurs, the energy produced becoming absorbed in pyrophosphate bonds, and
allowing oxidation of lactate to pyruvate once more. Reduction in oxygen concentration removes
oxidative inhibition, to facilitate further direct oxidation of pyruvate, with production of carbon
dioxide and oxidative energy .
The reactions outlined provide a balance between glycolysis, oxidation, and oxidative
phosphorylation, to maintain appropriate levels of oxygen, carbon dioxide, and lactate
concentrations within the cell. The resulting levels of adenosine triphosphate, and creatine
phosphate, determine stroke volume, and systemic blood volume, and the amounts of energy
storage, energy exchange, and free energy, characteristic of its level of activity. Energy exchange
is the important factor which maintains circulatory momentum, but free energy, energy exchange,
and storage, are all dependent on lactate concentration, and the maintenance of sufficient
pyrophosphate bonds which is related directly to it. Variation of lactate concentration leads to
alteration of each of these parameters, and particularly to momentum, energy storage, and
external work capacity, total accumulated energy, and systemic arterial blood pressure.
The balance between energy store, energy exchange, and free energy depends on glycolysis,
oxidation and oxidative phosphorylation distributing energy production within the cell.The
resulting balance determines the total energy produced by the ventricle and the directions in
which it is applied for the individual functions of storage, exchange and the free energy the cell
uses for its many and varied functions. Free energy is equivalent to the product of stroke volume
and systemic blood volume, or Q Vs. Circulatory volume depends directly on the concentration
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of stored energy within the cells, while stroke volume results from the combination of length and
viscosity, or stored energy represented by ATP, and accumulated energy concentration
represented by creatine phosphate. The balance between total ATP and creatine phosphate
concentration may be varied as length and viscosity vary, but the product of the two maintains
stroke volume and linear velocity of blood flow.
Stroke volume can be regarded as a function of stored and accumulated energy in the effector
cells, and in the cells of the myocardium. The proportion of energy contributed by ATP and
creatine phosphate may vary with changing circumstances, and is reflected in the physical
dimensions of the cells, when fluid moves across cell membranes during the cardiac cycle.
Elongation of the cell is associated with increased total cell content of ATP, while increased
cross sectional area results when creatine phosphate, and carbon dioxide concentration is
reduced. The energy produced by glycolysis might be the same, but on one occasion it represents
an increase in length rather than viscosity when cell length increases, while if the cell diameter
diminishes, creatine phosphate production is more dominant, and the concentration of creatine
phosphate increases in an equivalent fashion with the concentration of carbon dioxide which
remains in the cell. Stroke volume may remain constant, but in one situation length representing
ATP is the larger factor, while on another carbon dioxide production representing creatine
phosphate concentration contributes the larger amount of energy to moving the same stroke
volume. In one case length is increased, and in the second viscosity is the greater factor with
increased systemic blood volume, while if length and viscosity are both reduced, oxygen
concentration is increased and blood volume becomes more limited, and these have a
considerable influence on both the shape and energy production and distribution within the cell.
The relative change in cell shape representing a change in cell volume compared with length,
alters energy production and distribution between the cell and its surrounding fluid, and as a
consequence the amount of external work it is able to perform. Muscle fibre length is the most
important parameter governing external work performance by the myocardium, and leads to
changes in shape of the heart chambers in order for them to accommodate to the altered work
load.
Changes in ventricular shape follow alteration in momentum of the blood presented to the heart
chambers. It is change in momentum associated with effector cell activity, which determines and
regulates myocardial cell activity, to preserve the required level of momentum given to blood
entering the aorta, together with pulse rate and stroke volume , so that the average mean
momentum in the circulating blood is proportional to stroke volume times the force of ventricular
contraction. The ability to alter the amount of energy given to a particular volume of expelled
blood (stroke volume) not only implies the capacity to alter the momentum in the circulating
blood, but it also includes the capacity to alter work done for a particular physiological length
of myocardial muscle fibre. The latter implies the capacity to generate energy, and the ability to
alter oxygen consumption for a particular level of work performed.
The ratio of external work done / energy generated and oxygen used, is the mechanical efficiency
of the myocardium in performing the external work which maintains the circulatory momentum
at the level necessary to accomplish energy storage and exchange, and still maintain the free
energy best suited to cell function, by altering myocardial energy production as required.
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Consideration of myocardial efficiency becomes central to the relationship between myocardial
activity and cell function. Efficiency is altered by changing the speed with which a given volume
of fluid moves, or the momentum it is given compared with the rate at which energy is made
available to it. The rate at which energy becomes available, depends on the speed of muscle
contraction , or the time taken to effect a given amount of shortening. Because the response of
individual muscle fibres is `all-or-none', any contraction is with the maximal force which it can
make available under these circumstances, and the speed of contraction becomes regulated by
the load against which the contraction takes place. Slowing the contraction by an appropriate
loading, alters the speed of contraction, and the energy which is made available. A slower
contraction can perform the same work, but over a greater time interval, and therefore requires
less energy for a given amount of work. What happens is that a contracting muscle fibre has a
given length at the commencement of contraction, and also a given cross sectional area, and cell
volume. The cell volume may be the same whether the length is increased and cross sectional
area is reduced, or the length reduced and cross sectional area increased.
Because the ends of a longer fibre at diastole, may be approximated to a greater degree by
contraction than the ends of a shorter fibre, more external work is done by its contraction. At the
same time contraction can only occur if the shape and the volume of the muscle cell alters.
Shortening implies that the cross sectional area increases, or that fluid must leave the cell with
decrease in cell volume. As well as overcoming the resistance offered by the cell membrane,
momentum has to be given to the expelled fluid. Expulsion of fluid is facilitated if depolarisation
accompanies the stimulated contraction, enabling fluid and energy to leave the cell as it contracts,
allowing it to enter the extra-cellular fluid, and then the venous system. The energy released by
the contraction becomes greater as the resistance to outflow of fluid is reduced. The work
accomplished for this expenditure of energy, includes muscle shortening against a load, and it
also includes the momentum given to the expelled fluid leaving the cell.
The ratio of external work done approximating the muscle ends with energy expended, will be
varied by the amount required to give momentum to the expelled fluid, and the latter depends on
the speed of contraction. Slower contraction rate against an imposed load, limits the speed and
momentum of expelled fluid, allowing a greater force of contraction, and increasing its
mechanical efficiency. Mechanical efficiency comes to have considerable significance for energy
released, and external work done by the contraction, and for the energy exchange compared with
energy store for a given level of free energy in the cell. Efficiency depends on the volume of
fluid moved, and the speed at which it moves, and so on the momentum maintained in circulating
fluid, and on the energy provided by each ventricular contraction to increase momentum in the
whole of the systemic circulation. On the other hand the force of contraction depends on the
number of adenosine triphosphate bonds which are severed and the number increases with the
initial length of the myofibril, which is maintained by pyrophosphate bond attachments. Slowing
the contraction slows the rate at which ATP bonds are severed.
In venous return from the effector organs, momentum is proportional to `
, but tone in the
walls of the veins, together with internal resistance to flow, requires that a further factor
equivalent to `R', needs to be contributed with blood from the core organs, including the portal
system, and other core organs contributing blood to the inferior vena cava, in order to accomplish
ventricular filling. Venous blood from effector organs has energy from cell metabolism of
carbohydrate to increase its kinetic energy, but blood from core organs, some of which has to
pass through two sets of capillaries, must be given energy from some other source before it can
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be available for filling the heart chambers. The required energy needs to overcome internal
resistance to flow, and the further restriction imposed by venous tone (i.e., equivalent to `R')
before it can present at the atrium, with momentum equivalent to `Q R PR', to fill the ventricle
with sufficient linear velocity of flow for maintenance of pulse rate. Ventricular filling is `Q R',
or
, and linear velocity of venous blood, equivalent to pulse rate, is
, and the
required momentum is `Q v' , or
. This momentum is increased by a factor equivalent to
`l', the increase in velocity contributed by ventricular contraction, to produce energy proportional
to
, or `Q APs', to preserve circulatory activity.
The contribution of energy equivalent to `R', needed to ensure the return of blood from the core
organs, is provided by alteration of the pressure differential between the thorax, and the
abdominal cavity, through muscular activity in these regions, and particularly by the diaphragm,
which can alter the relative volumes by changed muscle tone, and relative pressures by muscle
contraction. Respiratory activity determines venous return from core organs, by changing
ventricular filling through the diaphragmatic restriction conveyed by the fibrous pericardium and
the negative pressure developed within the thorax, and opposed at the same time by venous tone
(proportional to oxygen concentration) and internal resistance to flow. While irregularity of the
respiratory pattern, means that its effect on venous return may not be uniform, excess blood may
be refluxed into the vena cava by right atrial contraction, and this may vary both liver
temperature, and the volume of blood in the portal venous system and vena cava as a proportion
of systemic blood volume. In other words, blood stored in the portal and abdominal veins may
be varied with respect to that in the pulmonary circulation, according to the contribution made
to ventricular filling.
Momentum in venous blood presented to the right atrium is `
is proportional to the linear velocity of venous blood or
the ventricle is `R Q' or
equivalent to `
' or Q PR, where pulse rate
. The momentum needed to fill
, so momentum in venous blood must be increased by a factor
' as it progresses from the capillaries to the left ventricle. Entry of blood into
the ventricle is subject to three separate influences;
restriction offered by the fibrous
pericardium and the `tone' of diaphragmatic muscle; the negative pressure maintained in the
chest by the elastic lungs when they expand with respiratory activity; and momentum imparted
to venous blood by atrial contraction. The nett result is to increase the residual momentum
producing left ventricular filling by a factor
.
The effect of negative pressure applied to the ventricle by respiratory muscles, and that of
contraction of the atrium, provide extra momentum for ventricular filling which is proportional
in amount to
(oxygen concentration in effector cells). The fibrous pericardium restricts
filling, but not uniformly. Depending on the tone in the diaphragm, the heart may become more
globular in shape, or more elongated in the longitudinal axis. In the former case stroke volume
and/or resistance / unit velocity / unit volume will be increased, while in the latter, pulse rate is
increased compared with stroke volume. Pulse rate appears to be regulated by receptors in the
walls or visceral pericardium of both ventricles and auricular appendages, and is associated with
the change of cardiac shape, allowing ventricular muscle length to vary with respect to
ventricular diastolic volume. The resultant momentum given to blood expelled to the pulmonary
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artery is
, or
. In the lungs , blood becomes almost completely saturated
with oxygen, and its viscosity is greatly reduced. Blood entering the aorta from the left ventricle
has momentum
, or Q v, because of decreased viscosity of arterial blood. Blood
returning to the right heart, has its momentum increased by a factor equivalent to tissue oxygen
concentration, through the combined effects of negative intra-thoracic pressure, and atrial
contraction. Within the lungs, blood momentum is increased by a further factor, also proportional
to tissue oxygen concentration, as the blood becomes fully saturated with oxygen, and its
viscosity and resistance to flow (both internal and external) is reduced, allowing an increase in
linear velocity of flow equivalent to the change in resistance, so the momentum of blood
presenting to the left atrium is equal to Q R PR, or `v Q'. Pulse rate is the same for each ventricle,
i.e.,
, leaving momentum proportional to `Q R', or
, to fill the left ventricle. Blood
entering the aorta increases momentum in the systemic circulation proportional to `Q v', and
kinetic energy proportional to `Q v lPR' or stroke volume times pulse pressure.
Kinetic energy expended by the time blood reaches the effector cells, is restored by a factor of
`l PR', the free energy available within the cells, preserving energy equivalent to `Q PPs' to
maintain the venous return, with a contribution equivalent to ` .vx' from glycolysis occurring
within the cells, to also maintain linear velocity in tissue fluid.
Atrial contraction has dual effects. Together with negative intra-thoracic pressure it increases
venous momentum to fill the ventricle, but the contraction also forces any excess blood to reflux
down the inferior vena cava, where it influences liver temperature, and affects metabolic activity,
including glyconeogenesis. Although ventricular diastolic volume may not be altered by atrial
contraction, pericardial restriction may produce variation of muscle fibre length at diastole, and
this leads to the concept of myocardial contractility, which reflects variation of volume flow
with time. Comprising four different aspects of linear velocity involved in myocardial
contraction, contractility employs them to illustrate active state, inotropic state, energy transfer
factor, and the circulatory ratio, which together define contractility by relating fluid movement
with time.
Ventricular volume at diastole determines the volume of fluid expelled by the following
contraction, while ventricular diastolic shape controls the manner in which energy associated
with stroke volume is applied within the circulation, and at the cell / extra-vascular fluid
interface. Longitudinal distention of the interventricular septum is associated with pulse rate, and
the linear velocity of venous blood entering the ventricle, with altered linear velocity given to
each ml. of expelled blood. Expansion of the transverse diameter of the interventricular septum
is associated with increased stroke volume, and momentum associated with it, rather than
velocity of moving blood. Changed radius of curvature of the lateral ventricular wall indicates
altered resistance to flow per unit velocity per unit volume in the arterial circulation.It is
particularly significant in the right ventricle where it changes the transfer of energy from muscle
contraction to generation of pressure in the ventricular contents, in proportion to `vd lPR/ v' (the
energy transfer factor).
This mechanism enables pulmonary diastolic blood pressure to become directly related to
pulmonary diastolic blood volume. The alteration of the ratio Q / Vp for the pulmonary
circulation, is overcome by an associated alteration in DPp / VPs, maintaining the efficiency of
12
the right ventricle. Adjustment of pulmonary blood volume in response to volume variation in
the systemic system, is effected by appropriate change in pulmonary diastolic pressure. The
association between venous pressure and ventricular filling may be adjusted by altering the
amount of venous reflux into the inferior vena cava through variation of ventricular end-diastolic
pressure to limit ventricular filling when the right atrium contracts. End-diastolic pressure results
largely from the tension applied to the fibrous pericardium by diaphragmatic `tone', in response
to changes in carbon dioxide content of circulating blood, and associates the amount of
ventricular filling with the shape the ventricle adopts at diastole. Adjustment of both venous
pressure and pulse rate occur reflexly with alteration of linear velocity of venous flow.
Equivalence between the parameters regulating cardio-vascular function, depends on the
relationship they each have with the concentrations of the gaseous metabolites, carbon dioxide
and oxygen, and with circulatory length, when `
'. Equivalent values for linear
velocity, pressure, momentum, and the volumes of body fluid compartments are all readily
obtainable, and form the basis for an algebraic model to describe circulatory activity in terms of
each of these parameters.
Fluid and energy must cross the extra-vascular space when it moves between effector cells and
the vascular system, and this involves movement in tissue fluid. Transfer between three
compartments is involved, and it occurs when momentum in one area is greater than in the
others, after due allowance has been made for the limitations on movement between the three.
The limitations are those of pressure and permeability differences, but movement is further
complicated by the nature of momentum itself, which involves movement of a defined quantity
at a particular linear velocity of flow. It may be the same for a small quantity moving at high
speed, as for a larger amount at a relatively low speed. The equivalence between quantity and
velocity may make the resultant momentum difficult to detect and quantify. At the further limit
of its distance from the heart, blood passes through small vessels with semi-permeable walls,
which allow fluid to move outside the walls, but retain the solid constituents of blood and larger
molecules, in colloidal solution.
The linear velocity of fluid leaving the vessel may not be large, while movement is transferred
to a large body of interstitial fluid, and momentum may be difficult to quantify. Nevertheless,
momentum transferred may be comparatively large, and capable of giving rapid motion to a small
quantity of fluid, as for example, the stroke volume, though when transferred to a large body of
interstitial fluid, momentum may be barely discernible, and consequently difficult to detect unless
it is concentrated again into a small volume, which may be transferred into the cells, the venous
system, or the heart chambers. The effects only become noticeable because of variation of linear
velocity of flow between different regions. When the ventricle contracts, the momentum given
to stroke volume is transferred to the whole of the systemic blood volume, and then to extravascular fluid, and linear velocity appears to diffuse completely. Nevertheless, momentum is not
lost, the same amount is contained in a larger volume of fluid, and maintained there until
concentrated once more into a smaller volume with a greater linear velocity of flow, when it
enters the cells to increase their volume, or the small veins to increase linear velocity of flow
there.
Momentum transmitted to the extra-vascular fluid is proportional to that within the blood stream,
reduced only by restricted permeability of the capillary wall, which depends on the oxygen partial
pressure locally available. Momentum transmitted to the cells is proportional to the systolic blood
pressure, or RlPR, where R represents cell accumulated energy at systole, and lPR, the free
13
energy available to the cell for metabolic processes, and to determine energy exchange with the
tissue fluid. Volume of the cells at systole, or R, is the diastolic volume,
, elevated by a
factor equivalent to stroke volume,
, contributed by the force of contraction of the ventricle,
lPR, balancing the free energy in the cell, which is also lPR. The energy store, and cell volume
at systole becomes proportional to `R', which has to be provided against the level of free energy
`lPR', producing total energy `RlPR'.
