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Cardiovascular Research 2002 54(3):568-575; doi:10.1016/S0008-6363(02)00253-5
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Copyright © 2002, European Society of Cardiology

Magnesium reduces myocardial infarct size via enhancement of adenosine mechanism in rabbits

Tomoyuki Matsusaka, Naoyuki Hasebe*, Yin-Tie Jin, Junichi Kawabe and Kenjiro Kikuchi

First Department of Internal Medicine, Asahikawa Medical College, 2-1-1-1 Midorigaokahigashi, Asahikawa, Hokkaido 078-8510, Japan

haselove{at}asahikawa-med.ac.jp

* Corresponding author. Tel.: +81-166-68-2442; fax: +81-166-68-2449

Received 13 August 2001; accepted 8 January 2002


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objectives: Clinical impact of magnesium (Mg) therapy remains controversial in acute myocardial infarction. We investigated the infarct size limiting effects of Mg and its mechanism in rabbits. Methods: Anesthetized rabbits underwent 30 min coronary occlusion and 3 h reperfusion in ten groups: (1) Control, (2) Low Mg, (3) Mg, (4) High Mg, (5) calcium (Ca), (6) Mg+Ca, (7) 8-phenyltheophylline (8PT), an adenosine receptor blockade, (8) 8PT+Mg, (9) {alpha}, β-methylene-adenosine diphosphate (AOPCP), a selective inhibitor of ecto-5'-nucleotidase, and (10) AOPCP+Mg groups. Infract size (IS) to area at risk (AR) was measured by triphenyltetrazorium chloride method. Results: The IS/AR ratio was significantly smaller in Mg, 27±3% (P<0.05) and High Mg, 24±2% (P<0.05) compared to Control, 50±3% and Low Mg, 42±4%. The IS limiting effects of Mg were abolished in 8PT+Mg, AOPCP+Mg and Mg+Ca. The IS/AR ratio correlated with neither rate-pressure products nor incidence of arrhythmia. Conclusion: Magnesium administration has an infarct size limiting effect independent of its effects on myocardial oxygen consumption and incidence of arrhythmia in rabbits. The infarct size limiting effect of magnesium is attributable, at least in part, to augmentation of adenosine mechanism.

KEYWORDS Adenosine; Calcium (cellular); Infarction; Ischemia; Reperfusion


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
Clinical application of magnesium remains controversial in acute myocardial infarction. Magnesium therapy has been reported to reduce mortality in acute myocardial infarction in Leicester Intravenous Magnesium Intervention Trial 2 (LIMIT-2) [1]. However, it could not demonstrate significant effect on mortality in International Study of Infarct Survival 4 (ISIS-4) [2]. Despite these conflicting results, several previous reports of experimental myocardial infarction have suggested that magnesium treatment is potentially effective to reduce ventricular arrhythmias [3,4], to reduce infarct size in dogs [5], in rats [6] and in pigs [7]. However the mechanism of its efficacy is still not fully understood.

Adenosine is a major cardioprotective substance in ischemia. Ischemic myocardium is salvaged by administration of adenosine [8] or by inhibition of adenosine breakdown [9]. The main pathway of adenosine synthesis in ischemic myocardium is decomposition of adenosine monophosphate by ecto-5'-nucleotidase [10,11]. Interestingly, magnesium is an important co-factor of 5'-nucleotidase [12]. Therefore we hypothesized that magnesium potentiates 5'-nucleotidase activity and protects ischemic myocardium.

Magnesium is known as a natural calcium antagonist [13], and calcium mediates the major mechanism of ischemia-reperfusion myocardial damage. Thus, we hypothesized that cardioprotective effects of magnesium is attributable, at least in part, to its calcium antagonistic action.

