Bronchial reactivity and intracellular magnesium

Transcription

Clinical Science (1998) 95, 137–142 (Printed in Great Britain)
Bronchial reactivity and intracellular
magnesium: a possible mechanism for the
bronchodilating effects of magnesium in asthma
Ligia J. DOMINGUEZ, Mario BARBAGALLO, Gabriele Di LORENZO, Agata DRAGO,
Santi SCOLA*, Giuseppina MORICI and Calogero CARUSO†
Istituto di Medicina Interna e Geriatria, Universita degli Studi di Palermo, Via del Vespro 141, 90127 Palermo, Italy, *ARNAS
Laboratorio Analisi Presidio Ospedaliero Civico e Benfratelli, Via Carmelo Lazzaro 2/A, 90100 Palermo, Italy, and †Servizio
Tipizzazione Tissutale Istituto di Patologia generale, Corso Tuckory 211, 90134 Palermo, Italy
1. Increased bronchial smooth muscle contractility with consequent bronchial hyperreactivity are
characteristic physiopathological events of asthma. Since magnesium intervenes in calcium
transport mechanisms and intracellular phosphorylation reactions, it constitutes an important
determinant of the contraction/relaxation state of bronchial smooth muscle. In the present study
we investigated the relationship between bronchial reactivity, assessed by methacholineprovocation test, and magnesium concentrations both at extracellular and intracellular levels
measured by spectrophotometry. Twenty-two patients with mild-to-moderate asthma and 38
non-asthmatic subjects with allergic rhinitis (24 allergic to Parietaria pollen and 14 allergic to
Grass pollen) were recruited to the study. Exclusion criteria included renal failure, hepatic
diseases, heart failure and arterial hypertension.
2. The salient finding of our study is that there is a strong positive correlation between bronchial
reactivity and the level of intracellular magnesium (r ¯ 0.72, P ! 0.0001), both when the groups
are analysed separately or together. Intracellular magnesium concentrations in the group of
patients with asthma were significantly lower (1.8³0.01 mmol/l ; n ¯ 22) when compared with
levels in rhinitis subjects allergic to Parietaria (1.9³0.01 mmol/l ; n ¯ 24, P ! 0.05), and with
levels in rhinitis subjects allergic to Grass pollen (2.0³0.03 mmol/l ; n ¯ 14, P ! 0.05). Serum
levels of the ion were similar in all groups.
3. We conclude that the level of intracellular magnesium may be an important determinant of
bronchial hyperreactivity, as supported by the significant positive correlation between these
two parameters in allergic patients with known bronchial hyperresponsiveness. This finding, in
addition to reports of the bronchodilating effects of magnesium administration in patients with
asthma, confirms the proposed role of this ion in the pathogenesis and treatment of asthma.
INTRODUCTION
Magnesium is closely involved in numerous important
biochemical reactions in the body, particularly those
processes that entail the formation and utilization of ATP
[1]. As a cofactor of over 300 intracellular enzymic
reactions utilizing high-energy phosphate bonds, magnesium has been implicated in smooth muscle contraction
Key words : asthma, bronchial hyperreactivity, bronchial smooth muscle, intracellular ions, magnesium.
Abbreviations : FEV , forced expiratory volume in 1.0 s ; PC, provocative concentration.
".!
Correspondence : Dr Gabriele Di Lorenzo.
# 1998 The Biochemical Society and the Medical Research Society
137
138
L. J. Dominguez and others
[1,2]. In fact, magnesium is a cation with modulatory
effects on the contractile state of smooth muscle cells in
various tissues : hypomagnesaemia leads to contraction [3,4] and hypermagnesaemia leads to relaxation
[5,6].
Magnesium has been shown to relax bronchial
smooth muscle in vitro [2] and to bronchodilate
asthmatic airways in vivo [7,8]. Potential mechanisms
for the direct relaxing effects of magnesium on
bronchial smooth muscle include calcium channel
blocking properties [9–11], inhibition of cholinergic
neuromuscular transmission with decreased sensibility
to the depolarizing action of acetylcholine [12,13],
stabilization of mast cells and T-lymphocytes [14,15],
and stimulation of nitric oxide [16] and prostacyclin
[17].