The momentum needed to provide this is proportional to `
' from the extra-vascular
compartment, assisted by the effect of oxygen locally on the cell membrane, which facilitates
fluid entry. Momentum is then proportional to
, and APs is represented as
.
Volume of the extra-vascular fluid at systole is proportional to `v' , and diastolic volume is
proportional to `l PR'. While the volume of the systemic circulation,`Vs', remains relatively
constant, the volume of the venous system, and the circulation to the effector organs are each
directly related to the internal resistance to blood flow,
, while the circulation to the `core'
organs is proportional to the total resistance to flow , or `R'. The momentum equivalent of
resistance to flow into the ventricle, the systemic circulation, the extra-vascular fluid, the effector
cells, and the venous system, are each proportional to `Q R', or
, but blood presenting at
the entry to the right atrium, only has momentum proportional to
, and further energy
needs to be supplied by respiratory muscle contraction, and/or atrial contraction, supplemented
by reoxygenation in the pulmonary circulation, to ensure left ventricular filling proportional to
, or `Q R'.
In the small vessels of the arterial system, mainly arterioles, stored potential energy from the
elastic arteries is converted to kinetic energy of flow by increasing the linear velocity of flow.
Regulation of the conversion is by increasing constriction of the vessels and the value of `R'
through adjustment of the oxygen concentration locally. The total resistance to blood flow is
increased over the internal resistance by a factor proportional to oxygen concentration, to give
resistance precisely equivalent to the increase in linear velocity of flow provided by the force of
ventricular contraction times the accumulated energy available in effector and myocardial cells;
or length squared, where length refers individually to the arterial and the venous systems, and
.
The increase in linear velocity limits lateral pressure on the vessel walls as blood enters the
capillaries, but almost immediately exchange of oxygen and carbon dioxide commences with
increasing viscosity, and internal resistance to flow, with rising lateral pressure, and fluid moving
to the extra-vascular space, proportional to internal resistance, and also stroke volume. The
momentum required is proportional to the cube of internal resistance times the oxygen partial
pressure, or `v R' , equivalent to `Q R' times internal resistance to flow. The increase in viscosity
becomes responsible for transferring fluid equivalent to stroke volume and energy equivalent to
, to the extra-vascular compartment, and eventually `Q R' to the effector cells, where
permeability is again affected by oxygen concentration, to increase the energy within the cells
by the change in passive permeability contributed by oxygen partial pressure, and to elevate `v'
to `Q R'.
14
Movement of fluid from the capillaries is limited by increase in osmotic pressure exerted by
plasma protein. Pressure increases until it balances vascular filling / oxygen concentration,
equivalent to l PR, which represents osmotic pressure at diastole, as well as diastolic extravascular volume, and free energy in the effector cells. Fluid leaving the blood vessels per beat
is equivalent to Q, and momentum available in extra-vascular fluid is
, or
.
This is momentum available at the cell membrane to provide fluid and energy exchange with the
cell compartment. At systole, the volume of extra-vascular fluid is proportional to `v' (stroke
volume times internal resistance to flow). The volume remaining in the blood vessels is Vs, and
is directly proportional to blood viscosity.
The interchangeable relationships between volume and velocity in the calculation of momentum,
allows the volume remaining in each region or system to also represent the energy available in
that volume. For example, as well as systemic blood volume, `Vs' also represents `strength' in
the effector cells; `v' indicates energy exchange with cells, as well as the volume of the extravascular fluid at systole, and `R' is proportional to the energy store in the cells as well as cell
volume at systole. The distribution of fluid between body compartments becomes dependent on
the energy represented by these volumes, and finally on the momentum equivalents available in
each.
The force of ventricular contraction represents energy contributed to the circulation per beat, and
is also indicative of energy expended and lost to the system per beat. It is matched by energy
produced by cell metabolism to produce venous return, and the latter is only maintained while
further energy is introduced to the circulation at cell level. It consists of energy from glycolysis,
which is equivalent to internal resistance to flow (and velocity of tissue fluid), and to further
energy from oxidation, proportional to viscosity, or carbon dioxide concentration, and to systemic
blood volume, so that `Q Vs' remains equivalent to `l PR'. Similar energy is expended in the
arterial circulation, to that required for the venous return, and the power needed to maintain the
circulation with average mean linear velocity , `v', is proportional to
per beat, and this
power allows the circulation to continue indefinitely while the energy equivalent `
' (energy
exchange times systemic blood volume times cell strength or `power') remains unchanged.
Continued circulatory activity depends on maintenance of cell energy exchange, and of cell
strength from beat to beat, both in the effector cells peripherally, and in the myocardial cells
centrally.
Energy exchange with cells is proportional to linear velocity, `v', and presupposes a relatively
constant value for average mean linear velocity of flow for the circulation to be adequate. The
other essential is an adequate volume of the systemic circulation, which requires cell `strength'
(
) to be kept at a relatively constant value. Provision of both stroke volume, and systemic
blood volume, is the basis for the circulatory ratio, upon which an adequate sustained circulation
depends, and which may be varied only by altering circulatory length, or `l', and the amount of
ATP in the active cells which it represents.
The metabolic mechanisms for providing adequate levels of stroke volume and systemic blood
volume, are those which also underlie cell energy production for both `internal' or circulatory
work, and external physical work performed by effector and myocardial cells. They include both
glycolytic and oxidative activity, and the relationships which regulate each with respect to the
other. The original observation by Pasteur, that oxidation inhibits fermentation (glycolysis), and
15
the converse observed by Crabtree, that fermentation inhibits oxidation, form the basis for this
relationship, and are thought to occur because of competition within the cell for available
inorganic phosphate, which is necessary for each group of reactions; a requirement that may
produce limiting effects of each upon the other. There are as well the inhibitory effects of the
respiratory gases. Increasing oxygen concentration inhibits the respiratory enzymes, while
increasing carbon dioxide concentration appears to limit glycolysis, while reducing the level of
persisting lactate. At the same time increased lactate concentration may reduce the inhibitory
effect of oxygen on respiratory enzymes, and increase the production of carbon dioxide.
These effects are explained by consideration of the three methods of energy production, which
may be involved. Besides glycolysis, and direct oxidation through the Kreb's cycle, there is also
the series of reactions which produce oxidative phosphorylation, with production of high energy
pyrophosphate bonds, accumulating energy as creatine phosphate, but with little alteration in free
energy level associated with the change. As creatine phosphate accumulates, pyrophosphate
bonds may be transferred to ADP to produce ATP associated with cell contractile elements,
increasing stored energy, and with change in the size and shape of effector cells. Oxidative
phosphorylation can only occur if both lactate and oxygen are present in sufficient
concentrations, and the concentration of each tends to rise with the residual concentration of the
other. Oxidative phosphorylation does not occur in the absence of sufficient lactate, which acts
as a hydrogen donor, and is itself oxidised to pyruvate, where it can enter the direct oxidative
pathway as acetyl- coenzyme-A. The direct oxidative pathway is inhibited or blocked, when
coenzyme-A acts as a hydrogen acceptor at the triose phosphate stage of glycolysis.
Pyruvate becomes reduced to lactate by accepting hydrogen from coenzyme-A, which may then
form acetyl-coenzyme-A, and re-enter the direct oxidative pathway by way of the Kreb's cycle.
Oxidative phosphorylation is able to `unblock' the glycolytic pathway, and facilitate the direct
oxidative pathway with reduction of oxygen concentration, increased carbon dioxide
concentration, and production of pyrophosphate bonds as creatine phosphate, and/or ATP,
without increasing the free energy in the cell, at least initially and while oxidation is limited.
Carbon dioxide concentration becomes equivalent to the concentration of creatine phosphate,
while circulatory length, `l', and `[lactate] . Vs,
' , is proportional to the amount of ATP in
the cells (so that
is proportional to the concentration of ATP in the cells); and
is the
total stored energy content of the cells after depolarisation, consisting of ATP content times the
fluid content, or cell volume, and represented by lactate concentration which maintains it.
Equivalent values representing `stored' energy (or
) and ATP concentration (or
and
the equivalents `cell strength' and systemic blood volume) appear because the amount of ATP
maintained in the cells is representative of circulatory length.The concentration of creatine
phosphate is proportional to that of carbon dioxide, and cell volume is proportional to tissue
oxygen concentration. Energy generation, application, and distribution, may be represented in
terms of `l',
, and
; or those parameters involved in regulation of metabolism; and
when expressed in the alternative terms of circulatory length, blood viscosity, and membrane
permeability, are able to regulate circulatory activity through generation of momentum in
proportion to the amount of lactate available in the cells.Adenosine triphosphate and creatine
phosphate appear to be readily interconvertible, allowing their concentrations to be equivalent
to each other. The result is that
,
, while
; pulse rate is
16
equivalent to the square of systemic blood volume, and ventricular efficiency is proportional to
the ratio of lactate concentration and oxygen concentration .
The balance between these parameters is maintained by glycolysis, oxidation, and oxidative
phosphorylation, which determine the relative values of vascular length and carbon dioxide
concentration in the tissues, because
so long as carbon dioxide concentration remains
proportional to creatine phosphate concentration in the cells, and systemic blood volume is
indicative of the cell concentration of ATP. Cell function may be expressed in terms of the
energy equivalents which originate from the balance between parameters, and the application
of energy to particular functional requirements. In particular, circulatory length becomes closely
related to the amount of energy generated by, and persisting within the cells at different phases
corresponding to those of the cardiac cycle. Energy stored by attachment of ATP to the extended
myosin chain, is directly proportional to the labile energy accumulated as creatine phosphate, and
the quantity of each form of pyrophosphate bonds is closely related with the other, with
circulatory length, and with blood viscosity and tissue oxygen concentration, and the amount of
oxidation and glycolysis needed for these reactions to occur.
Circulatory length is directly proportional to the ratio between potential energy represented as
systolic blood pressure, and kinetic energy and external work capacity represented as linear
velocity of flow throughout the cycle, related in turn to the concentrations of the respiratory
gases, and the labile element in energy accumulation, or `Q / Vs'. Increase in physiological length
in the circulation needs to imply an increase in lactate concentration, and an increase in the
circulatory ratio, together with the relative size of the circulation supplying the effector organs.
Tolerance to lactate reflects the capacity to alter physiological length, and any variation in lactate
concentration which may accompany the change.`The physiological length of the systemic
circulation is directly proportional to the amount of creatine phosphate and/or adenosine
triphosphate contained in the effector cells.' This principle underlies all circulatory activity, and
failure to conform to it produces functional disorder of a serious nature, which must be rectified
for normal function to resume.
Osmotic pressure exerted by the plasma proteins is also involved in maintaining blood volume
and `cell strength'. The amount of osmotic pressure varies in proportion to the systolic blood
pressure, the ratio between the two being represented by `R', or the energy accumulated within
the effector cells at systole. Osmotic pressure is equivalent to `l PR', the force of ventricular
contraction, the free energy necessary in the cells, and the diastolic volume of the extra-vascular
fluid, or
. The implication of this equivalent is that when reduction of circulatory length
threatens systemic blood volume, increase in pulse rate opposes the reduction, and helps to
maintain cell strength, allowing the circulation to continue with blood volume, and force of
ventricular contraction sustained despite the reduction in circulatory length, through an increase
in viscosity, and/or carbon dioxide concentration . Viscosity is as essential to circulatory activity
as lactate and oxygen concentration, although it requires retention of carbon dioxide through
respiratory activity, and alteration of the pulmonary circulation to sustain it.
The mechanics of the extra-vascular circulation, and the energy it requires, are centred about the
relative diameter of the arterioles, and the elastic arteries. Aortic distention is employed to store
potential energy, or the pressure generated by ventricular contraction. Arterial pressure forces
17
blood through the reduced diameter of the arterioles to generate increased linear velocity of flow,
and reduce the lateral pressure on the vessel walls through reduced filling of the more distal
vessels. Resistance to flow is increased when the internal resistance of the blood is elevated by
a factor proportional to oxygen partial pressure in the tissues, to equal `R', the accumulated
energy in the effector cells at systole. Linear velocity of circulating blood is increased by a factor
of `l' through ventricular contraction, but reduced by a factor of
through the restriction
imposed by `R', and it requires an elevation of velocity by a further fraction proportional to `l' in
order to generate the venous return. This factor is contributed by metabolism of the effector cells,
to maintain linear velocity in venous blood. In the mean time, linear velocity in the capillaries
is greatly reduced when viscosity increases with the gaseous exchange as oxygen concentration
falls and carbon dioxide concentration rises.There is a considerable increase in lateral pressure
which transfers fluid to the extra-vascular compartment, and the fluid loss is only limited by
increasing osmotic pressure of the plasma proteins, until its value is equivalent to diastolic
volume in the extra-vascular compartment, or `l PR'.
Peripheral resistance, proportional to `v R', is determined by the average mean linear velocity of
flow, the internal resistance to flow, or ` ', and the external resistance imposed by arteriolar
constriction, or
. The relationship between circulatory length, blood viscosity, and tissue
oxygen concentration, allows the energy produced by ventricular contraction, to be divided
between continuing intravascular circulatory activity, and cell metabolism. Energy is directed
towards overcoming the internal resistance to blood flow, to maintain momentum proportional
to
(or QlPR). At the same time, fluid volume equivalent to stroke volume, with energy
proportional to linear velocity of flow, is transferred first to the extra-vascular compartment, and
then to the effector cells, against the osmotic pressure of the plasma, and resistance offered by
membrane permeability. From the cells, membrane permeability, osmotic pressure of the plasma,
and further energy from glycolysis, all direct flow back into the venous system , and the venous
return.
The division of energy between alternative functions, arises through partition between internal
and external resistance, or viscosity, and arteriolar constriction related to oxygen partial pressure,
in constituting the final value of `R'. Pressure in the aorta (RlPR) after overcoming the resistance,
`R', leaves energy equivalent to plasma osmotic pressure (lPR) applied to stroke volume, to
continue the intra-vascular circulation. It also generates momentum equivalent to `Q R' , to
maintain linear velocity of flow, `v', with an extra factor proportional to oxygen concentration.
In the capillaries, internal resistance to flow is increased through increased viscosity from the
gaseous exchange, and as blood velocity slows, lateral pressure equivalent to `Q R' forces fluid
from the capillary into the extra-vascular compartment, against both rising osmotic pressure, and
membrane permeability. Rising osmotic pressure restricts fluid exchange when the pressure
reaches an equivalent level with diastolic volume in the extra-vascular fluid, and oxygen partial
pressure.
The volume transferred is limited to be equivalent to stroke volume, while velocity becomes
, i.e., average mean linear velocity , or`v', times oxygen partial pressure in the tissues,
over level of permeability of capillary membrane, proportional also to oxygen concentration.
The oxygen partial pressure elevates `R' above `Q' in the arterioles, but oxygen concentration
18
increases the resistance offered by the capillary membrane to an equivalent extent in the
capillaries, and transfer of energy across the membrane is reduced from `Q R' to
, or `v'.
Total energy transferred across the membrane is `Q v' , equivalent to `R Vs l PR' , the minimal
energy required to be present to sustain circulatory activity. The relationship between it and
circulatory momentum is `Q v / Q l PR' , or `l', the increment in velocity given to blood by
ventricular contraction, and dissipated during the cardiac cycle. Linear velocity is reduced in the
capillaries by increased viscosity; and energy required to maintain flow to the venules against
internal resistance is used for that purpose, while energy also equivalent to internal resistance to
flow times `l PR', gives movement to fluid passing through the capillary membrane against
resistance provided by reduced permeability (
). Fluid volume and energy related to the
stroke volume is contributed to the extra-vascular volume at diastole against restricted
permeability proportional to oxygen concentration, and the extra-vascular volume at systole then
has momentum proportional to
, which is equivalent to the ratio of momentum in the blood
vessels and oxygen concentration (
). The extra-vascular volume at systole, `Vx', is
proportional to `v', and the linear velocity in this compartment is vx, or
Fluid momentum available at the cell surface is
.
, but the passive permeability of the cell
membrane increases the effective value to `v Vs', while increasing cell volume proportional to
oxygen concentration raises the energy level to `R Q Vs'. Energy made available to the cell is
`RlPR' or `APs' at systole, and `v' , or `DPs' at diastole. Systemic blood volume is increased by
systole, but has decreased again at diastole, when blood fills the ventricle prior to its next
contraction. Fluid volume exchanged between cells and extra-vascular fluid is proportional to
stroke volume, which first enters the cells , and is then expelled to the extra-vascular fluid once
more; the energy exchanged is ` ', or `v', the average mean linear velocity of flow, which is
proportional to the fluid and energy exchanged with the cells, and is also related to the
momentum needed for the venous return, although it must be augmented by respiratory activity
for the circulation to continue.
Distribution of the energy produced by ventricular contraction is regulated by aortic distention
to store potential energy which is converted to flow energy by passage through the arterioles.