The objectives of the present study were to determine whether magnesium administration limits the infarct size in acute myocardial infarction in rabbits, and if so, whether the mechanism is mediated by adenosine or by magnesium–calcium interaction. To accomplish these goals, we tested the effect of magnesium administration with or without adenosine receptor antagonist, inhibitor of ecto-5'-nucleotidase and exogenous calcium infusion in experimental acute myocardial infarction in rabbits.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
2.1 Animal model
Japanese white male rabbits weighing 2.5–3.5 kg were anesthetized by an intravenous sodium pentobarbital, 30 mg/kg, intubated with an endotracheal tube and connected to a respirator (Model SN-460-6, Shinano, Japan) with 100% oxygen. Left thoracotomy was performed in the fourth intercostal space and the heart was exposed. A 4.0 silk thread with taper needle was passed around the large branch of left circumflex coronary artery. The end of silk was threaded through a small vinyl tube to make a snare for coronary artery occlusion. Myocardial ischemia was confirmed by ST segment elevation of electrocardiogram and regional cyanosis. A polyethylene catheter was inserted into carotid artery for blood sampling and continuous monitoring of aortic blood pressure by a pressure transducer (AP-601G, Nihon-Kohden, Japan). Another polyethylene catheter was inserted into jugular vein for infusing agents tested. Electrocardiogram was monitored continuously throughout the experiment (AC-610G, Nihon-Kohden, Japan). All data were recorded by a data analysis system (Mac Lab/8e, AD instruments, USA) and analyzed by a personal computer.

The present study was reviewed and approved by the Committee of the Ethics on Animal Experiments in Asahikawa Medical College and according to The Law (No. 105) and Notification (No. 6) of the Japanese Government.

2.2 Experimental protocols
The experimental protocol was summarized in Fig. 1. The rabbits were assigned to ten groups and underwent 30 min coronary artery occlusion (CAO) and 180 min reperfusion (CAR).


Figure 1
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  		Fig. 1 Experimental protocols. Control rabbits (n=7) underwent 30 min coronary artery occlusion (CAO) and 180 min coronary artery reperfusion (CAR). Mg group (n=10) was pre-treated with magnesium sulfate (1 mg/kg per min) before CAO, followed by maintaining dose (0.14 mg/kg per min) throughout CAR. High Mg group (n=5); 7.5 and 1 mg/kg per min, Low Mg group (n=5); 0.14 and 0.02 mg/kg per min. Ca group (n=5); 0.8 mg/kg per min of calcium dichloride followed by maintaining dose of 0.1 mg/kg/min. Mg+Ca group (n=5) was treated with Mg and Ca. 8-phenyltheophylline (8PT) group (n=5) received 8PT (1 mg/kg bolus i.v.) 25 min before CAO. 8PT+Mg group (n=7) was treated with Mg and 8PT. {alpha}, β-methylene-adenosine diphosphate (AOPCP) group (n=5) received AOPCP (0.75 mg/kg per min) before and during CAO. AOPCP+Mg group (n=5) was treated with AOPCP and Mg. PS, physiological saline; IS/AR, measurement of ratios of infarct size (IS) to area at risk (AR).

 
(1): Control group (n=7) underwent CAO and CAR with physiological saline (PS) infusion. (2): Low magnesium group (Low Mg group, n=5) was pre-treated with magnesium sulfate infusion (0.14 mg/kg per min, 30 min) before CAO and maintained during CAO and CAR (0.02 mg/kg per min, 210 min). (3): Magnesium group (Mg group, n=10) was pre-treated with magnesium sulfate infusion (1 mg/kg per min, 30 min) before CAO and maintained during CAO and CAR (0.14 mg/kg per min, 210 min). (4): High magnesium group (High Mg group, n=5) was pre-treated with magnesium sulfate infusion (7.5 mg/kg per min, 30 min) before CAO and maintained during CAO and CAR (1 mg/kg per min, 210 min). (5): Calcium group (Ca group, n=5) was pre-treated with calcium chloride infusion (0.8 mg/kg per min, 30 min) before CAO and maintained during CAO and CAR (0.11 mg/kg per min, 210 min). (6): Magnesium and calcium group (Mg+Ca group, n=5) was simultaneously given magnesium and calcium as described above. (7): 8-phenyl theophylline (8PT; Sigma USA), a non-selective adenosine receptor antagonist [16] group (8PT group, n=5) received 8PT (1 mg/kg bolus i.v.) 25 min before CAO. (8): 8PT and magnesium group (8PT+Mg group, n=7) was given both 8PT and magnesium solution. (9): {alpha}, β-methylene-adenosine diphospate (AOPCP; Sigma USA), a selective inhibitor of ecto-5'-nucleotidase [10,11] group (AOPCP group, n=5) received AOPCP (0.75 mg/kg per min [17], from 30 min before CAO and during CAO), and (10) AOPCP+Mg group was given AOPCP and magnesium solution.