On the basis of the critical role of magnesium in the
regulation of bronchial smooth muscle cell contractility
via effects on calcium transport activation, calcium
cellular content, and phosphorylation}dephosphorylation intracellular reactions, it has been proposed that the
intracellular magnesium level may determine the excitability of these cells [1,2]. Magnesium deficiency, either
absolute or relative, may then lead to an increased
excitability of bronchial smooth muscle with a consequent bronchoconstriction [13]. In accordance with this
hypothesis, Britton et al. [18] demonstrated that dietary
magnesium intake is independently related to lung
function and to the occurrence of airway hyperreactivity,
suggesting that a low magnesium intake may be involved
in the aetiology of asthma.
Additionally, current clinical data have demonstrated a
bronchial myorelaxant action of magnesium sulphate
administration during bronchospasm [7,8,19–22]. The
cellular mechanisms responsible for this bronchodilation
remain to be elucidated but may involve bronchial
smooth muscle relaxation similar to magnesium’s effects
on vascular smooth muscle via calcium antagonism [9–11]
or some other mechanism [12–16].
We have recently demonstrated that subjects with
rhinitis allergic to Parietaria pollen may have methacholine-provocation test values in the asthmatic range,
and are at higher risk of developing non-specific bronchial hyperresponsiveness when compared with subjects
allergic to Grass pollen who exhibit methacholine test
values in the normal range [23].
The purpose of this study was to investigate the
relationship between non-specific bronchial reactivity
and the level of magnesium, both at an intracellular level
and in the serum, in three groups of subjects : (a) asthmatic
patients with known bronchial hyperresponsiveness ; (b)
patients with rhinitis allergic to Parietaria pollen, who
may have normal or compromised bronchial responsiveness ; and (c) patients with rhinitis allergic to Grass
pollen, who have normal bronchial responsiveness to
methacholine [23].
SUBJECTS AND METHODS
Subjects
We studied a total of 60 subjects, selected from the
ambulatory Allergy Clinic of the Istituto di Medicina
Interna e Geriatria from the University of Palermo.
Twenty-two subjects (mean age, 33.7³2.0 years ; male}
female, 4}18) had a confirmed diagnosis of mild-tomoderate asthma according to the American Thoracic
Society’s definitions of asthma [24]. These subjects had a
baseline forced expiratory volume in 1.0 s (FEV . ) of at
"!
least 80 % of the predicted value and a provocative
concentration of inhaled methacholine causing a 20 % fall
in FEV . (PC ) % 4 mg}ml. All patients with asthma
"!
#!
were allergic to Parietaria pollen, which is an Urticacea,
and the most important rhinitis-provoking plant in
Southern Europe [25]. In addition there were 24 subjects
with rhinitis allergic to Parietaria pollen (mean age,
33.9³1.9 years ; male}female, 7}17), and 14 subjects with
rhinitis allergic to Grass pollen (mean age, 27.7³1.4
years ; male}female, 3}11). The clinical characteristics of
the three groups are reported in Table 1.
The protocol was approved by the Ethics Committee
of the Istituto di Medicina Interna e Geriatria and was
conducted according to the guidelines of the Declaration
of Helsinki (1989). Informed consent was obtained from
each subject. Patients with renal failure, hepatic diseases,
heart failure or arterial hypertension were excluded from
the study. None of the patients was taking steroids,
calcium or diuretics. Bronchodilating therapy and antihistamines were discontinued 72 h before the provocation test with methacholine and blood sampling.
Lung function and non-specific bronchial
reactivity measurements
Bronchial hyperresponsiveness was evaluated with the
methacholine-stimulation test described by Chai et al.
[26] and used before in our laboratory [23,27]. FEV .
"!
was measured with a Gould 2400 automated system,
taking the highest of three successive measurements,
provided that the difference between measurements was
within 100 ml. All patients with asthma had a basal
FEV . of at least 80 % of the theoretical value. After
"!
baseline determination of FEV . , subjects inhaled five
"!
puffs of saline solution ; this diluent value was considered
as the control, and if the FEV . variations were within
"!
10 % of baseline, the patients were entered into the study.