The linear velocity of flow which is generated, leads to reduction in lateral pressure exerted on
arteriolar walls, otherwise equivalent in value to `R', or the product of internal resistance to flow
and vascular constriction produced by oxygen concentration in the tissue fluid. Arteriolar
constriction requires associated increase in linear velocity of flow, in order to reduce the tension
in the vessel walls, but this has to be achieved by increased tension in the walls of the elastic
arteries, and increased systemic blood pressure. As a result the increase in velocity, produces no
mechanical problems for these vessels, although if there should also be an increase in linear
velocity of diastolic flow, the associated limitation of vessel volume and diameter, may produce
a typical appearance of `silver wiring' in those vessels which can be observed directly, e.g., in the
retina.
For optimal function, diastolic linear velocity in these small vessels is limited by increasing
internal resistance to flow in the capillaries when the exchange of metabolic gases alters blood
viscosity with circulatory fluid and energy passing to the extra-vascular compartment. The ratio
of pressure and flow energy is regulated by the permeability of the capillary membrane, and
19
responds to the oxygen partial pressure in the vicinity with changed linear velocity, blood
viscosity, and gas concentrations in the capillaries. The lateral pressure generated by these
changes which might normally arise with reduction of `v/R' (and reduced osmotic pressure of
plasma proteins) may be avoided by loss of fluid through the capillary wall, to augment extravascular volume, without increasing any distending pressure on the capillary wall until osmotic
pressure increases sufficiently to prevent continuing fluid loss, and allow fluid to reenter the
capillary as linear velocity diminishes further.
Fluid entering the capillary is assisted by increased energy contributed by the effector cells,
proportional to `v' (energy exchanged), and `l PR', (cell free energy), which together supply
energy equivalent to pulse pressure. The extra factor in energy production from cell metabolism
is transferred to the venous system and venous return. After overcoming the internal resistance
to flow from the increased viscosity of venous blood, momentum in blood presenting at the
atrium is proportional to
, or `Q PR', the cardiac output. Average mean momentum in
blood is `Vs v', and in extra-vascular fluid is
, but at the cell / fluid interface, increased
passive permeability proportional to oxygen concentration, allows fluid entering the cell to have
momentum proportional to `Vs v' again.
The cell volume increase is proportional to oxygen concentration, and momentum times cell
volume allows energy within the cell to approach systolic blood pressure. The fluid exchanged
with the cell is proportional to stroke volume, which first enters the cell and then is expelled
again, giving exchange of energy proportional to `v; with volume exchanged proportional to `Q'.
With contributions from the ventricle and the effector cells each proportional to `Q', the kinetic
energy generated is proportional to
Vs, where `Vs' is `cell strength', produced by energy
concentration within the cells, and resulting from the amount of ATP arising from oxidative
phosphorylation, and the persisting cell volume proportional to
. Energy equivalent to the
internal resistance to flow is lost in each half of the circulation in overcoming resistance, so the
maximal kinetic energy present at any time is proportional to pulse pressure (proportional to v
l PR, or energy exchange times free energy in cell).
Production of creatine phosphate by oxidative phosphorylation, also allows direct oxidation of
pyruvate and regulates carbon dioxide concentration, while alteration of circulatory energy and
its distribution, depend on the relationships between `Q', `R', and `Vs', or , l, and
.
Systemic blood volume is increased if linear velocity increases at a greater rate than resistance
per unit volume per unit velocity, and Vs increases as R diminishes. If linear velocity slows,
lateral pressure is increased but loss of fluid from the capillaries is limited by the osmotic
pressure of the plasma (which may be increased by systolic arterial pressure, and reduced by `R',
and its maximal value becomes proportional to `l PR').
The intra-vascular circulation depends upon the volume of fluid moved, the linear velocity at
which it moves, and the resistance per unit volume per unit velocity which opposes the motion.
Velocity times volume is proportional to fluid momentum, while
, and these relationships
allow the circulation to be described in terms of length and viscosity while it is confined within
the blood vessels. The relationship between length and viscosity arises because of the
interconvertibility of ATP and creatine phosphate within the cells, when creatine phosphate has
accumulated as the result of oxidative phosphorylation. The amount of ATP is proportional to
20
`l', and that of creatine phosphate is proportional to
and the concentration of creatine phosphate; and
, where
is equivalent to
is proportional to cell volume. The
concentration of carbon dioxide represents` ' , the viscosity of blood , and if the concentration
of ATP is equivalent to that of creatine phosphate, then `
', or `Vs', and `
',
`
',`
', and `
', or `
The volume of systemic blood is
'.
, and systemic blood
volume would then seem to depend on the concentration of creatine phosphate maintained in
the effector cells. Linear velocity increases as the square of systemic volume, and lateral pressure
is reduced because linear velocity depends on the square of length and the square of volume. The
latter is preserved by plasma osmotic pressure, and the oxygen concentration, but only while
linear velocity can be maintained. Should linear velocity be reduced, both length and volume are
reduced with limitation of circulation in the capillaries, and loss of fluid and momentum to the
extra-vascular.fluid.
The sequence of events following expulsion of ventricular content is raised pressure and
distention in the aorta, and increased linear velocity of flow in the smaller arteries and arterioles,
but with limited pressure on their walls. Constriction of arterioles limits volume flow, but there
is no increase in lateral pressure while linear velocity is sufficient. In the capillaries on the other
hand, increasing viscosity transfers fluid and velocity to the extra-vascular compartment, with
an appropriate fall in `Vs', by an amount equivalent to stroke volume. For a given value of `R'
or `l', `
', while `
' for a given value of `
'; and
for a given
value of
. The implication is that once blood leaves the aorta, there is little or no pressure
on the walls of arterioles or capillaries, constriction of the former leading to increased linear
velocity, while reduction of velocity in the capillaries, allows fluid to leave the circulation up to
the limit imposed by increasing osmotic pressure.
Pressure on arteriolar walls only increases when the aortic pressure and fluid momentum passing
to the extra-vascular fluid, are no longer equivalent, and fluid movement cannot occur without
loss of energy. The amount of fluid movement which allows little or no pressure on the vessel
walls, determines the size of the vessels supplying a particular area. It is achieved by variation
of length with respect to viscosity to maintain the levels of `Q', `v', `R', and `Vs' within
acceptable limits, and mainly by adjustment of oxygen concentration affecting membrane
permeability compared with blood viscosity; i.e., the concentrations of oxygen and carbon
dioxide in the tissues of the effector organs.
Because `l' is related to lactate levels, and ` ' to carbon dioxide levels, the adjustments follow
a pattern dictated by lactate concentration and utilisation for a given concentration of carbon
dioxide; i.e., viscosity and momentum maintained in the blood, which also regulates oxygen
concentration. Difficulties arise and adjustments become necessary , when the concentrations of
carbon dioxide, oxygen, and lactate, vary with respect to each other, and particularly when lactate
concentration and required circulatory momentum, no longer remain within the limits which are
appropriate for the level of activity and metabolism required.. With the distribution of fluid
21
between body compartments, further apparent anomalies arise. Fluid movement may be
illustrated using finger plethysmography, and has implications for each area, which affect flow,
momentum, volume and resistance. In arterial vessels, added volume affects first potential
energy, and then kinetic energy of flow; with regulation of diameter of the small vessels altering
linear velocity and lateral pressure on the vessel walls. In the capillaries, linear velocity is
reduced again, when viscosity and capillary permeability alter with changing gas concentrations.
The flow pattern is altered with the change in velocity and vascular volume, when fluid passes
out of the capillaries, altering the osmotic pressure of plasma protein, as well as the gas content
of the tissue fluid. In the arteries and arterioles, lateral pressure may increase as arterial pressure
first rises, but then falls again as linear velocity also increases, and these changes of lateral
pressure produce a palpable pulse wave. In the capillaries, changing velocity and viscosity move
fluid into the extra-vascular space, influenced by the gas concentrations, and increasing osmotic
pressure. The momentum available with this fluid transfer is
, and produces average
mean momentum in extra-vascular fluid
, an increase proportional to
, the amount of creatine phosphate available in the cells, and equivalent to
`l', or the amount of stored ATP the cells contain, and produced by their own metabolism. At
the cell / tissue fluid interface, momentum is increased by a factor
(increasing passive
permeability and cell volume) equivalent to
.
(or R v ) the pressure equivalent of
the peripheral resistance. Volume of the extra-vascular fluid at systole is
, the linear velocity
is
, and momentum is
. The energy accumulated within the cell is
,
equivalent to the systolic arterial pressure.
The circulation is maintained by the contribution of cell energy proportional to `l PR' from cell
metabolism, of which ` ' (cell ATP times concentration of creatine phosphate) overcomes
internal resistance to flow from increased viscosity, and
is cell strength, proportional to
systemic blood volume, and provided by elevation of stored energy concentration, or [ATP].
Elevation of blood viscosity allows the blood volume to increase, despite any loss of pressure on
the vessel walls when linear velocity also increases `
' , so that both volume and velocity
increase when viscosity is greater.
The linear velocity increase is proportional to the square of viscosity, and while systemic blood
volume is represented by viscosity, the extra factor, ` ', restores the loss of volume associated
with linear velocity of flow. Linear velocity of flow may be represented as the product of
`vascular filling' times systemic blood volume, or `R Vs times Vs'. The momentum at the atrium
is `Q PR', and momentum proportional to core organ circulation , `R' , needs to be contributed
to that from the venous return from effector organs, i.e., `Q' , to complete ventricular filling of
the left ventricle.The additional momentum is provided by respiratory muscles producing
negative pressure in the chest, re-oxygenation of blood in the lungs, and atrial contraction. In the
arterial system, increased linear velocity of flow is associated with reduced volume of the vessels
through which it flows, and reduced circulatory volume overall, but in the venous system,
increased velocity produces increased circulatory volume, and the energy for this increase comes
from energy from cell metabolism equivalent to `l PR'. The momentum equivalent for ventricular
filling is transferred from the ventricle to the cells, and then back to the veins and heart, through
22
changing blood viscosity, and permeability of membranes. It is sustained by cell metabolism,
both glycolysis and oxidation, with appropriate energy development and distribution. The
facilitating effect of oxygen partial pressure on cell permeability and volume, allows fluid
presenting at the cell surface with momentum proportional to `v' , to become equivalent to
within the cell.
Fluid exchange between cells and extra-vascular fluid may be modified in response to several
different parameters. Of prime importance is the momentum available at the cell / tissue fluid
interface, and sufficient momentum must be available before any interchange can occur.
Variation of oxygen concentration may alter both the passive permeability of the cell membrane,
and the cell volume, and momentum is elevated by a factor of
, from `
to
`
, and equivalent to systolic arterial pressure within the cell. Change in permeability
depending on the balance between carbon dioxide and oxygen concentrations, determines the
relative volumes of the cells and tissue fluid, i.e., `v / R', or `PR'.
Passage of fluid between these compartments from cell to tissue fluid, depends on the cell
concentration of `ATP', or
, which represents systemic blood volume. Blood volume
increases as the strength and the active permeability of the cells is increased. Fluid leaving the
cells is proportional to glycolysis, ` .vx', and `v' (representing cellular energy exchange, and
the volume exchanged per beat and linear velocity of tissue fluid). It represents the increase in
kinetic energy per beat used to expand cell volume against the stored energy present as `ATP',
providing `Q' to volume expansion, and `Q Vs' , to provide free energy, or `l PR', in the cell.
Free energy initiates glycolysis, and releases further energy proportional to ` .vx' , as well as
cell strength proportional to `Vs', to extra-vascular fluid, to overcome internal resistance to flow
in the veins (with momentum proportional to pulse rate squared).
Depolarisation of the cell membrane, augments fluid exchange with increase in `Q' and`Vs', but
it then requires rapid restoration of cell volume before any further contraction is possible. The
energy represented by extra fluid exchange, also means increased external work from muscle
contraction, or `tone' , which becomes an essential element in circulatory activity. Distribution
of cell energy between fluid exchange, and external work capacity from muscle contraction,
depends on cell energy produced compared with cell volume. Energy production depends on the
initial length of the cell, and the amount of `ATP' needed to keep its fibres extended, while
volume depends on cell diameter compared with its length, and the ratio of length / volume is
ATP content / oxygen concentration, or `contractile strength'. Greater strength means more
contractile energy compared with retained energy store, or l.PR/l.
, i.e., contractility or
,
where vx represents cell permeability, and vx is the increased linear velocity given to tissue fluid
as a result .
The momentum given to this fluid is less if the contraction is slowed by an appropriate loading,
and a slower contraction means greater efficiency for producing external work through reduced
free energy in effector cells, and reduction of pulse rate in the ventricle. There are three factors
which need to be considered as affecting muscle contraction:1. Diastolic length of the contractile fibres which is proportional to the energy released (Starling's
Law)
23
2. Loading in comparison with work done represented as 'Length / Tension development time'
or L/vx.(intra-cellular factor affecting contraction speed)
3. Ease of contraction depending on ejection of fluid from cell to tissue fluid; i.e., contractility,
or
.
The combined result is proportional to
L represents inotropic state, while active state
or
representing the energy developed,
equivalent to
, the
ratio of pulse rate with diastolic energy store remaining in effector cells (in the absence of
depolarisation). The most appropriate circulation for maximal physical exertion requires
increased `Q / Vs' and increased cell and circulatory length. The mechanical efficiency of the
myocardium is proportional to `L', and for any given ratio of `ATP / [CP]',
, but
as the ratio increases with `ATP>[CP]', myocardial efficiency depends on an increase in `l'
(and/or
), while if `ATP<[CP]', increased efficiency depends on
increasing rather
than `
', and eventual decrease in effector organ circulation compared with systemic blood
volume. The increase in length means an increase in lactate concentration , which assumes great
significance for ventricular efficiency.
‘Creatine Phosphate’
constant, then [A.T.P.]
; [A.T.P]
L
, and if oxygen concentration is
, or systemic blood volume, and while
is constant, [creatine
phosphate] is proportional to [A.T.P.], and variation of [creatine phosphate] with respect to
[A.T.P.]represents alteration of oxygen concentration, or cell volume, with change in value of
vx, the ratio
reduction of
, contractility, and active state. This allows alteration of ‘vx’, with relative
and increase of
, followed by increase in oxidative phosphorylation, and
[A.T.P.] to increase glycolysis, the concentration of blood glucose, and Type II diabetes. It can
only be changed by increase in
and [creatine phosphate] and pulse rate, but there can be
partial adaptation by increase in efficiency, increased ‘L’, and essential hypertension.
Essential hypertension develops with increase in lactate concentration plus increased pulse rate,
i.e., with increased vascular filling(R ) and circulatory momentum(
). The ratio of
[lactate]/PR is less altered because both lactate concentration and pulse rate are increased, and
‘v’ does not increase as much as ‘APs’. There is a decrease in the ratio of
and also of
APs/DPs, with a fall in the ratio of concentrations of oxygen with carbon dioxide, and so of their
product. Increased vascular filling helps to maintain ‘vx’and momentum of tissue fluid
maintained by essential hypertension to some degree, while labile hypertension increases ‘vx’
(with tachycardia) and vascular hypertension reduces its value (with loss of circulation of tissue
fluid and bradycardia).
Physical fitness comes to depend on the ratio `ATP' / `[CP]' in effector organs as work level
increases. An increase in `ATP' relative to `[CP]' produces an increase of the circulation to the
effector organs, unless circulatory length is matched by the concentrations of carbon dioxide and
oxygen. Should `[CP]' decrease compared with `ATP', the result is improved bronchodilatation
24
unless the altered carbon dioxide concentration can be matched by altered systemic circulatory
volume, and it is this relationship which limits physical activity, which is only maximal when
the two balance each other.
The relationship `
' regulates circulatory activity, and each of the parameters which
are encountered, can be expressed through relatively simple re-arrangements of `l', ` ', and
. For example, pulse rate is equivalent to ` ', which may also be written as `l /
'
because `l /
]' is proportional to ` ' , and because of the equivalence of these values, pulse
rate is the ratio of `venous volume' / `arterial volume'. By using these or similar equivalents, it
is relatively simple to determine the factors which maintain arterial blood pressure, which is
alternatively, `v.l'; `R.l.PR'; `R.Q.Vs'; or
;
'; `
'; and so on. Blood pressure
maintenance essentially depends on `lactate concentration', and on the pulse rate; or the
relationship persisting between oxidative phosphorylation to increase stored energy as ATP, and
direct oxidation to produce
as well as high energy phosphate bonds and creatine
phosphate. Carbon dioxide concentration and that of creatine phosphate are each directly
proportional to systemic blood volume, while their product is proportional to pulse rate. Direct
oxidation is limited by oxygen concentration, and facilitated by lactate , though carbon dioxide
concentration inhibits lactate production by glycolysis, and as a result, reduces myocardial
efficiency.
What emerges is that systolic blood pressure represents two distinct applications of energy:- 1.
Energy available for external work, for example by muscle contraction, which is related to
circulatory length and lactate concentration.
2. Energy available to enable blood to perfuse the tissues, which is related to ` ' (viscosity and
systemic blood volume).