We chose 1 mg/kg per min of MgSO4 infusion as the initial dose in Mg group. This dose is comparable with the clinical use of magnesium [14,15], particularly with the protocol of LIMIT-2 [1] and ISIS-4 [2], i.e. the initial dose of 8 mmol magnesium followed by the maintaining dose of 2.7 mmol/h in LIMIT-2 and 3 mmol/h in ISIS-4. The initial dose of 1 mg/kg per min of MgSO4 and maintaining dose of 0.14 mg/kg per min in Mg group were convertible into approximately 8 mmol of initial dose followed by 2.7 mmol/h of maintaining dose for 67 kg body weight of human. In pilot experiments, we tested dose–responses in hemodynamics with MgSO4 infusion. The rate-pressure product, an index of myocardial oxygen consumption, was slightly but significantly decreased by 7.5 mg/kg per min or greater doses of magnesium infusion. Therefore, we chose 7.5 mg/kg per min of magnesium for 30 min as the initial dose of High Mg group, and the equal total amount of magnesium was administered in the following 210 min, i.e. at 1 mg/kg per min as the maintaining dose, which was an identical infusion rate with the initial dose of Mg group. Similarly, we chose 0.14 mg/kg per min of magnesium as the initial dose of Low Mg group, which was an identical infusion rate with the maintaining dose of Mg group.

Large dose of calcium infusion produces positive inotropic response [18]. Therefore, we chose an initial infusion of 0.8 mg/kg per min followed by a maintaining dose of 0.11 mg/kg/min of calcium chloride, which was an identical molar dose to magnesium of Mg group. In the preliminary study, we confirmed these doses of calcium chloride did not significantly affect hemodynamics.

2.3 Analysis of infarct size and area at risk
After 180 min of CAR, rabbits were heparinized (2000 U i.v.) and killed with a lethal dose of pentobarbital. The excised heart was mounted on a Langendorff apparatus and perfused at 60 mmHg with saline for 30 s to wash out blood. The coronary snare was retightened and Evans blue solution (0.1%) was infused to determine the area at risk. The heart was cut into 3 mm transverse slices and incubated in 1% solution of triphenyltetrazolium chloride (TTC) in pH 7.4 sodium phosphate buffer for 20 min at 37 °C. Area at non-risk was stained blue. Normal myocardium in area at risk (AR) was turned bright red and infarct myocardium in AR was turned pale gray. The areas were determined on each slice by a planimetry method. The actual sizes or volumes of infarcts (IS) and AR in each slice were obtained by multiplying the slice thickness by the measured areas and then calculated IS/AR ratio in each heart.

2.4 Blood gas analysis and serum ionized Mg2+ and Ca2+ measurement
Blood samples were collected through a catheter inserted into carotid artery. The sample was quickly sealed in a heparin-coated syringe, and promptly analyzed. Blood gas was checked with a blood gas analyzer (Model 850, CIBA CORNING, Japan). Serum Mg2+ was measured with ionized Mg2+ analyzer at pH 7.4 (NOVA CRT8, NOVA biomedical, USA). Serum Ca2+ was measured with ionized Ca2+ analyzer (ICA2, Radiometer, Denmark).