Subjects were then asked to inhale increasing concentrations of methacholine, ranging from 16 to 5120 µg}ml,
administered with a MEFAR nebulizer (Markos, Monza,
Italy). FEV . was measured 90 s after each concentration
"!
step. The provocation test was terminated when FEV .
"!
fell by at least 20 % with respect to the baseline value
(PC ®FEV . ) or when a maximum cumulative dose
#!
"!
had been given. Log-cumulative methacholine doses were
Intracellular magnesium in asthma
Table 1
Clinical data of patient groups studied
Values are means³S.E.M. Mgi, intracellular magnesium ; Mge, serum magnesium ; NS, not significant.
Patient group …
Age
FEV1.0
FEV1.0 (%)
Methacholine (mg/ml)
Mgi (mmol/l)
Mge (mmol/l)
Asthma
33.7³2.0
2.82³0.1
95.6³2.4
260.6³40
1.8³0.01
0.9³0.03
Rhinitis
Parietaria
Grass
P
33.9³2.0
3.05³0.1
101.8³2.4
1470.8³73
1.9³0.01
0.9³0.02
27.7³1.4
3.32³0.1
98.7³1.5
2028.6³56.9
2.028³0.04
1.016³0.01
NS
! 0.05
! 0.05
! 0.01
! 0.05
NS
plotted against FEV . to obtain the methacholine PC
"!
#!
value by linear interpolation.
Magnesium measurements
After overnight fasting a blood sample was collected
from each subject into tubes containing heparin. Erythrocyte intracellular magnesium levels were determined
according to the method described by Paolisso et al. [28].
Briefly, erythrocytes were isolated by centrifugation
(5000 r.p.m. for 15 min) and the precipitate was washed
three times with an isotonic saline solution (150 mmol}l
NaCl). Cells were counted to normalize samples, and
were then lysed osmotically by the addition of deionized
water, allowing the solution to stand for 30 min. After
this the solution was centrifuged and the supernatant
used for magnesium determinations. Serum and erythrocyte magnesium concentrations were measured by
atomic absorption spectrophotometry (Cobas DP25).
All assays were performed in duplicate.
Statistical analysis
The results are expressed as means³S.E.M. One-way
analysis of variance with appropriate post hoc test for
multiple group comparisons was performed. To evaluate
the relationship between specific bronchial reactivity,
intracellular and extracellular magnesium concentrations,
we calculated Spearman’s correlation coefficients, utilizing SPSS 6.0 software. A P value % 0.05 was considered
statistically significant.
RESULTS
Basal FEV . , percentage FEV . and methacholine con"!
"!
centrations (PC ®FEV . ) for both asthmatic and rhini#!
"!
tic subjects are shown in Table 1.
Intracellular magnesium levels were significantly lower
in patients with asthma (1.8³0.01 mmol}l) compared
with the levels in patients with allergic rhinitis Parietariasensitive (1.9³0.01 mmol}l ; P ! 0.05) and in patients
with subjects with Grass-sensitive allergic rhinitis
Figure 1 Individual intracellular magnesium (Mgi) values in
patients with asthma (E ) (n ¯ 22), Parietaria-sensitive
allergic rhinitis (_) (n ¯ 24) and Grass pollen-sensitive
allergic rhinitis (^) (n ¯ 14)
Mean values are given in Table 1.
(2.028³0.04 mmol}l ; P ! 0.05) (Table 1 and Figure 1).
Serum magnesium levels were comparable in all groups
(Table 1) and within the normal range [1].
Looking at the relationship among the different variables, we found a highly significant correlation between
intra-erythrocytic magnesium and the response to inhaled methacholine (PC ®FEV . ) in the three groups
#!
"!
of subjects studied when analysed together (r ¯ 72, P !
0.0001) or separately (asthma : r ¯ 0.80, P ! 0.0001 ;
Parietaria-sensitive rhinitis : r ¯ 42.2, P ! 0.05 ; Grasssensitive rhinitis : r ¯ 83.6, P ¯ 0.0002) (Figure 2). The
relation between serum magnesium and PC ®FEV .
#!
"!
was not statistically significant for all groups (P " 0.05).
FEV . and intracellular magnesium were not correlated
"!
in subjects with asthma(P " 0.05).