Energy used for one purpose reduces that available for the other. If `l' is increased there is a
relative reduction in ` ', and energy for perfusion, which depends on the amount of oxidation
and
]. The values of `l' and` ' need to be so regulated that there is an optimal balance
between energy store, and energy for perfusion, and the efficiency of the circulation is determined
by the balance. The level of blood pressure which is maintained depends on the relative values
of `l', and ` ', which are particularly important for exercise, and the development of physical
fitness, where tissue perfusion needs to be as restricted as possible to allow maximal energy
store, and external work performance.
Where it is necessary to increase perfusion, cell `free' energy must also increase; ` ' (and vx )
must increase rather than `l', and blood volume rather than circulatory length and stroke volume,
so that `Q/Vs' is reduced and efficiency falls, with increased `active state' rather than `inotropic
state'. This is what is involved in elimination of body heat and temperature control, but it also
requires an increase in `free' energy, and cell temperature.For this reason there is an increase in
cell temperature when the energy necessary for tissue perfusion has to be increased.
Increase in the circulation associated with `core' organs , and particularly if associated with
pregnancy, introduces a different problem. The uterus requires an increased blood supply, and
as a `core' organ that means an increase in `R', and in order to maintain a sufficient size of the
circulation without an increase in blood pressure, it requires an equivalent increase in `Q' (or
25
circulation to the `effector cells'). There must be a sufficient increase in perfusion energy (i.e.,
in ` ' or `Vs') together with a similar increase in `Q', or `l. ', so that the circulation to effector
organs at least is equal to the circulation to the `core' organs, and `R/Q' , or
is not increased.
Extra lactate is available from the foetal circulation, but the critical factor for increased perfusion
is increased oxidation. If oxidation is sufficient, then `Q' and `Vs' are maintained compared with
`R', with limitation or reduction of `
', and there is no increase in blood pressure (which may
even fall if `
' is reduced compared with `l' and ` '). If oxidation is not sufficient, `Vs' and
`Q' are both reduced compared with `R', the circulation is restricted overall leading to an increase
in blood pressure, and the onset of `toxaemia' of pregnancy. Normal pregnancy requires
increasing `free energy', associated with increased ` ', and increased `Q'
Interference with oxidation, leads to reduced perfusion, reduced circulation, increased blood
pressure, and eventual damage to `core' organs, placental insufficiency and vascular occlusion,
and even foetal and eventually maternal death.
Circulatory volume is determined by the relative level of oxidation, ` ', and cell `free'
energy.(L.PR) If the rate of oxidation is not sufficient it results in relative `hypovolaemia'. On
the other hand if `
' is increased, it may result in reduced perfusion, and eventually
`ischaemia' associated with increasing energy store.If ischaemia is artificially relieved (e.g., by
coronary bypass operation) much more energy is required to maintain the perfusion at a greater
level, with increased oxidation and `free' energy level, but with reduced cell energy store, and
myocardial reserve.
Failure of the ventricle occurs when the energy store (equivalent to `R') is progressively reduced
compared with ` ' for whatever reason. To compensate for this imbalance requires an increase
in `inotropic state' , with `L' increased with respect to `circulating volume, and eventually lactate
concentration progressively increasing compared with ` ' (so called `lactic acidosis') One
adaptation which may slow down the development of ventricular failure is the onset of
hypertension in response to increased lactate concentration. There are several types of clinical
hypertension, and the classification depends on the balance between [lactate] and pulse rate, or
blood volume (
and ). The most severe form is `vascular hypertension' with a progressive
increase in lactate concentration, and a reduction in blood volume and pulse rate, reduction in
tissue perfusion, with eventual ischaemia and/or vascular occlusion, and early death.
`Essential hypertension' is the most commonly seen form of hypertension. It is relatively benign,
and may be present for many years without much apparent harm. In this form there is
comparatively mild elevation of both lactate concentration and ` ' , or in other words there is
increased cell energy storage, and work capacity, together with increased tissue perfusion, and
so little evidence of ischaemia for many years. There is however an increased work load on the
myocardium, which may become hypertrophied and eventually fail, and there is also the
possibility of progression to vascular hypertension (as a `malignant' phase) with subsequent rapid
deterioration of vessels and `target' organs. This form of hypertension appears to be
constitutional, where there may be altered permeability of cell membranes, detectable in a `prehypertensive phase'.
26
In `labile hypertension' there is an increase in ` ' and a decrease in `lactate concentration',
with greatly increased perfusion of tissue but reduced cell energy `store'. It is characterised by
increased pulse rate (and circulating volume). As the name implies it is not constant, but varies
with pulse rate, and may be reduced temporarily by exhibition of lactate whether exogenous or
endogenous. The three clinical forms may be differentiated by means of the `Lactate Tolerance
Test', or the response to administered lactate. The test is not without inherent danger, especially
when given to persons with an already elevated lactate level. A simpler method of separation is
to divide the systolic blood pressure by the square of the pulse rate. This gives a figure which is
theoretically equivalent to lactate concentration times oxygen concentration, and because it is non
toxic and non invasive, is greatly preferred as a clinical aid. In practice the ratio of systolic
arterial pressure and pulse rate is a simpler guide. If systolic blood pressure is recorded in mm.
Hg., and pulse rate in beats per minute, the normal value of the ratio is roughly about 2.0 For
vascular hypertension a value above 2.5 is significant, while below 2.0 indicates labile
hypertension, and `essential hypertension' falls between the two. The changes in the circulation
with different types of hypertension are illustrated in tables 1 and 2, where the parameters
involved may be calculated from systolic blood pressure and pulse rate according to the
principles outlined in the text. What emerges is the gross restriction of the circulation in 'vascular
hypertension' compared with 'essential hypertension', while in 'labile hypertension' tissue
perfusion is increased with respect to work performance.(In table1 only energy to maintain the
size of the circulation and the distribution of energy between fluid compartments have been
allowed for, but without allowance for external work capacity. In table 2, energy
or
augmented stroke volume has been included by allowing for the increased linear velocity of flow
given to arterial blood by ventricular contraction. The volume and length of the circulation is
shown as greatly expanded as a result, and it indicates the essential contribution to external work
capacity which must be available as 'kinetic mode' for the living state to continue.)
The syndrome of `Bronchial Asthma' is centred about the permeability of cell membranes. As
with essential hypertension, there appears to be a constitutional problem in the makeup of cell
membranes of certain individuals which renders the cells more sensitive to certain molecules in
the environment which can alter their permeability, and their size, shape, energy content and
energy exchange. Up until now, attention has been mainly focussed on the cells of the respiratory
tract, and their reaction to various allergens, with the variations of the immune response they
exhibit, including contraction of involuntary muscle, and abnormal secretion of glands. The
present contention is that these reactions are more widespread than the respiratory symptoms
might suggest, and the local relief of symptoms has only a marginal effect on the disordered
metabolism of the `effector cells', and the circulatory disturbances associated with it. With
essential hypertension, there appears to be a disturbance of `passive' permeability, which allows
sodium ions to enter the cell more freely than is usual, leading to increased cell volume, and
energy storage (and eventually to hypertrophy of myocardial cells). The permeability disorder
with asthma accentuates `active permeability', with abnormal loss of cell volume and the ability
to store energy, with reduction of `[lactate]' and the gas concentrations in tissue fluids. The
syndrome of 'asthma' appears when storage and accumulation of energy in effector cells at systole
is reduced to the stage that it becomes insufficient to maintain muscular and circulatory activity.
Stored energy within the effector cells eventually becomes exhausted with muscle weakness, and
restricted venous return, and reduced circulation to the effector organs. This follows when the
gas concentrations are varied, because all circulatory parameters are functions of the levels of
respiratory gases.
27
Ventricular filling may be accentuated in an emergency by altering intrathoracic pressure to
augment sudden effort, by expiration against a closed glottis ( Valsalva manoeuvre) , and the
bronchial spasm of asthma has a similar effect, maintaining the circulation until `stored energy'
in the cells can be restored, and in this regard, the violent muscular efforts at respiration may
have a beneficial effect in the temporary time frame until cell energy store is renewed. Steroid
to alter cell permeability, and glycolysis from catecholamines to increase lactate availability are
more obvious measures which may be taken, and there is anecdotal evidence of the benefit of
lactate administration in the short term. Powerful bronchodilators may be contra-indicated unless
they have an even greater effect on glycolysis and lactate production than on the bronchial
musculature.
There is some similarity between bronchial and cardiac asthma insofar as a fall in lactate
concentration is associated with each. In bronchial asthma the lactate level is reduced from a
normal or even initially reduced level, but in cardiac asthma the reduction is from a considerably
elevated level, and follows when even more lactate becomes available. The anomaly may be
reproduced on some occasions in persons with vascular hypertension, by administration of lactate
in the lactate tolerance test, when there follows a dramatic fall in lactate to below the level seen
in the normal individual. This presumably indicates an increase in gluconeogenesis from removal
of an inhibitory state which had supported a higher concentration of lactate in the hypertensive
individual in order to maintain an adequate circulation in the face of relative ischaemia. The
sudden fall in lactate concentration may then initiate bronchospasm to support ventricular
efficiency through raised intra-thoracic pressure, until lactate concentration and cell energy is
again restored. Oxygen administration can assist by increasing cell volume and energy store.
Sudden falls in lactate concentration may occur in sleep associated syndromes such as sleep
apnoea, hibernation, and hypothermia, and on occasion circulatory arrest may supervene.
Arrest may occur more readily when glyconeogenesis in the liver is first appearing, and the
control of lactate level is perhaps a little erratic. Such a situation may arise in the newborn, with
the change from carbohydrate to fat metabolism which must occur with ingestion of milk fat, and
may possibly contribute to S.I.D.S., especially when there is a dearth of involuntary movement
to augment lactate concentration (e.g., as in the` Moro reflex').
Mountain sickness may occur when the concentration of the respiratory gases, oxygen and carbon
dioxide, are both reduced, and there is a reduction in the circulatory length which can be
supported without circulatory insufficiency appearing. The condition is accentuated unless
muscular activity is restricted until acclimatisation takes place. In the absence of increased gas
concentrations in inspired air, increased tolerance to exercise (and lactate) can only occur through
increase in blood viscosity. Circulatory length , and [lactate] from exercise can only be tolerated
if the product `
' is suitably increased through increased blood viscosity, with increase in
red cell content, and this is a major element in acclimatisation to high altitude, though there are
other adaptations which increase gas availability to the cells, to some degree.
One implication of augmented stroke volume from conversion of ' ' to 'v' (i.e., kinetic energy)
through aortic elasticity, would be provision of oxygen from ' ' to leave 'v', and this oxygen
would become available to effector cells and to venous return in effector organ capillaries.
Movement of aortic blood from inside the thorax however allows oxygen content to be reduced
from the loss of 'negative pressure', so there is a reduction in 'oxygen load' presented to the
28
myocardium that might interfere with production of tissue fluid. Lactate concentration is reduced
instead. with reduction of vascular filling, associated with decreased linear velocity of blood flow
and tissue fluid volume. There is increased linear velocity of flow, and reduced lactate
concentration for the same value of ' ', with increased aortic elasticity, associated with
augmented stroke volume, with reduced resistance and greater momentum present in the arterial
circulation..Reduction of aortic elasticity reduces volume flow and increases resistance to
impede the circulation and reduce its effectiveness, so it becomes imperative to maintain aortic
elasticity so far as possible. 'Effector cell survival' is maintained as well as 'functional mode and
work capacity' if aortic elasticity is maintained at an increased level. (see table 2)
When the level of energy in a volume of fluid is increased, it results in a greater amount of
motion of the particles which constitute that fluid. Motion may be disorganised, and appear as
heat with a rise in fluid temperature, but if the motion of particles is coordinated or organised in
any way, movement of the fluid as a whole will result, and part at least of the temperature
increase, appears instead as momentum given to the fluid. When fluid moves, it transfers energy
from one position to another, and is then able to perform work. If the volume of fluid moved is
divided into small portions by permeable membranes to form `cells', further organisation of the
energy of motion can occur by separation into smaller but discrete variable volumes with
differing linear velocities in the fluid content in each, though the overall momentum might
remain the same.
The relationship of volume and linear velocity of fluid in the separate cells, but with equal
momentum available to each, then requires alteration in individual volumes and `shapes',
reflecting the individual linear velocity of flow available in the contained fluid. Semipermeable
membranes allow limited fluid movement across them, but ensure that much fluid is retained in
the `cell' by the osmotic activity exerted by molecules of various dimensions which cannot
penetrate the cell wall. Osmotic activity of this nature partly disappears when the cell membrane
is depolarised, and the contents of the cell may then only be preserved by resistance to fluid loss
by opposing pressure in the tissue fluid, equivalent to `diastolic energy store', or R / Vs', which
must be present on each side of the cell membrane. The total of the energy present without
depolarisation must then become equivalent to
, or the lactate concentration times oxygen
concentration which is present. The significance of [lactate] is that it represents the energy
required on each side of the cell membrane to maintain cell energy at diastole which is necessary
for normal circulatory function.
This is an outline of the principles underlying the circulation of body fluid, and its relationship
to energy development and transfer across cell and capillary membranes to initiate the `venous
return', and circulation of the blood. Development of an algebraic model allows an indication of
the relative amounts of energy and fluid movement produced, and the distribution of energy and
movement needed to support both the circulation, and the amount of extra work it can produce.
Through exploration of the characteristics demonstrated by the model, the limiting parameters
for circulatory activity have then been developed and applied to increase understanding of some
relatively common cardio-respiratory syndromes. The latter are examined in terms of circulatory
length, blood viscosity, and membrane permeability, which are related to each other by the
expression
' , and regulated by `
. Regulation of the values of `R'
(and square root of
,or ‘energy of oxidation / circulatory length’) and `PR' (
,or ‘energy of
29
glycolysis / systemic blood volume’ ) controls circulatory activity, and the overall linear velocity
of blood flow (R.PR).
It appears that energy to maintain the mammalian circulation can be roughly divided into three
groups. That which is most apparent is the kinetic energy associated with the circulation of the
blood, and the momentum which it has from systemic arterial blood pressure and the circulating
blood volume, and related carbon dioxide concentration present in effector cells. But before there
can be any energy of movement, there must be accumulation &/or storage of energy in the cells
and other fluid compartments of the body to initiate and maintain it, and this is potential energy
associated with energy accumulated within these fluid compartments from beat to beat, and
controlled by the concentration of oxygen available, and 'R.v'. A further supply of energy is
associated with cell permeability and volume, proportional to vx and
, or 'l', i.e.,
, the gas concentrations present in the cell.
The total energy required at systole in effector cells is proportional to 'R.v.R.L.PR.L.PR', or
proportional to
.PR. One factor ‘
’ needs to be present throughout the tissues at all
times (except for a short period at diastole) and represents the peripheral resistance. It has the
function of maintaining energy levels in each fluid compartment as well as determining the size
and shape of cells and blood vessels, the volume of both the blood and heart cavities, and
maintaining momentum in the circulation between heart beats. The shortfall in energy at diastole
(
or stroke volume) needs to be replaced at systole before function can resume, and it is
provided by 'Q' from ventricular contraction, which replaces ' ' in effector cells to restore 'R',
and 'l' in tissue fluid to increase its volume from 'l.PR' to 'v', and so increase stored energy to be
equivalent to peripheral resistance. It is then able to maintain vascular size and volume for the
remainder of systole, and allow adjustments of compartment volumes and energy movements,
after 'Q.R.L.PR' has been restored again by energy 'Q.L.PR' from glycolysis and 'free energy'
generated in effector cells to replace stroke volume and energy of ventricular contraction
expended in arterial momentum, and cell and tissue fluid volumes lost at diastole. This energy
and fluid adjustment is sufficient to maintain the life process for a short while, but it is not
sufficient to maintain external work capacity.
The other factor, which is of equal value, is the product of cell length and the increase in blood
pressure above atmospheric associated with each ventricular contraction, and subsequently partly
dissipated before the next beat, by which time it is reduced to the diastolic value 'v' with loss
of energy ‘
' as the linear velocity of flow diminishes from the peak systolic value 'v.L'
to the diastolic value 'L.PR'. At the peak value 'R.LPR' is increased by 'L' from the product of the
gas concentrations to be equivalent to 'R.v' as mentioned, .with energy 'R' dissipated from 'v.L'
to 'L.PR' as the linear velocity is reduced, to maintain an average mean value
'v' during
ventricular contraction. Energy proportional to '
' is lost from the cell until carbon dioxide
concentration is replaced by cell metabolism following the loss of stroke volume to tissue fluid
with the energy exchange. The additional energy from permeability differences between effector
cells, tissue fluid, and systemic blood volume are respectively 'L' for effector cells, 'vx' for
tissue fluid, and ' ' for systemic blood volume, but the latter requires a factor
to also
be contributed either from respiratory activity, or from depolarisation of effector cells, to enable
30
power in tissue fluid
to be elevated to 'R.v. ' in venous blood and so able to
complete ventricular filling. It is these adjustments which allow the calculation of vascular
length, blood volume, and stroke volume in table 2.