2.5 Effects of magnesium on myocardial ecto-5'-nucleotidase activity
The ecto-5'-nucleotidase was extracted from rabbit myocardium according to the method previously reported by Kitakaze et al. [11], and its activity was assessed by the enzymatic assay technique [19]. The amount of extracted ecto-5'-nucleotidase was corrected by the amount of protein, measured by the method of Lowry et al. [20]. The extracted ecto-5'-nucleotidase, AMP, and 1 to 100 mmol/l of magnesium solution were mixed in vitro and incubated in pH 7.4 buffer for 15 min at 37 °C. AMP was decomposed into adenosine and free phosphate (Pi+) by 5'-nucleotidase. Thus, the activity of ecto-5'-nucleotidase was assessed as the amount of Pi+, which was produced theoretically in an equal molar amount to adenosine by decomposing AMP. The amount of Pi+ was measured by molybdate spectrophotometric assay.

2.6 Statistical analysis
All values were expressed as mean±S.E., except for serum Mg2+ and Ca2+ levels as mean±S.D. Repeated-measures ANOVA was used for comparisons between baseline and subsequent values. For infarct size data, one-way ANOVA was used to determine whether there were differences among the seven groups. A value of P<0.05 was considered statistically significant.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
3.1 Hemodynamic data
Table 1 summarizes the changes in rate-pressure product, an index of myocardial oxygen consumption obtained by multiplying systolic arterial blood pressure and heart rate of each group. The rate-pressure products were comparable in all experimental groups under the baseline conditions. They were not significantly affected by the pretreatment with any agents except for a high dose of magnesium and AOPCP infusion. In High Mg group, the rate-pressure product was significantly decreased compared to the baseline level, and to the levels in Control group after 30 min of high dose magnesium infusion. In AOPCP and AOPCP+Mg groups, the rate-pressure product was significantly decreased after 30 min of AOPCP infusion, i.e. at CAO 0 min. However, they were gradually retrieved after stopping infusion, and no significant differences were observed at CAR 60 min compared with Control group. The rate-pressure products were gradually decreased in all groups as time elapsed, however, it was prominent in High Mg group compared to the Control group (P<0.05).


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  		Table 1 Changes in rate-pressure products

 
3.2 Infarct size
There were no significant differences in AR (cm3) among ten groups (0.93±0.08 in Control, 0.87±0.12 in Low Mg, 0.90±0.07 in Mg, 0.86±0.10 in High Mg, 1.01±0.11 in Ca, 0.92±0.12 in Ca+Mg, 0.83±0.10 in 8PT, 0.88±0.07 in 8PT+Mg, 1.02±0.12 in AOPCP, 0.90±0.11 in AOPCP+Mg). The IS/AR ratios of all groups were summarized in Fig. 2. The IS/AR ratio in Control group was 50±3%. It was significantly smaller in Mg group, 27±3% (P<0.05) and in High Mg group, 24±2% (P<0.05), but not in Low Mg group, 42±4% compared to the Control group. The IS/AR ratios were not significantly different in Ca group, 49±4% and Mg+Ca group, 38±4%, in 8PT group, 49±4% and 8PT+Mg group, 42±4% as well as in AOPCP group, 50±4% and AOPCP+Mg group, 41±4% compared to the Control group.


Figure 2
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  		Fig. 2 Ratios of infarct size to area at risk (IS/AR) in each group. The %IS/AR was significantly suppressed in Mg and High Mg groups, but not in Low Mg group compared to Control group. In Ca, 8PT and AOPCP groups, %IS/AR were not affected by the treatment with each agent, however, the infarct size limiting effects of Mg were abolished by the pretreatment with Ca, 8PT and AOPCP. Values are given as mean±S.E. *P<0.05 vs. control.

 
3.3 Arrhythmias
The incidence of arrhythmia was assessed by the sum of numbers of arrhythmia at six time points for 1 min each: just before CAO, 10 min after CAO, just before CAR, 10 min after CAR, 60 min after CAR and 180 min after CAR. In all groups, arrhythmias were similarly and frequently observed at the early phase of CAO and CAR. There were no significant differences in the incidence of arrhythmias among groups. The incidence of arrhythmia was 19±3 beats/min (bpm) in Mg group, 15±6 bpm in High Mg group and 17±5 bpm in Low Mg group, which were not significantly different from 20±7 bpm in Control group.