DISCUSSION
Magnesium’s role in asthma was first suggested by
anecdotal reports of favourable effects of magnesium
sulphate administration in acute exacerbations of asthma
139
140
Figure 2 Relation of intracellular magnesium (Mgi) levels to
methacholine-induced bronchial reactivity (PC20®FEV 1.0, in
µm/ml) in patients with asthma (E) (n ¯ 22 ; r ¯ 0.80, P !
0.0001), Parietaria-sensitive allergic rhinitis (_) (n ¯ 24 ;
r ¯ 42.2, P ! 0.05) and Grass pollen-sensitive allergic rhinitis
(*) (n ¯ 14 ; r ¯ 83.6, P ¯ 0.0002)
As shown in the graph, there is a positive significant and continuous correlation
between these two parameters in all the patients (n ¯ 60 ; r ¯ 0.72, P !
0.0001).
over 50 years ago [29,30]. Later, Durlach [14] reported a
reduction in serum magnesium levels during the acute
attack of asthma. More recently, the possible role of
magnesium in the pathogenesis of bronchial constriction
as well as in its treatment has regained considerable
attention, particularly because of several reports confirming positive results of magnesium administration in
acute airway constriction [7,8,19–22,31], although some
studies have reported negative results [32–37]. Even in
the absence of an acute exacerbation, the functional
pulmonary tests have been shown to improve with the
administration of intravenous magnesium [38], and
the action of magnesium appears to be additive to the
bronchodilating effect of the anti-asthmatic drugs terbutaline [39] and salbutamol [40]. However, the mechanism of these effects has not yet been clarified.
The processes of contraction and relaxation of the
myofibrillar proteins in bronchial smooth muscle cells
are the result of phosphorylation and dephosphorylation
reactions regulated by specific enzymes and by the
intracellular content of calcium [1,2]. Since bronchial
smooth muscle cells possess only one membrane system
and a scarce sarcoplasmic reticulum, calcium transport
across the cellular membrane is the most important
regulator of intracellular calcium content, which is mainly
attained by the action of a calcium}magnesium-dependent membrane ATPase, and by voltage and receptoroperated calcium channels [1].
The enzymes that regulate phosphorylation}dephosphorylation reactions are from two classes : protein
kinases and phosphoprotein phosphatases. The first
group includes myosin kinases which phosphorylate
myosin chains, and the second group includes myosin
phosphatases which dephosphorylate the light chains of
myosin. Myosin phosphatases are calcium-dependent
enzymes, whereas myosin kinases are magnesiumdependent enzymes [1,3]. Since magnesium is involved in
calcium transport across the cellular membrane [9–11],
which determines intracellular calcium content, both
types of enzymes are directly or indirectly influenced by
intracellular magnesium levels [1,3]. Such effects of
magnesium would be expected to result in relaxation of
bronchial smooth muscle and reduction of the airway
reactivity to inhaled bronchoconstrictor agents.
Our results demonstrate that in cells from patients
with asthma and from patients with rhinitis, the levels of
intracellular magnesium are directly and strongly related
in a continuous manner to the reactivity of the bronchial
airway, measured as the concentration of inhaled methacholine causing a 20 % fall in FEV . (PC ®FEV . ).
"!
#!
"!
Erythrocytes provide a feasible experimental model that
has been demonstrated to allow repeatable and accurate
measurements of intracellular ions [28,41,42]. In agreement with our findings are reports demonstrating that
magnesium administration specifically reduces methacholine- and histamine-induced bronchoconstriction in
patients with asthma [43,44]. This relation may also help
explain the favourable action of magnesium supplementation during acute asthma attacks. Although the intracellular and serum levels of magnesium in all the
patients were in the normal range, we found a significantly lower level of intracellular magnesium in patients
with asthma when compared with cells obtained from the
non-asthmatic subjects with allergic rhinitis. Interestingly, Parietaria-sensitive patients, who have been demonstrated to be at higher risk of non-specific bronchial
hyperresponsiveness [23], had an intermediate magnesium level compared with those of asthmatic and those
of Grass-sensitive patients, who have normal bronchial
responsiveness [23]. This parallels the continuous relation
of PC ®FEV . and intracellular magnesium in the
#!