The total oxidation energy required to maintain the circulation and the life process is proportional
to
; equivalent to the cube of 'power' and totalling
, but it also requires a
contribution from glycolytic energy proportional to
the circulation. Of this, oxidation provides
(
) to total
, and glycolysis contributes
to maintain
(or
to
assist kinetic energy given to fluid leaving effector cells following depolarisation and a further
factor of
to balance fluid content of the main body compartments with each ventricular
contraction) made up of peripheral resistance (
), and augmented stroke volume
(
).and the respective fluid volumes representing the energy producing blood flow which
must be contributed to the circulation as well as peripheral resistance by each ventricular
contraction.
Energy is also required to accomplish 'external' work as well as that to maintain viability, and
it is furnished by the increased linear velocity of flow given to stroke volume as 'augmented
stroke volume', proportional to
.
. The cube of momentum represents three separate
factors. One factor maintains the shape and volume of the vascular system, one the energy
distribution between fluid compartments, and the third accomplishes external work performance,
and maintains cell energy store between beats The total energy which must be provided is
proportional to momentum of circulating blood cubed, each factor representing 'stored energy',
'kinetic energy' of fluid movement (which between them provide the necessary energy for
viability to persist) and accumulated energy as augmented stroke volume required for external
work performance, necessary to overcome the interaction with the external environment, an
essential condition for survival both for the individual and the species.
Continued maintenance of viability requires the provision of momentum in tissue fluid at all
times. Further energy is required to adjust the volumes of the fluid compartments and allow
movement of fluid between them to sustain viability, and a third amount of energy to sustain
external work capacity to overcome the necessary interaction with the external environment.
The parameters which define this energy may all be represented as multiples of the gas
concentrations present in effector cells which have the function of adjusting them so that optimal
energy is maintained for the necessary functional level best suited to that particular activity. The
only variables regulating function are changing concentrations of the respiratory gases. The
continuing life process depends on keeping the gas concentrations in the correct proportions so
that functional activity is represented by manipulation of the individual gas concentrations rather
than the number of multiples necessary to produce the individual circulatory parameters which
remain in constant proportions to each other.
In this account of the physical aspects of the life process, the concentrations of the respiratory
gases have been given special emphasis because their relationship with each other is considered
to be the basic mechanism which regulates the state of living. A satisfactory but closely
regulated concentration of oxygen in the effector cells is necessary to maintain the cell volume
and energy store (effector cell survival mode) while similarly regulated carbon dioxide levels
control movement of fluid and kinetic energy between cells and tissue fluid depending on the rate
31
at which carbon dioxide is made available through metabolic and oxidative enzyme activity
(functional or kinetic mode). The gas concentrations become dependent on each other, and need
to be closely adjusted for function to proceed satisfactorily, and ultimately to maintain the life
process, which must preserve the relationship.The life of individual effector cells requires oxygen
concentration to remain at a satisfactory level if the function of the cell is to continue, though
both life and function can be suspended by reducing cell temperature and enzyme activity to a
sufficient extent for metabolic processes to cease until conditions are reversed.
Stored energy and kinetic energy are both involved in cell function, and the product of oxygen
concentration with that of carbon dioxide determines both cell and circulatory length, while
oxygen represents cell volume, and carbon dioxide is inversely related to cell cross sectional area,
so their relationship maintains cell shape as well as size, and movement of fluid and energy both
into and out of the cells with changing metabolism. This movement becomes the basis for
circulatory activity which is also regulated by the gas concentrations and their ratios, extending
to contraction of the ventricles of the heart, the volumes of the circulations both pulmonary and
systemic, and the linear velocity of flow of blood in both arteries and veins. Movement of fluid
and energy across both cell and capillary membranes is also regulated by the gas concentrations,
while the movement of fluid is further modified by the concentration of lactate on either side of
the cell membrane through combination with carbon dioxide to become proportional to length
squared and the retention of energy within the cells, until carbon dioxide is expelled with the rise
in cell energy, allowing lactate concentration to increase once more. The rise and fall of cell
lactate concentration with alternating carbon dioxide concentration facilitates the movement of
fluid and energy in each direction, first into the cell and then returning fluid and energy to tissue
fluid later in the cardiac cycle. In this sense it becomes the basis for a 'pump' mechanism to move
fluid, energy, and ions backwards and forwards in association with changes in gas concentrations
and their ratios.This mechanism is not available for capillary membranes, but movement across
the latter is regulated by the osmotic pressure of the plasma proteins, and variations of pressure
and momentum with the pulse wave. It eventually becomes clear that the only variables which
regulate each circulatory parameter are changes in concentration of oxygen and carbon dioxide
necessary to alter these, with each parameter representing fixed multiples of the gas
concentrations.Alteration of the concentrations of respiratory gases change energy accumulation
in effector cells, while variation in the ratio of the concentrations control the linear velocity of
tissue fluid, and the rate at which fluid leaves the cell, which together represent cell contractility.
Energy provided for the circulation comes firstly from oxidation to produce carbon dioxide and
water from carbohydrate, protein and fat. It also requires glycolysis to produce carbon dioxide,
and [lactate](from pyruvate) but does not use oxygen. Oxidation of carbohydrate requires oxygen,
and produces carbon dioxide and water, and glycolysis produces carbon dioxide, and lactate but
without oxygen being used. Oxidation energy requires oxygen and produces carbon dioxide and
water, whereas glycolytic energy produces carbon dioxide and lactate concentration but without
any oxygen being used. Glycolysis produces 'oxygen debt', and increased [lactate] which
indicates increased oxygen debt (hydrogen available for oxidation) and also oxygen assembled
as oxygen debt (held in the blood by weak hydrogen bonding) until it is eventually combined
with oxygen to produce water. At the same time the energy from this reaction removes water
from orthophosphate to produce pyrophosphate absorbing the energy from hydrogen oxidation
to produce high energy phosphate bonds, or cell energy storage associated with increasing cell
32
length. As glycolysis increases so does 'oxygen debt', or 'oxygen debt' becomes proportional to
glycolytic energy. To restrict production of lactate, another source of kinetic energy is needed in
place of that from glycolysis, and this comes from 'stored cell energy' or ' ' times 'contractility',
or 'pulse rate squared times R'. 'Augmented stroke volume' then restricts lactate concentration,
and is in turn restricted by it, because it represents an alternative source of kinetic energy, but
without increase in oxygen debt; (i.e., [lactate ] restricted, and stored energy restricted, with
increased kinetic energy from 'contractility', and 'R', from 'augmented stroke volume' (
)
Energy provided in the circulation varies in its origin depending on the activity. The initial energy
is oxidative energy proportional to ' ' , i.e.,
, or
, and it provides
'stored energy' in effector cells 'R', which then represents oxidative energy, and consists of
. Both the squares of oxygen concentration and carbon dioxide concentration are
involved to produce 'R'. This energy is potential energy only, and to produce kinetic or functional
energy, it must be provided with pulse rate energy from glycolysis (i.e., 'R.PR' to produce fluid
motion 'v' ).
Potential energy '
', while kinetic energy requires an extra factor of 'PR'. or
without further oxygen concentration to produce momentum ' or 'v' 'R.PR', the average mean
linear velocity of flow. In order to provide for external work performance, further energy '
'
has to be provided equivalent to '
' to increase kinetic energy at the expense of 'oxygen load',
and this comes from '
'. There are four factors each 'PR' that have to be available for
ventricular function from oxidation, glycolysis, and
from '
', or kinetic energy at the
expense of reduced potential energy or [lactate]. Increased [lactate] associated with glycolytic
energy and increased potential energy is necessary to produce sufficient oxygen load for
oxidation of hydrogen to take place, but once this hurdle is overcome [lactate] is reduced once
more to allow further kinetic energy with linear velocity of flow, to increase as oxygen
concentration is reduced..
Although in this account, both carbon dioxide and oxygen concentrations are regarded as
variables controlling cell and circulatory dimensions, alteration of oxygen concentration in
effector cells would appear to be extremely limited because it is required to maintain 'effector cell
survival mode', which is the prime condition for the life process to continue, and must be
fulfilled before movement of fluid and energy is possible in a sustainable way. In practicable
terms 'oxygen concentration' becomes a virtual constant (maintained in effector cells by oxygen
storage mechanisms) and life is soon extinguished when these are depleted. Alternatively,
increase in cell oxygen content soon leads to metabolic difficulty with inhibition of respiratory
enzymes if it is allowed to continue. This leaves only carbon dioxide with any latitude for
variability unless cell volume changes are associated with changes in cell fluid content to alter
energy relationships and modify cell function accordingly. In this sense the circulatory variables
become the concentrations of the oxidation products of carbon and hydrogen (i.e., carbon dioxide
and water). The respiratory system is largely responsible for excretion of carbon dioxide, while
water is excreted by the skin to control body temperature, and by the kidneys which excrete
solids in watery solution, as well as any excess water available after losses from skin, bowel, and
33
respiratory systems. It then seems appropriate to examine the metabolic and excretory functions
of the renal tract to supplement those of the circulation, and these are considered in the next
section.
Because changes in oxygen concentration are maintained at a minimal level so that oxygen
concentration squared remains fixed, allowing little or no oxygen inhibition, while function
remains within a normal range, oxygen load can only be altered by change in the value of the
diastolic length of ventricular muscle fibres represented as 'L'. Any increase in lactate
concentration is limited to increase in 'L', while increase in carbon dioxide load is also limited
by increase in oxygen load ( L), but mainly dependent on carbon dioxide concentration, with
increased ventricular load mainly confined to increased carbon dioxide load and proportional to
'augmented stroke volume'. The product '
', becomes '
' if oxygen
concentration is unaltered. Lactate concentration becomes proportional to 'L', and 'R' proportional
to '
', with '
', while '
'are unchanged, allowing '
'.
Vascular filling becomes proportional to stroke volume while oxygen concentration remains
constant in value. Effector cell survival mode is proportional to '
'; and '
' is effector
cell survival mode times another factor of '
' to modify the vascular system by increase in
aortic volume with a proportional increase in arteriolar tone (i.e., constriction) becoming
proportional to increase in linear velocity of flow, and the volume of tissue fluid, (also regulated
by capillary permeability and so oxygen concentration) at the same time limiting 'vx', the linear
velocity of tissue fluid (proportional to '1/v', so that 'v' times 'vx' is proportional to momentum
of tissue fluid) and '
' or contractility is limited by 'v' at the capillaries and increased at the
effector cells.
The oxygen load is limited by aortic elasticity and the latter reduces arteriolar constriction and
'L', and increases 'vx', maintaining 'L.vx' or pulse rate (limited in turn by Marey's reflex, and
preserving stroke volume and the carbon dioxide load). Energy in the circulation is proportional
to '
' i.e., augmented stroke volume times peripheral resistance or '
',
representing momentum from ventricular contraction resolved along three dimensions at right
angles, each proportional to momentum, and totalling '
or all of the energy from
ventricular contraction. i.e., '
'and proportional to '
'
. There is another factor contributed to carbon dioxide load when effector cells are depolarised,
produced by glycolysis to maintain movement in the tissue fluid and venous return and
proportional to ' '. This is probably the flow energy observed by Corcondilas et al. (1964). It
appears anaerobically without any consumption of oxygen, but with energy of glycolysis
contributed to the circulation to increase carbon dioxide load, and so circulatory energy to be
proportional to '
', or '
'. It is equivalent to circulatory power cubed, or one
factor of power for each dimension of energy produced by ventricular contraction, resolved at
right angles.
The energy provided by ventricular contraction per beat is proportional to the product of oxygen
load and carbon dioxide load accepted by the ventricle. Oxygen load is represented by the lactate
concentration maintained in the plasma, while carbon dioxide load is proportional to the stroke
volume. The total ventricular load is that presented by the total gas load moved around the
34
circulation, so that the volumes of carbon dioxide and oxygen remain inversely proportional to
each other, while their product is proportional to the diastolic length of the ventricular muscle
fibres cubed. The diastolic length of ventricular muscle fibres resolved in each of three directions
is proportional to the product of oxygen and carbon dioxide concentrations maintained in the
tissues, and the total energy represented is proportional to the product of the three directions of
resolved energy, and so proportional to the diastolic length of muscle fibres cubed, to represent
the total energy which must be available, though the direction of application of the energy may
not always be the same, so that stroke volume, pulse rate, and resistance per unit volume per unit
velocity may each vary with respect to the others, requiring different levels of energy applied to
each. The total energy may nevertheless remain the same with proportional alterations of 'Q', 'PR',
and 'R', but allowing total energy to remain proportional to 'Q' times 'v', or 'carbon dioxide load
cubed' , equivalent to 'L cubed', times 'carbon dioxide concentration cubed'. Carbon dioxide
concentration is also furnished by glycolysis along each direction at right angles, with carbon
dioxide liberated without oxidation occurring. When the effector cell is depolarised and active
permeability suddenly increased, carbon dioxide is lost from the cell with sudden loss of 'vx', but
increased outflow of fluid to extravascular extra-cellular space, and increased venous blood flow
as observed by Corcondilas et al. (1964). There is a sudden fall in carbon dioxide concentration
which is replaced by glycolysis, and maintains the increased flow with extra carbon dioxide from
glycolysis replacing that from tissue oxidation, and increasing carbon dioxide load by a factor
of ' ', or .’ ‘ for each of three dimensions
'L' and a corresponding increase in carbon
dioxide load, while oxygen load is unaltered until the increased oxygen load (increased lactate
concentration) which soon follows, and inhibits further glycolysis.
Increased lactate (approximately 20% of that produced as above, and remaining after
glyconeogenesis) and carbon dioxide together increase cell energy content and 'R' with
repolarisation, but carbon dioxide is then replaced with oxygen so there remains increased lactate
concentration (or oxygen load) but without increased oxygen concentration. These conditions are
those suitable for 'oxidative phosphorylation', with reduction of lactate concentration and oxygen
load as pyrophosphate bonds increase energy storage at the expense of lactate and oxygen, which
are reduced allowing increase in pyruvate, and activity of respiratory enzymes to increase once
more with resumption of Kreb's type oxidative activity, while restricting cell volume and passive
permeability. These reactions are able to regulate cell oxygen content, but there remains a further
factor of oxygen concentration to be restricted. This is proportional to arterial volume, and the
oxygen concentration is increased as arterial volume is increased. It can be restricted by aortic
elasticity which reduces aortic volume and stored oxygen in the aortic wall. This stored oxygen
is released as aortic volume decreases again, and then passes with the pulse wave to the muscular
arteries and arterioles to constrict them in turn.
The amount of arterial constriction depends on the amount of stored oxygen made available from
the distended aorta, and is smaller when the available oxygen is reduced. Both oxygen load and
arterial constriction are reduced, so linear velocity of flow through the arterioles is less, and
tissue fluid volume is reduced while velocity of tissue fluid is maintained. This mechanism is
able to restrict oxygen load and vasoconstriction in arterioles with a corresponding increase in
carbon dioxide load appearing as augmented stroke volume and increased external work capacity.
Oxygen load in the circulation is represented by three factors each proportional to oxygen
concentration, and each affecting stored energy in each of three areas; viz. stored energy in
effector cells ( oxygen concentration); passive permeability of effector cells (also oxygen
concentration); and volume of elastic arteries ( inversely constriction of muscular arteries and
35
linear velocity of tissue fluid, and directly volume of tissue fluid and the linear velocity of
blood flow in the arterioles). Each of these three is proportional to oxygen concentration, and
together they represent the oxygen load (or lactate concentration).accepted by the left ventricle.
(lactate concentration
times vx, equivalent to 'L times
') .
There is increased oxygen load, but reduced ‘R’ unless carbon dioxide is provided from
glycolysis, or increased ‘L.PR’ , with cell free energy and heat, and cell genetic activity. Reduced
cell heat (L.PR) results in reduced glyconeogenesis, reduced stroke volume and carbon dioxide
load, but increased oxygen load to maintain ‘R’. The real problem is inhibition of oxidising
enzymes with increasing oxygen concentration, and reduced glyconeogenesis with carbon
dioxide provided from glycolysis, but with reduced stroke volume and reduced genetic activity,
and the likelihood of increased effector cell volume with energy diverted from cell activity to
increase cell volume and increase circulatory resistance, or ‘R’. Increased oxygen load or lactate
concentration appears when oxygen utilisation is reduced, and production of carbon dioxide from
oxidation enzymes is reduced, and the result is then termed ‘oxygen debt’, proportional to lactate
concentration. It appears when the consumption of oxygen is reduced, and carbon dioxide
production is also less, while oxygen concentration and oxygen load are increased. Oxygen debt
implies retention of increased oxygen load , but reduced oxygen consumption with reduced
carbon dioxide load and stroke volume.