3.4 Relationship between infarct size and rate-pressure products, or incidence of arrhythmia
The infarct size and rate-pressure products in Control, Low Mg, Mg and High Mg groups are plotted in Fig. 3. High Mg group showed relatively smaller infarct size and lower rate-pressure products. However, there was no significant relationship between infarct size and rate-pressure products in four groups. The infarct size and incidence of arrhythmia in Control, Low Mg, Mg and High Mg groups are plotted in Fig. 4. There was no significant relationship between infarct size and incidence of arrhythmia.


Figure 3
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  		Fig. 3 Scatter plots of rate-pressure products (x103 mmHg/min) vs. ratios of infarct size to area at risk (%IS/AR) in Control and magnesium treated groups. There were no significant relationships between the two parameters. Control ({diamondsuit}, n=7), Low Mg ({circ}, n=5), Mg ({square}, n=10) and High Mg (bullet, n=5) groups.

 

Figure 4
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  		Fig. 4 Scatter plots of incidence of arrhythmia vs. ratios of infarct size to area at risk (%IS/AR) in Control and magnesium treated groups. The incidence of arrhythmia was compared by summing up numbers of arrhythmia at six points for 1 min each, just before CAO, 10 min after CAO, just before CAR, 10 min after CAR, 60 min after CAR and 180 min after CAR. There were no significant relationships between the two parameters. Control ({diamondsuit}, n=7), Low Mg ({circ}, n=5), Mg ({square}, n=10) and High Mg (bullet, n=5) groups.

 
3.5 Effects of magnesium on myocardial ecto-5'-nucleotidase activity
The changes in Pi+ levels in the assay system, reflecting the activity of ecto-5'-nucleotidase was summarized in Fig. 5. Magnesium increased Pi+ levels, which was produced theoretically in an equal molar amount to adenosine by decomposing AMP, in a dose-dependent fashion. It suggested that magnesium potentially enhances ecto-5'-nucleotidase activity and increases production of adenosine in rabbit myocardium.


Figure 5
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  		Fig. 5 Magnesium and ecto-5'-nucleotidase activity in rabbit myocardium. The extracted ecto-5'-nucleotidase, AMP, and 1 to 500 mmol/l of magnesium solution were mixed and incubated in pH 7.4 buffer for 15 min at 37 °C. Magnesium increased Pi+ levels, which was produced theoretically in an equal molar amount to adenosine by decomposing AMP, in a dose-dependent fashion. It suggested that magnesium potentially enhances ecto-5'-nucleotidase activity and increases production of adenosine in rabbit myocardium.

 
3.6 Serum Mg2+ and Ca2+ levels
The changes in serum ionized Mg2+ and Ca2+ levels are summarized in Table 2. In Control group, serum Mg2+ and Ca2+ levels were not significantly changed throughout the experiment. In Low Mg, Mg and High Mg groups, after the pre-treatment with magnesium, serum Mg2+ levels were significantly increased from 0.58±0.03 to 0.71±0.07 mmol/l just before CAO (at CAO 0 min) in Low Mg group (P<0.05), from 0.59±0.03 to 0.84±0.07 mmol/l (at CAO 0 min) in Mg group (P<0.05), and from 0.57±0.03 to 1.98±0.07 mmol/l (at CAO 0 min) in High Mg group (P<0.05). Serum Ca2+ level was not significantly affected by magnesium administration. After pretreatment with calcium, serum Ca2+ level was significantly increased from 1.59±0.11 to 1.77±0.14 mmol/l (at CAO 0 min) in Ca group (P<0.05). Mg2+ level was not significantly affected by calcium administration. In Mg+Ca group, serum Mg2+ and Ca2+ levels were both significantly increased (P<0.05).


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  		Table 2 Changes in serum ionized magnesium and calcium levels

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
This is the first report on the mechanism of infarct size limiting effect of magnesium in acute myocardial infarction. Magnesium administration demonstrated an infarct size limiting effect independent of its energy sparing and anti-arrhythmic effects in rabbits. This effect of magnesium was abolished by an adenosine receptor antagonist and an ecto-5'-nucleotidase inhibitor, suggesting that the effect is attributable, at least in part, to augmentation of adenosine mechanism.