"!
three groups of subjects. Thus we cannot exclude the
possibility that a relative intracellular magnesium deficit
may contribute to the bronchial hyperreactivity characteristic of patients with asthma. As such, a relative
intracellular magnesium deficiency in asthma may favour
the movement of calcium to inside the smooth muscle
cell, leading to a potentiation of myosin phosphorylation
and rendering the cell more contractile. On the other
hand, magnesium may determine the sensitivity of the
bronchial smooth muscle to acetylcholine. An excess of
magnesium may decrease the depolarizing action of
acetylcholine, resulting in a depressed excitability of the
bronchial smooth muscle cells.
Since magnesium is predominantly an intracellular ion,
and there is a concentration gradient between the extraand intra-cellular compartments [1], serum levels of
magnesium may not reflect intracellular magnesium
content. The apparent lack of correlation between levels
Intracellular magnesium in asthma
of serum and tissue magnesium makes it difficult to
interpret their relationship. Further, considering only
magnesium levels in the serum, it is possible to overlook
an intracellular hypomagnesaemia [3], which may correspond to a true reduction in total body stores of the ion.
In fact, and in agreement with our results regarding
serum magnesium levels, Falkner et al. [45] found no
difference in this parameter in patients with asthma
during acute exacerbation compared with a non-asthmatic population. They concluded that serum magnesium
measurements are not clinically useful for predicting the
severity of the attack, nor are they predictive of the
response to magnesium infusion [45].
Regarding the role of magnesium as a determinant of
bronchial hyperreactivity, an interesting study by Britton
et al. [18] demonstrated significant positive independent
associations of dietary magnesium intake with lung
function, airway reactivity to inhaled methacholine and
respiratory symptoms (wheezing) in the general population. Since most of the magnesium present in food is
lost in cooking or refining, diets that provide a high
proportion of daily energy requirements from refined or
processed foods are likely to be low in magnesium [46].
Unfortunately, in Westernized countries processed food
accounts for a substantial proportion of the diet, which
increases the likelihood of true or relative magnesium
deficiency [13]. This deficit in body magnesium may
contribute to an increased contractility of smooth muscle
in several organs and tissues like the vascular wall,
inducing vasoconstriction, and producing bronchoconstriction in the bronchial smooth muscle cells [1,3,47].
It is noteworthy that some of the medications used in
the treatment of asthma may affect the metabolism of
magnesium, either directly or indirectly by affecting the
metabolism of calcium, sodium or other ions. As such, it
has been observed that theophylline given intravenously
during asthma attacks increased total mean urinary
excretion of magnesium, calcium and sodium [48].
However, in another study evaluating the effects of longterm oral β -agonists on magnesium and potassium levels
#
in skeletal muscle biopsies, there was no significant
difference between the measurements of the ions before
and after 2 months of oral therapy. It is noteworthy that
skeletal muscle magnesium in the patients with asthma
was lower both before and after the therapy when
compared with the non-asthmatic controls [49].
This is the first report relating intracellular magnesium
concentrations and bronchial reactivity. Although a
magnesium depletion during asthma attacks was first
suggested [14], a recent report did not find any difference
in intracellular magnesium concentrations between
patients with asthma and normal controls [50]. In another
study, Fantidis et al. [51] demonstrated a decreased
magnesium content in polymorphonuclear cells from
patients with asthma in resting conditions, between acute
attacks. Although it is not easy to reconcile these
contrasting results, a possible explanation for the differences observed is that most of these studies included
subjects with dissimilar age ranges, which probably
makes them incomparable, since intracellular magnesium
varies substantially with age [52]. Nevertheless, our data
clearly demonstrate that the intracellular content of
magnesium is significantly and continuously connected
to bronchial reactivity.
In conclusion, the strong relationship between intracellular magnesium levels and methacholine bronchial
reactivity suggests that magnesium alterations may play a
role in the pathogenesis of asthma bronchoconstriction
and may help explain the favourable effects demonstrated
after magnesium administration in patients with asthma.
ACKNOWLEDGMENT
This work was supported by a grant from Ministero
dell’Universita' e della Ricerca Scientifica e Tecnologica
(60 %) to G. D. L.
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Received 11 February 1998; accepted 26 March 1998

Bronchial reactivity and intracellular magnesium

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