The pulse rate varies in response to the requirement to maintain fluid volumes in body
compartments by altering the linear velocity of flow of blood and other body fluids as may be
necessary to achieve satisfactory filling. Variations in pulse rate occur with alteration in blood
viscosity and glycolytic activity in response to changing respiratory gas concentrations.. The
experiments illustrated in figures 5 to 11 show changes in pulse rate when vascular and
ventricular filling, and the volumes of the main body compartments (of cells, tissue fluid, and
blood vascular system) are challenged experimentally.
"The pulse rate represents the amount of glycolytic energy needed to maintain vascular filling
at an adequate level with respect to the oxygen load required for a particular (level of ) activity."
Adequate lactate concentration is essential to maintain viability of effector cells, and its absence
at an adequate concentration, leads to the syndrome of 'asthma' as an initial symptom, while
persistent elevation of lactate concentration may result in hypertension, and eventual destruction
of function in the arterial system . Elevation of carbon dioxide load (stroke volume) on the other
hand may assist in prolonging the productive life span if both carbon dioxide concentration and
bicarbonate concentration can be persistently elevated over the period (life span), and this
particularly seems to be the case with certain herbivores. Cell size and shape are related to the
energy available which needs to be regulated to maintain oxygen concentration and cell volume.
Cell volume depends on close regulation of oxygen concentration by removal of lactate
concentration (or oxygen load) regulated in turn by glyconeogenesis; i.e., lactate concentration,
cell free energy (heat and cell temperature). and an adequate concentration of carbon dioxide (in
excess of oxygen concentration, and so increase in carbon dioxide concentration, and reduction
in that of oxygen and cell ‘size’).
Put in another way, energy provided to the circulation may be as potential energy, kinetic energy,
or as ‘free’ energy, the latter appearing as heat with increased temperature of the active tissues.
36
Potential energy is for the most part produced by oxidation of hydrogen and/or carbon to produce
water or carbon dioxide, while kinetic energy is associated with fluid motion and the available
pulse rate, and free energy increases cell temperature as heat increases.
Potential energy indicates ‘stored ‘ or accumulated energy proportional to multiples of ‘L’, and
multiples of pulse rate as kinetic energy and potential energy are diminished to produce
unorganised or ‘free’ energy, becoming energy in its most unorganised form.
Stored energy is typically associated with increasing diastolic length of effector cells, and most
readily expressed as increased multiples of ‘L’; kinetic energy is an indication of the movement
of fluid volumes, and expressed as increased pulse rate and carbon oxidation, while ‘free’ energy
appears as stored and/or kinetic energy are reduced with the energy then appearing as ‘heat’ with
rising cell temperature from multiples of ‘L’ and ‘PR’ as the values of kinetic energy change to
heat.
Stored energy represents physical dimensions of cells, kinetic energy is increasing pulse rate and
oxidation of carbon, and free energy is reduced physical dimensions and reduced chemical
activity, both following physical activity and accumulation of heat energy as coordinated fluid
movement is lost. Free energy follows when ‘L.PR’ appears as part of the energy produced from
the product of energy necessary to overcome the product of internal resistance (L ) and
systemic blood volume ( ) to produce ‘L. ’, and heat production from this resistance to flow.
The free energy is required to maintain ‘vx’(the linear velocity of tissue fluid) and maintain fluid
movement while the remaining heat is absorbed in the production of glycogen from [lactate],
increased carbon dioxide and heat energy. As ‘vx’ is increased, so is the energy available for
glyconeogenesis with reduction of lactate concentration and oxygen load , but increased carbon
dioxide load and stroke volume. If ‘vx’ is diminished, there is a fall in carbon dioxide
concentration compared with that of oxygen, and increased cell volume, but reduction of active
permeability and linear velocity of tissue fluid. These are the conditions that lead to neoplasia,
and loss of genetic activity, with potentiation of cell multiplication and the appearance of new
growths.
Reduction of cell volume but maintenance of the ‘oxidation energy’ to produce increased
carbon dioxide concentration from oxidation are the conditions that lead to increased carbon
dioxide load and stroke volume. Glyconeogenesis then controls effector cell volume and
oxidation energy, and is able to restrict the tendency to neoplasia, and growth of neoplastic cells,
while reduced glyconeogenesis encourages ‘neoplasia’, and division of ‘effector cells’.
Because the concentrations of oxygen and carbon dioxide are the only variables controlling
energy production, they must also control the rate of cell division, and increase in cell volume.
The implication is that neoplasia must be very greatly modified by glyconeogenesis which
regulates the ratio of carbon dioxide concentration with oxygen concentration. or ‘vx’, and so the
amount of kinetic energy remaining at diastole, as well as the oxygen load, and the ‘level of
function’ remaining in the circulation at diastole. In this way it becomes a ‘trigger’ for producing
‘neoplasia’ when there is aberrant metabolic activity with increased oxygen concentration, and
cell volume, but neoplasia can be avoided if cell volume is controlled at an adequate level. The
ratio ‘vx’ indicates that between ‘augmented stroke volume’ and ‘peripheral resistance’, or
kinetic and available ‘stored energy’ which may be altered by increased glyconeogenesis.
As well as the concentrations of the respiratory gases on which the metabolic, functional, and
structural characteristics of effector cells largely depend, there are a large number of other factors
37
which influence cell, organ, and tissue structure and function, largely by varying the structure of
effector cells, and consequently their metabolism, energy production, and usage. These factors
make up the chromosomes and genetic code, and because of their influence on structure, have
a large part to play in functional activity and the energy exchange that determines the cell size
and shape.
Genetics and cell function.
If the oxygen and carbon dioxide concentrations are the only variables that affect energy
exchange in the ‘effector cell’ and circulation, it is only reasonable to assume that variation in
cell function from genetic influence is likely to function by altering the metabolic gas
concentrations in ‘effector cells’. This could only occur as the result of metabolic change in
activity from alteration in cell permeability, and probably ‘active permeability’ of effector cell
membranes, as a continuing result of genetic influence. Although it is the metabolic gases which
regulate cell function, this effect must be continually influenced by the genetic background
present in each cell, affecting cell membrane permeability, and so ‘vx’, upon which the gas
concentrations have their effect, after the functional background is set by genetic makeup over
the life of the individual; i.e., the metabolic gases are responsible for function, but the level of
this function is set by the genetic makeup of the cell, or genome over the life of each individual
member of the species.
“Genes act by regulating definite chemical events”. It is this postulate which earned G.W.Beadle
the Nobel prize in 1958. That is to say, genes influence metabolic activity or the ratio
,
and the linear velocity of tissue fluid, whatever other effects they may have. Because ‘active
state’ regulates ‘
’ with respect to oxidation energy, ‘L’, it regulates genetic effects with
respect to oxidation energy, or ‘contractility’ with respect to ‘oxidation energy’ and so genetic
effects become proportional to glycolytic energy, or increased ‘active state’ inhibits ‘neoplastic
activity’.
The suggestion is that genes are ‘turned on’ by increase in the ratio of carbon dioxide
concentration with oxygen concentration, and when this level is diminished (as activity is
reduced again) they need to be ‘turned off’ as carbon dioxide concentration diminishes again.
Under usual circumstances this may require an increase in oxygen concentration with the
potential to increase cell division unless carbon dioxide concentration can be diminished by ‘antioxidant’ to reduce both carbon dioxide production and the level of ‘free radicles’ which is
associated with it, without increasing the concentration of oxygen from its existing level. The
function of ‘anti-oxidants’ may be to allow reduction of carbon dioxide and cell function without
excessive increase in cell volume and oxygen concentration while reducing cell functional
activity.
The effect of the genetic makeup of cells must be in evidence from the time of their formation,
so it is able to influence the structural and functional activity as well as energy exchange,
circulatory momentum, and cell ‘free energy’ required. As a result the optimal conditions for
function, including the gas concentrations must also be varied, and directly represented in cell
dimensions, size, and shape, to become ‘optimal conditions’ for function at all times to vary the
concentrations of oxygen and carbon dioxide in the same way as the environmental supply of
oxygen, and metabolic supply of carbon dioxide.
38
Genetic factors then are important in determining cell dimensions and other characteristics, and
cannot be separated from the circulatory momentum and body structure of the mature individual,
even though their effect on function will be relatively constant, and not so varied as
environmental influence, including the gas concentrations, which vary with changing activity.
The result of genetic activity is then relatively constant, while gas concentrations vary with body
function and metabolism. The gas concentrations may be more variable, while genetic factors
have a more constant influence. It is respiratory activity that determines the changes in cell size
and shape, while the genetic code determines the mean values rather than any rapid changes in
momentum or cell dimensions which result from altered work performance. At the same time
cell volume needs to remain fairly constant while cell length, ’L’, and cross sectional area ,
‘1/ ’, vary to maintain cell oxygen concentration and volume, by altering carbon dioxide
concentration instead. Oxygen concentration in the effector cells needs to be maintained at a
relatively constant value to prevent pressure on cell volume to proceed to cell division, which is
increased if oxygen concentration is increased. There is reduction in cell activity and function
if oxygen concentration is increased leading to cell division; i.e., the tendency towards neoplasia
increases if oxygen concentration is increased and reduced if carbon dioxide concentration and
circulatory momentum is increased instead.
The suggestion is that genetic influences generally do not increase neoplastic tendencies, which
with the exception of possible mutations, are much more likely to follow distortion of gas
concentrations, and increased oxygen load. Lactate concentration and oxygen load needs to be
regulated, and reduced at diastole by glyconeogenesis, and increased momentum. The implication
is that increase in peripheral resistance leads to glycolysis, while increased ‘augmented stroke
volume’ is proportional to kinetic energy and glyconeogenesis, or the ratio of glyconeogenesis
/ glycolysis is proportional to ‘vx’.
There are two mechanisms that allow energy levels and cell size and shape to be altered. The first
is by changes in the gas concentrations in effector cells, and the physical effects that follow. The
second is through genetic factors which can optimise cell size, shape, and energy levels for a
particular function or set of circumstances by adjusting cell size shape and energy exchange (cell
permeability) in any way set by genetic inheritance and enzyme activity, but which can also alter
cell size, shape, and energy store and function secondarily. Genetic inheritance produces
optimum function and cell mechanics with secondary effects on energy and cell size, and it is
the primary changes in cell gas levels as these concentrations alter with activity which have the
main effects on cell mechanics.
The major regulator of circulating gas levels is glyconeogenesis, or the conversion of lactate to
glycogen to reduce cell oxygen load with respect to carbon dioxide load, that has the major effect
on cell dynamics, by increase or decrease in ‘vx’, and the distribution of energy during the
cardiac cycle (including glyconeogenesis) and the relationship between augmented stroke volume
and oxygen load and so effector cell volume at diastole. Regulation of oxygen and carbon dioxide
concentrations is the most important factor in energy generation and distribution to maintain cell
size, shape, and energy content commensurate with required function and the continuing ‘life
force.
It would seem that neoplastic disease is associated with increased volume of some individual
effector cells, and subsequent reduction in cell function as energy exchange and stroke volume
39
diminish, and contractility is reduced compared with oxygen load. There follows restriction of
the circulation with increased peripheral resistance which accompanies any increase in glycolysis.
To return the effector cells to more normal function requires an increase in ‘vx’ and the fluid and
energy exchange with tissue fluid; i.e., increased ‘v’, and increased ‘vx’, or increased momentum
of tissue fluid at diastole together with ‘free energy’, or ‘
’and ‘L.PR’, to increase
glyconeogenesis and reduce the concentration of lactate. Increase in circulatory momentum and
‘free energy’(or cell heat) are required to increase glyconeogenesis and reduce the volume of
effector cells, and so the likelihood of cell proliferation and immaturity of the resulting daughter
cells; i.e., the condition of neoplasia. Cell division and resulting immaturity is only overcome
with improved function, and increase in ‘v’ and ‘vx’, or glyconeogenesis with reduced residual
lactate concentration at diastole. Cell immaturity is even more likely if there is restricted cell
length (restricted oxidative energy) to accentuate the increase in effector cell volume with raised
oxygen concentration but without significant increase in systolic blood pressure.
The logical treatment for neoplastic disease in effector cells, is to restore cell function, with
reduced cell volume and increased energy exchange and so ‘vx’, by increasing glyconeogenesis
(and ‘vx’) compared with oxygen load (lactate concentration) allowing an increase in stroke
volume (and so carbon dioxide load), as the essential factor to preserve normal cell function. The
inverse ratio, ‘1/vx’, indicates the likelihood of neoplastic disease developing somewhere in the
body, because it represents the ratio of oxygen load / stroke volume for all cells surrounded by
tissue fluid and so the ratio cell volume / stroke volume and reduced functional capacity of
effector cells leading to development of neoplastic disease if oxidation capacity and ‘vx’ is
persistently reduced.
In the expression
which has been termed ‘The Law of the Circulation’, ‘L’
represents the diastolic fibre length of ventricular muscle, and carbon dioxide concentration is
proportional to the energy available from oxidation of carbon, while oxygen concentration
indicates the limit of oxygen concentration necessary for survival of effector cells It also
represents the concentration of oxygen available for oxidation of hydrogen from the
concentration of lactate which remains available in the circulation (so called oxygen debt) and
the amount of high energy pyrophosphate bonds that can be produced at any time.
Carbon dioxide concentration represents energy from oxidation of carbon, and oxygen
concentration represents energy from oxidation of hydrogen to water from the excess lactate
present, and the product of the concentrations of oxygen and carbon dioxide is the energy
available from ventricular contraction produced from the diastolic length of its muscle fibres, and
so the oxidation energy per beat. The expression
means energy from oxidation
of carbon times energy from oxidation of hydrogen from the available oxygen concentration, is
proportional to the ventricular energy output as required by ‘Starling’s Law’, and it represents
the energy from oxidation per beat.
Oxygen Load, Hypertension, and Neoplastic change.
The oxygen load can be represented as proportional to ‘L.
energy, or
’ where ‘L’ represents oxidation
, and its significance varies whether ‘L’ or oxygen concentration is the
more important factor. If ‘L’ is increased oxidation energy is increased compared with cell
volume (cell length increased while cell volume is little changed) and it implies that oxidation
40
energy is increased with increase in cell efficiency to offset any restriction in carbon dioxide
concentration, but with increase in systolic blood pressure, and little change in cell volume. But
if cell length is restricted and oxygen concentration increased, there is no increase in oxidation
energy, and a significant increase in cell volume (and reduced ‘vx’). There is reduced functional
capacity, reduced energy exchange and stroke volume. The associated increase in cell volume
increases the likelihood of cell division, and production of immature cells (i.e., cells with
restricted cell function, and restricted ‘v, Q, and LPR’).
These are the conditions for neoplasia to occur, and they increase as functional capacity (and
production of carbon dioxide) is reduced. With reduction of carbon dioxide concentration, ‘L’
is also reduced, and stroke volume greatly reduced as the degree of malignancy is increased.
Neoplastic change can only be restricted if functional capacity and oxidative energy is increased
again, and oxygen concentration and cell volume return to a more normal level. This can only
occur if there is increased ‘vx’, and reduction of oxygen concentration and lactate concentration
as a result. That is, there needs to be an increase in glyconeogenesis to reduce lactate
concentration and oxygen load by increasing cell functional activity once more.
Retrieval of kinetic energy in the systemic circulation.
At diastole, both circulation energy and potential energy remain in the systemic circulation.
Some energy (kinetic energy of flow) remains
and is carried over into the next beat
through ventricular filling, and diastolic linear velocity of flow; i.e., ‘QRLPR’. Of this
energy,
is supplied by respiratory activity, but ‘Q.PR’ and ‘L.PR’, or vascular filling (Q.L)
and kinetic energy remain from the previous beat, and with oxygen concentration squared from
respiration provide ventricular filling for the next beat. But there is still potential energy (lactate
concentration) and ‘free energy’(or LPR) times linear velocity of tissue fluid (vx), and equivalent
to
, or
(i.e, momentum) which remains and needs to be converted to ‘stored
energy once more by glyconeogenesis. In order for more complete conversion of lactate
concentration to glycogen, an adequate supply of carbon dioxide concentration is required as well
as ‘free energy’ (L.PR or cell heat ) and linear velocity of tissue fluid (vx).
Glyconeogenesis requires lactate concentration, an excess of carbon dioxide concentration, or
heat energy, and linear velocity of tissue fluid, to ensure more complete glyconeogenesis, and
energy transferred to store, with minimal lactate concentration remaining (i.e., minimal oxygen
load presented to the ventricle, and relatively maximal kinetic energy, carbon dioxide load or
stroke volume). Maximal carbon dioxide load means more complete glyconeogenesis (energy
transferred to store, as well as increased stroke volume, to maintain ventricular efficiency, and
this is the function of glyconeogenesis which must be encouraged by maintaining ‘vx’ in tissue
fluid or ‘ ’ in circulating blood volume).
If glyconeogenesis is not adequate, there remains increased lactate concentration and reduced
‘vx’, with lactate concentration increased with respect to stroke volume, and ventricular
efficiency only maintained by increased lactate concentration and hypertension, instead of
increased stroke volume and ‘normal’ blood pressure, which is the desirable result, and is only
obtained by reducing the concentration of lactate through glyconeogenesis.
Nevertheless, body cells have a limited life cycle. New cells arise by division of pre-existing cells
which increase in volume and then division to produce cells which increase in volume until their
41
function improves to prevent any further volume increase as the cells become more mature.
Mature cells have increased functional capacity but restricted volume and restricted capacity for
reproduction. Cell maturity is indicated by increased function and limited volume, or increased
‘contractility’ for a given value of oxidation energy
‘L’; i.e., by increasing ‘active state’
compared with ‘inotropic state’, and ‘active state’ becomes a measure of cell maturity. At the
same time increasing ‘active state’ limits cell reproduction and ‘neoplasia’ because neoplastic
disease occurs as active state is reduced. Increased active state is necessary to limit cell
reproduction, and the increased production of immature cells which occurs if active state is
reduced, and cell function limited.
Increase in ‘inotropic state’ (and diastolic length of ventricular muscle fibres) leads to increased
oxidation energy and increased cell energy store compared with cell function (contractility); i.e.,
increase in the ratio
, and increased blood pressure, while increased contractility compared
with ‘L’ leads to increased cell function , but limited cell reproduction. Prevention of neoplastic
disorder requires increased
compared with ‘L’, or increased ‘active state’. Increase in
‘inotropic state’ leads to increased cell energy store and hypertension, but reduced ‘vx’.
Active state is the ratio between glycolytic energy and peak potential energy available at systole;
(i.e.,
, or
)proportional to
Derangement of the ratio ‘vx’ is the problem that leads to neoplasia and that can only be avoided
if ‘vx’ is continually maintained in all areas of activity so that carbon dioxide concentration is
increased as oxygen is diminished. This remains a limiting factor for all circulatory activity
compared with oxygen load, and a necessary factor in preventing neoplasia, which depends on
maintaining the oxidising capacity of respiratory enzymes ( the ratio of carbon dioxide
concentration compared with that of oxygen).
Momentum in tissue fluid at diastole is proportional to the square of the pulse rate, and
equivalent to the cardiac output in the systemic circulation, while augmented stroke volume is
‘v.PR.Q’, or ‘Q. power output’ by each dimension of the ventricle. The product ‘R.v.
’
determines the amount of carbon dioxide from oxidation of carbon contributed to stroke volume,
and is equivalent to carbon dioxide concentration produced by glycolysis. The energy remaining
in the circulation at diastole is partly disposed of as augmented stroke volume, but this still leaves
the oxygen load (i.e., lactate concentration) to be converted back to ‘stored energy’ to control
oxygen load at the ventricle. The conversion is accomplished by glyconeogenesis, and for this
process to proceed adequately requires lactate concentration, kinetic energy (i.e., pulse rate) , and
‘free energy’ (cell heat), all in adequate amounts. Lactate concentration can then be reduced to
a minimal level by glyconeogenesis, which then controls effector cell volume for the ensuing
beat. Control of the volume of effector cells (with a fixed value of cell length) limits the strain
on cell size and dimensions. If ‘L’ is allowed to increase cell size is more readily accommodated
(with reduced ‘active state’) and there is increased lactate concentration and the oxygen load,
resulting in increased systolic blood pressure. If glyconeogenesis is adequate, diastolic blood
pressure (or ‘v’) is reduced to a more constant level. Systolic blood pressure is regulated by ‘L’,
and lactate concentration, while diastolic blood pressure is regulated by glyconeogenesis to vary
lactate concentration, and maintain effector cell volume, and limit cell multiplication
42
(neoplasia). Neoplasia of effector cells is controlled by increasing glyconeogenesis, and
hypertension by reduced oxygen load in effector cells. Glyconeogenesis at diastole limits
neoplasia in effector cells , while reduced oxygen load limits development of hypertensive
disease. (But excessive loss of effector cell energy and volume, produces asthmatic symptoms
unless the lactate concentration is maintained.) Neoplasia is limited while cell function and
energy exchange is maintained, but if the exchange is inadequate, or if it falls off with age over
time, cell reproduction and neoplasia is encouraged (with post mature or immature cells). While
the energy exchange is maintained, neoplasia is less evident.
The circulation needs a constant value of oxygen concentration and oxygen load. This can be
achieved by increasing carbon dioxide load rather then oxygen load, with changes in stroke
volume to maintain control. Alternatively there may be restriction of oxygen load through
transferring energy by increased glyconeogenesis which becomes a necessary adaptation to
maintain cell volume and oxygen concentration. Limitation of neoplasia needs increased stroke
volume and glyconeogenesis, and increased stroke volume to prevent hypertension (i.e.,
increased ‘free energy’ , increased kinetic energy, and increased momentum of tissue fluid.)
Increased circulatory momentum is a first step to reduce neoplasia and slow down its progression.
The underlying problem is interference with respiratory enzymes to vary the ratio of the gas
concentrations and the dysfunction that occurs as a result. Loss of oxidising capacity of
respiratory enzymes inevitably increases with age, and the steps that lead to this loss of function
are unclear. However preservation of oxidising capacity can be maintained for some time by
adequate circulatory momentum and glyconeogenesis, and this is a first step towards avoiding
or slowing down neoplastic disorder and hypertensive disease.
The algebraic model of the circulation provides the basis for a working hypothesis for production
of hypertension and vascular disease, as well as neoplastic disorder through alteration of oxygen
load and effector cell volume with reduction of ‘vx’, and circulatory momentum when oxygen
and carbon dioxide loads vary in the circulation. Of these oxygen concentration needs to be kept
relatively constant, and the only variable becomes the concentration of carbon dioxide and stroke
volume while function remains within the ‘normal’ range. ‘Abnormal’ function requires changed
oxygen concentration; when it is either increased with increased cell volume and oxygen
concentration, or decreased with excessive cell permeability (i.e., asthma) with reduced oxygen
load.
Adaptations to maintain the oxygen concentration when it would otherwise be altered, are
hypertension to increase oxygen load (but not oxygen concentration) ; and asthma to increase
carbon dioxide concentration but not the oxygen load ,[lactate], through bronchial constriction.
Part of the adaptation is to vary carbon dioxide concentration inversely with oxygen load,
[lactate], to maintain ‘L’ in asthma, and reduced carbon dioxide concentration to limit ‘L’, and
prevent oxygen concentration increasing further in hypertension. Increased ‘L’ leads to increased
efficiency in hypertension to limit oxygen concentration, and reduced efficiency in asthma as
carbon dioxide concentration is increased instead.
If these adaptations should prove to be insufficient, increased oxygen concentration leads to
excessive cell volume and may produce neoplasia rather than hypertension, while reduced
oxygen concentration in asthma becomes peripheral circulatory failure as the concentration of
43
carbon dioxide is further increased with excessive ‘active permeability’, and reduced cell volume
to an excessive degree.
Oxygen concentration does not increase if ‘L’ is increased instead (with increased energy output
but constant cell volume), but if ‘L’ is limited through reduction of carbon dioxide concentration,
then oxygen concentration increases and predisposes to neoplasia, or increased reproduction to
produce immature and poorly functioning daughter cells. The latter only occurs if carbon dioxide
concentration (and so ‘L’) is reduced, and the concentration of oxygen is increased as that of
carbon dioxide falls. Cell volume may increase leading to neoplasia, but oxygen concentration
can be limited by glyconeogenesis or oxidative phosphorylation so the concentration of oxygen
only increases if that of carbon dioxide is reduced, and there is reduced oxidation energy, and so
reduced diastolic muscle fibre length in the left ventricle, that becomes necessary to produce
neoplasia. Prevention of neoplasia requires the concentration of carbon dioxide to be maintained
with limited oxygen concentration as glyconeogenesis is increased.
The balance between the concentrations of carbon dioxide and oxygen in effector cells is ‘vx’,
and it governs the movement of fluid from cells to extravascular fluid. As ‘vx’ increases cell
volume is reduced; i.e.,
(or
) is the critical ratio for increasing cell size, and
neoplastic change. If ‘
’ is increased there is reduced or no neoplasia, but if it is
reduced, neoplasia is more likely to occur in ‘vulnerable’ cells of glands and epithelium /
endothelium; i.e., cells where there is an additional factor as well as the circulatory gas
concentrations, for example, a carcinogenic substance in the environment which may change
either cell permeability, or the gas ratio in the cells (either carcinogens or even genetic factors
that may change the gas ratio in particular cells) but the main problem is the gas ratio available
from the circulation, and the resulting circulatory dynamics.
Augmented stroke volume is ‘Q.v.PR’, or stroke volume given extra momentum from power
developed from ventricular contraction; i.e., the increased kinetic energy from increased
ventricular diastolic fibre length increases effector cell length for the same oxygen concentration
in the cells and so cell volume. There is increased oxygen load but not oxygen concentration,
and increased oxygen load is proportional to ‘L’ (and increased efficiency of the circulation for
the same oxygen concentration).The augmented stroke volume gives kinetic energy proportional
to ventricular diastolic fibre length of ventricular muscle, and maintains diastolic momentum
proportional to pulse rate squared from ‘
’.
The important factor is ‘vx’ which maintains momentum and the increased ratio ‘
’
necessary from the increased kinetic energy provided to effector cells per beat, and transferred
to glycogen store by glyconeogenesis at diastole.Excess circulatory activity from increased
momentum at systole, is transferred to glycogen store at diastole with reduction of lactate
concentration, cell heat, and extra concentration of carbon dioxide load to reduce oxygen load
at systole. Oxygen concentration in the cells remains constant as a result of cell energy store at
systole and diastole, and the transfer of excess oxygen load to glycogen to remove cell heat and
diminish the concentrations of both carbon dioxide and oxygen as well as the oxygen load
(lactate concentration).
Reduction of oxygen load keeps the cell oxygen concentration and cell volume at a constant level
depending on the amount of glyconeogenesis at diastole. If ‘L’ is restricted when the oxygen load
44
is elevated, it results in increased effector cell volume and possible neoplastic activity. The latter
is restricted if oxygen concentration is unaltered, and with ‘L’ increased instead, and persistent
increase in carbon dioxide concentration to restrict neoplasia.
Replacement of poorly functioning effector cells (i.e., cells either damaged or degenerated so that
function is disturbed) is accomplished through changes in ‘vx’. As the ratio of
falls,
glyconeogenesis is diminished and lactate concentration increased and oxygen load increased
with increased pressure on effector cell volume and cell division, to produce daughter cells that
only become fully functional as carbon dioxide concentration increases with respect to that of
oxygen, to limit further cell division and increase functional activity. Cell replacement is then
regulated by ‘vx’, and maintenance of linear velocity of tissue fluid, with glyconeogenesis to
keep ‘vx’ constant and proportional to the ratio of carbon dioxide load with oxygen load. If the
ratio varies without correction, proliferation of poorly functional effector cells may occur to
produce neoplastic disease if the ratio is reduced, and reduced oxygen concentration (asthma or
peripheral circulatory failure) if the carbon dioxide load increases significantly compared with
lactate concentration (which must be maintained).
Increased cell length and energy store leads to increased circulatory momentum, but unchanged
cell volume, resulting in hypertension rather than neoplasia. Reduced energy store at diastole
(i.e., lactate concentration) gives diminished work capacity, and eventually reduced oxygen
concentration and peripheral circulatory failure, with bronchial asthma limiting peripheral failure
as the lactate concentration falls and carbon dioxide concentration increased.
With cardiac asthma the progression to peripheral failure is more likely, with reduced work
capacity, and bronchial constriction as oxygen concentration falls. Passage of blood through the
lungs results not only in oxygenation of haemoglobin, but also in increased linear velocity of
flow, from ‘L.PR’ in systemic venous blood to ‘v’ in blood entering the left ventricle and then
transferred to arterial blood to provide ‘v.Q.PR’(augmented stroke volume)’ at systole. Effector
cell energy and volume remains constant if cell energy is proportional to cell length, so that ‘L’
increases rather than oxygen concentration to produce increased lactate concentration and oxygen
load. The increased energy depends not only on increased cell length, but also on increased
kinetic energy with increased linear velocity of flow of augmented stroke volume which is
necessary to increase momentum but not oxygen concentration. If momentum is not increased
then increased oxygen concentration is inevitable, and increases the possibility of neoplasia,
because of the absence of increase in carbon dioxide concentration required to prevent it. This
increase in carbon dioxide load must come from increased oxidation energy to increase kinetic
energy at the expense of oxygen load and lactate concentration.
If cell oxygen load is increased for any length of time, there is increased effector cell volume
followed by division of cells to produce daughter cells with reduced functional activity; i.e.,
neoplastic characteristics become likely if ‘L’ is reduced, while hypertension follows if ‘L’ is
increased , and ‘asthma’ if oxygen is reduced together with oxygen load. Increased lactate
concentration produces hypertension if cell volume is constant but neoplasia is more likely if cell
volume increased and ‘L’ reduced, while there is asthma if the oxygen load is reduced, but if it
is not relieved may result in peripheral failure if the increase in carbon dioxide and reduction in
oxygen load is sufficiently great.
45
There is an anomaly in the provision of energy to effector cells as a result of augmented stroke
volume. The provision of kinetic energy is greater than the energy to maintain the circulation by
a factor proportional to Q times PR which is equivalent to that required for maintenance of the
circulation (also Q times PR), so the energy provided is ‘
’. If Q times PR is the energy
required to maintain the circulation, what happens to the further factor of ‘Q.PR’? It must lead
to function of a different nature in the effector cell, and presumably to increase in activity of
genes and chromosomes commensurate with increase in kinetic energy entering the cell and
leading to ‘activation energy’ which allows genetic activity to optimise effector cell activity for
the particular cell function required . It would appear that the energy appears as ‘active state’,
or energy
‘vx’, and
(which is ‘active state’).The supposition is that ‘active state’
represents the energy available for increased genetic activity in effector cells for each cell
function the gene or genes make optimal at that time, and which is made available by increase
in the ratio ‘vx’, or alteration of the ratios of the respiratory gases.If the ratio is inadequate
effector cell function becomes inadequate, and cell function is directed instead to reproductive
activity, or ‘neoplasia’.
Energy available for the life process with genetic activity depends on ‘active state’ and is
proportional to
, or ‘contractility’ over ‘oxidation energy’, equivalent to
, and ‘vx’ is
proportional to energy for genetic function, or the ratio ‘systemic blood volume’ over ‘systemic
arterial volume times restricted pressure within the thorax’, and turned on by ‘vx’, the linear
velocity of tissue fluid, and equivalent to the energy for initiation of gene activity.
Circulatory momentum , or ‘ .v’, is the kinetic energy that maintains life, and overcomes the
energy for cell survival. Both energy for cell survival, and kinetic energy for gene activity must
be available for the cell to function at its optimum. Although ‘vx’ may be required to ‘turn on’
genetic activity, the amount of that activity is ‘R.vx’ (L.PR) or cell temperature, which then
becomes necessary for the equivalent amount of genetic activity, and without this energy the
continued life process is not possible. In egg laying mammals it is clearly temperature which is
responsible for initiating and continuing incubation, and so commencement and continuation of
gene activity (which requires appearance and increase in ‘vx’) i.e., temperature adjustment to
increase genetic activity followed by increase in momentum, and circulatory activity.
All cell function requires increased kinetic energy which is proportional to ‘vx’, and
, and ‘active state’ i.e., ‘
’. ; ‘vx’
linear velocity of tissue fluid, and also
to cell function (i.e., ‘gene activity’). Gene activity times linear velocity of tissue fluid (i.e.
‘contractility’) constitutes the energy of the life process which must be continually present while
life persists, firstly to maintain circulatory activity (extra-vascular fluid motion) and secondly to
enable genetic function, and the level of cell function made available (and each of these two
functions require equivalent increase in kinetic energy levels (
) or partitioning of available
energy between ‘
’ and kinetic energy or ‘
’.
46
This necessity for increased carbon dioxide can be met from two sources, oxidation of carbon
or oxidation energy, and glycolysis of glucose /glycogen, to produce carbon dioxide without
involvement of oxygen. Oxidation and glycolysis are both necessary to maintain the necessary
level of carbon dioxide for the life process. Oxidation needs an effective level of oxidising
enzymes, while glycolysis requires a suitable supply of high energy phosphate bonds to supply
energy for combination with glucose and enable breakdown to triose phosphate as part of the
glycolytic reaction. The level of carbon dioxide concentration to maintain kinetic energy and cell
temperature needs both of these activities, and if either is limited carbon dioxide load is
inadequate, and the free energy for initiation and maintenance of genetic activity is inadequate,
and becomes replaced with oxygen load, with increased cell volume and numbers, and neoplasia.
If circulatory energy generation is proportional to ventricular diastolic fibre length cubed, and the
product of the respiratory gas concentrations are also proportional to ‘L’, it follows that the ratio
of carbon dioxide and oxygen concentrations (or vx) may also act as a key to indicate whether
vx will indicate the onset or reduction of the cell energy available to increase kinetic energy of
flow (tissue fluid momentum) as well as the energy to increase cell genetic activity, or the
increased effector cell energy diverted to increasing cell volume, so‘vx ‘indicates the retention
of cell energy to maintain cell function, compared with that given to cell volume, and leading to
eventual loss of function, and possible neoplasia.
If ‘L’ is proportional to diastolic ventricular muscle fibre length, and also proportional to the
product of carbon dioxide and oxygen concentrations, the effector cell permeability to respiratory
gases also becomes proportional to this relationship. The increase in effector cell volume is
proportional to cell oxygen, and any increase in cell oxygen level requires more energy, and less
energy is then available for active permeability.Active permeability is proportional to the volume
of fluid leaving the cell and the work it is able to perform. Increased cell energy is only possible
if oxygen concentration is restricted, and effector cell energy is then available for cell function,
movement of tissue fluid, and genetic activity in the cell proportional to carbon dioxide
concentration.Carbon dioxide load is proportional to carbon dioxide concentration and stroke
volume. The ratio of stroke volume / oxygen load must regulate stroke volume compared with
cell volume if cell activity and function is allowed to continue. Increase in ‘vx’, leads to
glyconeogenesis and removal of lactate concentration if cell ‘free’ energy (heat) is available and
associated with increased momentum in tissue fluid. Extra cell energy then leads to energy
storage as glyconeogenesis, and allows stroke volume to increase compared with oxygen load.
The concentrations of oxygen and carbon dioxide are the essential factors in provision of cell
energy in both ventricular muscle and effector cells.When oxygen concentration is adequate to
maintain the viability of effector cells, this concentration must remain at a constant value, and
the required energy is then proportional to carbon dioxide concentration cubed, and so this
represents the energy produced by glycolysis to maintain circulatory energy at an adequate level.
If pulse rate is not sufficient, ventricular energy can only be maintained by increase in oxygen
load and concentration, and can only be reduced if carbon dioxide is increased to maintain energy
production. When pulse rate and carbon dioxide concentration are sufficient or in excess, energy
is removed from the circulation by glyconeogenesis with carbon dioxide increased instead of
oxygen, and increasing stroke volume, and effector cell temperature to increase ‘vx’ and tissue
fluid momentum. There is reduced effector cell work capacity and reduced cell volume, with cell
energy used to increase cell function (including genetic activity). If on the other hand energy is
directed to increasing cell volume with increased concentrations of lactate and oxygen, more
energy is directed to cell volume, and increased neoplasia, unless cell length becomes greater
47
compared with oxygen concentration and cell volume with the extra energy producing increased
systolic pressure..To maintain cell function requires increased ‘vx’ and ‘PR’, and tissue fluid
momentum, or greater ‘ ’ compared with oxygen concentration, and kinetic rather than potential
energy. The problem with increased oxygen concentration is the increased energy directed
towards increase in volume of effector cells, but loss of cell(& genetic) activity, and eventual
death. To prevent neoplasia needs increased cell free energy or heat, and increased ‘ ’ and ‘PR’,
as well as lactate concentration to reconvert energy to store.
Oxidation energy, representing energy released through oxidation of carbon to carbon dioxide,
and water from oxidation of hydrogen, is a main source of energy to maintain the circulation and
continuing life. However it is not sufficient on its own to maintain kinetic energy, and a
continuing circulation, which requires oxidation energy originally ‘stored as potential energy’,
and needing kinetic energy indicated as ‘vx’ to maintain fluid movement as linear velocity of
tissue fluid to be contributed as ‘carbon dioxide energy’ from glycolysis of glycogen, so kinetic
energy is produced through the product of ‘vx’ and ‘oxidation energy from energy first ‘stored’
as diastolic length in ‘effector cells’, as multiples of ‘L’, and ‘L.vx’, or pulse rate. Factors
indicating kinetic energy all appear as multiples of ‘vx’, and ‘L’, with ‘vx’ only produced as the
result of glycolysis, which then becomes essential to produce kinetic energy in the circulation in
association with energy of oxidation stored in effector cells. Glycolytic energy is only produced
from glycogen in the absence of oxygen, which requires oxidation energy to produce kinetic
energy of blood flow or other tissue fluids. It is necessary to maintain genetic activity through
activity of ‘vx’ , and it is only produced through glycolysis to maintain sufficient carbon dioxide
in relationship with oxygen concentration to provide genetic function.
For effector cell function there has to be sufficient energy present as ‘free energy’, or cell
temperature, proportional to ‘vx’, and linear velocity of tissue fluid. The ratio
or‘vx’
represents the free energy available from glycolysis, with carbon dioxide concentration increased
with respect to oxygen concentration, and proportional to ‘L.PR at cell level and
overall
(the product of free energy and momentum of tissue fluid).
Cell free energy is proportional to energy from glycolysis
while cell stored energy
, and overall energy
(equivalent to
or potential
energy times kinetic energy associated with glycolysis) the two sources of energy responsible
for kinetic energy, which is the product of the two.
If there is insufficient carbon dioxide produced from oxidation of carbon, it may be partly
replaced from glycolysis (i.e., kinetic energy), but if glycolysis should be inadequate for any
reason so that carbon dioxide is still inadequate, glyconeogenesis is not possible and the life
process is seriously interrupted, with oxygen load reduced as well as carbon dioxide load, and
heat production replaced by oxygen concentration and neoplasia in place of ‘vx’ concentration,
and genetic activity, with restriction of ‘L’, and cessation of the circulation as an end result.
A further factor ’L’ is usually produced by oxidation of carbon but appears as further kinetic
energy associated with movement of stroke volume through ventricular contraction, and total
kinetic energy then results from the product of ‘L times glycolytic energy to produce ‘L.
’&
to produce the kinetic energy present in tissue fluid. If ‘vx’ is reduced, effector cell free energy is
48
reduced compared with oxidation energy, or oxidation energy over glycolytic energy is ‘L’. If
oxidation energy over glycolytic energy is increased , it is by multiples of ‘L’, while if ‘L’ is
reduced compared with oxidation energy, cell functional energy falls . Any reduction in glycolysis
leads to reduced cell function (including genetic function) and results in increased cell volume
with increased oxygen concentration , leading to cell multiplication and ‘neoplasia’.
Neoplasia is then related to reduced glycolysis, and reduction of ‘L’, and reduced carbon dioxide
load or stroke volume. Restoration of stroke volume requires increased carbon dioxide
concentration compared with oxygen concentration, or increase in ‘vx’ with increased genetic
function as well as circulatory function. Alternatively it requires increased ‘L’ , and increased
‘L.PR’.
To reduce neoplasia needs increased ‘free energy’, glycolytic energy, and effector cell functional
activity to maintain genetic activity, and reduced cell volume. Neoplasia may result from reduced
‘L’, and /or ‘vx’(i.e., PR) or
increase in effector cells which increase in size and number but
lose much functional capacity in the process.
“Contractility”or ‘
i.e., the ratio ‘
’is the indicator of energy available for genetic activity in ‘effector cells’;
; or kinetic energy /cell energy store. “Contractility” is an indicator of the
liability for neoplastic change in functioning cells, and ‘active state’ is proportional to the ratio of
‘contractility / L’, while contractility is the product of ‘active state’ and ‘inotropic state’.
Circulatory activity can be best expressed as related to three levels of activity. Potential energy
is a function of multiples of ‘L’, the diastolic length of ventricular muscle fibres, while kinetic
energy is a function of multiples of pulse rate. There is another large energy accumulation
represented by ‘flywheel type’ energy that must be continually present in the circulation as
diastolic blood pressure equivalent to ‘v’, the velocity of diastolic blood flow; and total circulatory
energy is determined by values of ‘L’,’v’, & ‘PR’, and related to pulse pressure (i.e., proportional
to ‘v.L.PR’)with a total value of ‘
’, or three factors of ‘power developed by each of the
three dimensions of ventricular function for each heart beat’. This energy is distributed between
‘augmented stroke volume’, ‘the structure of the circulatory system as size and shape of blood
vessels proportional to Q.R’, and the glycolytic energy per beat , proportional to ‘
’, for a total
value of ‘Q.v.LPR’ times ‘RQ’, or ventricular filling, times ‘
’, or total of ‘
’,
equivalent to ‘
’per beat. This energy is produced by oxidation of carbon, or
, then
elevated to ‘ ’ by ‘L’ from kinetic energy (
or glycolytic energy
,times L from
ventricular contraction to produce stroke volume which is an essential element of kinetic energy).
Energy provided to the circulation by ventricular function depends on the diastolic length of
ventricular muscle fibres times multiples of pulse rate, and continued activity requires maintenance
of these parameters over the duration of the living state. ‘R’ or is produced by oxidation, while
oxidation and glycolysis each provide
(i.e., equivalent values)by different mechanisms. These
values need to remain equivalent with the same value of carbon dioxide concentrations for
adequate function of the circulation. If there is any alteration, adequate artificial replacement by
pacemaker is required to maintain normal activity, if the ratio ‘vx’ is to remain reasonably constant
49
with values of carbon dioxide and oxygen concentrations suitable to maintain kinetic energy from
the diastolic length of ventricular muscle fibres on the one hand and internal resistance to blood
flow and systemic blood volume on the other. Otherwise glycolytic energy and oxidation energy
from carbon residues become uneven and the loss of this balance alters the production of carbon
dioxide from each source. This leads to distortion of the gas ratio, and the relative production of
carbon dioxide by each process, as glycolysis and oxidation become uneven. It leads to altered
glucose levels from glycolysis, compared with that needed for oxidation of glucose, and this
becomes a likely cause for diabetes which is independent from that resulting from inactivity of the
pancreatic islets as an initial cause. It becomes a possible source for Type II diabetes, in some
individuals, because of inadequate oxidation of carbon, and accumulation of glucose as the
concentration following glycolysis exceeds that usually necessary for oxidation of pyruvate.
‘Active state’is proportional to the ratio of glycolytic energy / potential energy available at systole,
and increased glycolysis only becomes possible if there is an increase in the cube of pulse rate
compared with potential energy available at systole (the level of systolic pressure developed) and
this is proportional to
, equivalent to
or ‘active state’. Reduced active state implies
increased neoplastic change unless it is corrected by an increase in carbon dioxide concentration.
Usually this is a temporary increase in neoplasia only, and rapidly overcome as effector cell
function is improved with improved cell ‘maturity’. It becomes permanent if increased maturity
of cells is not possible because reduced carbon dioxide concentration becomes a permanent
reduction with a permanently reduced carbon dioxide level, and with reduced glyconeogenesis,
pulse rate, and tissue fluid momentum, and permanently raised concentration of blood glucose,
with raised value of ‘diastolic length of ventricular muscle fibres’ , but increased efficiency
(inotropic state).
Raised active state is required to increase effector cell pulse rate squared, with respect to ‘R.L’, or
, equivalent to
, or ‘contractility’ over ‘inotropic state’.and these are the conditions
necessary to maintain effector cell temperature (L.PR) and genetic activity, and inhibit increase
in effector cell volume and ‘neoplasia’. Increase in the ‘diastolic length of ventricular muscle
fibres’, or ‘L’, implies increase in ‘inotropic state’, with increased cell efficiency and arterial
pressure associated with permanently increased concentration of blood glucose from persistently
increased lactate concentration, and oxidative phosphorylation with facilitation of production of
glucose phosphate rather than increased carbon dioxide and pulse rate because of improved cell
mechanical efficiency and limited effector cell temperature and genetic activity.
Increase in contractility with respect to inotropic state can only be produced by increase in effector
cell temperature or cell heat (i.e., L.PR) essentially increase in PR with respect to L, or increase
in glycolytic energy with respect to inotropic state (effector cell efficiency) and increase in ‘active
state’ at the expense of ‘inotropic state’, and this is the required basis to maintain genetic function
and reduce effector cell volume and cell reproduction. Continuation of genetic function and
function of effector cells only persists while ‘active state’ is kept at a suitable level compared with
‘inotropic state’ in the circulation, to restrict the concentration of oxygen and effector cell volume,
and avoid increasing subacute‘oxygen toxicity’, leading to ‘neoplasia’.
50
If effector cell heat is not increased, there can be no increase in glycolytic energy because of
unaltered pulse rate, and no increase in pulse rate, because inotropic state is increased instead with
increase in oxygen partial pressure unless it is replaced by increase in lactate concentration and
systolic blood pressure (i.e., increased cell efficiency limiting the increase in oxygen concentration
and cell volume). Cell energy is limited by raised oxygen load as cell efficiency increases and
restricts effector cell volume by increasing diastolic fibre length of ventricular muscle, with
increased systolic blood pressure (and inotropic state instead) with increased lactate concentration
and oxidative phosphorylation in its place. There is increased oxygen load replacing that of carbon
dioxide load as efficiency increases, and increased ‘L’ rather than pulse rate. There is a limit to
the possible increase in inotropic state, so this is only a temporary adaptation until it can be
replaced by raised concentration of carbon dioxide in place of oxygen load, with rising effector
cell temperature as carbon dioxide concentration is increased. If no increase in carbon dioxide
load is possible, there is increased oxygen load through increase in effector cell length, or if this
cannot occur, an increase in oxygen concentration and effector cell volume and permanent
‘neoplasia’ becomes inevitable.
The condition of ‘neoplasia’ implies restriction of ‘0 ’, and / or ‘vx’ with increase in effector cell
volume, which becomes permanent with reduced effector cell temperature and pulse rate and
reduced ‘active state’. There is an increase in the number of immature effector cells which
continues unless prevented by an increase in pulse rate and carbon dioxide concentration to
increase cell maturity, function, and the restricted increase in effector cell volume.
Increased ‘active state’ requires an increase in contractility, and / or reduced ‘inotropic state’, with
improved genetic activity, and function of effector cells to inhibit neoplasia. Reduced ‘active state’
requires an increase in ‘inotropic state’, and / or oxygen concentration with reduced effector cell
function’ “Normal” cell function requires that active state and inotropic state are balanced to
maintain constant cell volume, and ‘vx’ (contractility) together with effector cell function, and
these are balanced by the temperature of effector cells and ratio of pulse rate squared over ‘R.L’,
or active state which is maintained.
Increasing ‘active state’ reduces the liklihood of neoplasia, which may instead be increased as the
level of ‘inotropic state’ (or L) i.e., efficiency becomes greater. If there is neoplasia, there is
reduced ‘active state’ as inotropic state increases (within limits) with reduced contractility
(
)and increased ‘L’, and cell efficiency. There is reduced cell and body temperature, and
reduced pulse rate (with hypopyrexia) compared with potential energy (systolic blood pressure)
and reduced glycolytic energy (
or reduced cell temperature).
Production of neoplasia requires reduced glycolytic energy and pulse rate, increased inotropic
state,. and / or ‘L’, but it is inhibited by increased body temperature and pulse rate, or PR / L
(i.e., ‘vx’). If PR is reduced and L increased it gives rise to neoplasia (L / vx), or reduced
‘contractility’ leads to neoplasia with an increased ratio of effector cell volume over pulse rate
(
) representing chronic oxygen toxicity. (Acute oxygen toxicity is represented by the
experiments detailed in Figure 22. with restriction of pulse rate with excessively increased heat
load, compared with chronic or subacute oxygen toxicity which may produce ‘neoplasia’,
unless PR squared over R is increased, to become equivalent to vx squared, or ‘contractility’.
The moderating effect of ‘inotropic state’ in increasing efficiency is overcome by the rapid
51
increase of oxygen load exceeding the capacity of ‘L’ to increase the adaptation of cell
efficiency at a sufficient rate.)
The variable production of [lactate] compared with pulse rate, and [creatine phosphate] results
from changes in oxygen concentration in effector cells, which increases effector cell volume
and lactate concentration if oxygen concentration increases, but which falls if carbon dioxide
concentration is increased, while that of oxygen is diminished, with restricted cell volume and
increased ‘active state’. So ‘active state’ increases in value compared with ‘inotropic state’ but
with increase in ‘contractility / ‘L’, and change in ‘vx’, and tissue fluid momentum, if pulse
rate and glycolytic energy is increased compared with systolic blood pressure and increased
potential energy from greater ventricular muscle fibre length, and ‘R.L.PR’.
‘
’is the oxidation energy produced in effector cells, and equal to
each ventricular dimension, and
, or L.PR for
, or maximal genetic function (while PR/L=vx or
minimal genetic function and cell activity proportional to cell temperature.) Maximal genetic
function is the greatest level of cell function and genetic function possible, and the ratio of
oxidation energy times pulse rate. (as the result of augmented stroke volume) and potential
energy at systole (=
, or
). If cell temperature is exceeded, with cell temperature >
, after including aigmented stroke volume, it results in heat exhaustion when effector cell
temperature is greater than
and
and glycolytic energy, which is maximal genetic work
capacity i.e., vx for each cardiac dimension and functional capacity of the heart.and necessary
for
(glycolytic energy) times PR (from augmented stroke volume) to be equivalent to
‘R.L.PR’ to prevent heat exhaustion, or a maximal increase of PR compared with potential
energy of effector cells (see Fig 15.1 to 15.4). .