The clinical application of magnesium in acute myocardial infarction remains controversial because of the conflicting results of previous clinical trials. In LIMIT-2, magnesium administration demonstrated the 24% reduction in the 28-days mortality rate [1]. However, in ISIS-4, magnesium administration did not show a significant effect on the mortality rate [2]. One of the reasons suggested was a lower mortality rate of the Control group in ISIS-4 [21,22]. It is possible that the effects of magnesium is not sufficiently powerful to demonstrate significant reduction in mortality rate in mild to moderate acute myocardial infarction, which has already received interventional therapy and full medication of other effective agents. The timing of administration of magnesium is another question about the efficacy of magnesium in myocardial infarction. It has been reported that magnesium therapy started early after reperfusion is effective to reduce infarct size in swine model [7]. In contrast, magnesium therapy reduced infarct size when administered before, but not after reperfusion in canine model [5]. In either case, the timing of magnesium therapy remains controversial. In the present study, we focused on the mechanism of efficacy of magnesium on the reduction of myocardial infarct size, which is one of the major determinants of the mortality rate in acute myocardial infarction [23].

We tested three doses of magnesium infusion. High dose of magnesium significantly reduced the myocardial infarct size accompanied by a significant reduction of rate-pressure products. The negative inotropic and chronotropic actions of high dose of magnesium potentially produce energy sparing effects and reduce the myocardial infarct size. Other two doses of magnesium did not affect rate-pressure products, however, the middle dose, not the low dose of magnesium demonstrated a similar infarct size limiting effect. The average infarct size of Control group in the present study was comparable to other previous reports [24–27]. These results suggested that the infarct size limiting effect of magnesium is dose-dependent, but independent of its energy sparing action.

Another possibility is the anti-arrhythmic effects of magnesium [3,4], however, it is uncertain whether the anti-arrhythmic effect produces the infarct size limiting effects. In the present study, we could not observe a significant anti-arrhythmic effect of magnesium. It could be explained by the differences in the experimental models and protocols. It has been reported that magnesium does not demonstrate significant anti-arrhythmic effects in myocardial infarction in dogs [5] and rats [6]. In either case, we could not find significant relationship between the infarct size and the incidence of arrhythmia. We believe that a sufficient dose of magnesium infusion, which is comparable with the clinical use of magnesium [14,15], can reduce the myocardial infarct size independent of its anti-arrhythmic effects in rabbits.

Adenosine is one of the major cardioprotective factors in myocardial ischemia–reperfusion [8,9,28]. In the present study, 8PT, a nonselective adenosine receptor antagonist abolished the myocardial infarct size limiting effects of magnesium, indicating that adenosine mediates those effects of magnesium in rabbits. Magnesium acts as a cofactor for more than 300 enzymes [29], one of which is 5'-nucleotidase [10], the main enzyme mediating adenosine production in ischemic myocardium [11]. We confirmed that the activity of ecto-5'-nucleotidase extracted from rabbit myocardium was enhanced by magnesium in a dose dependent fashion. More importantly, AOPCP, a selective inhibitor of ecto-5'-nucleotidase, abolished the myocardial infarct size limiting effects of magnesium. The energy sparing effect, i.e. reduction of rate-pressure products by AOPCP was potentially opposite to the enhancement of infarct size. The dose of AOPCP in the present study was a sufficient dose to fully block native ecto-5'-nucleotidate in rabbit heart [17]. These results suggested that the infarct size limiting effect of magnesium is mediated, at least in part, by adenosine through the enhancement of ecto-5'-nucleotidase activity.

Calcium overload in myocardium is one of the most important mechanisms of myocardial reperfusion injury [30,31]. It has been reported that the pretreatment with calcium channel antagonist produces infarct size limiting effects [32–35]. Amlodipine reduced the infarct size in feline isolated hearts with attenuation of calcium overload [35]. In the present study, calcium administration abolished the infarct size limiting effect of magnesium, suggesting a competitive interaction between magnesium and calcium in ischemia–reperfusion myocardium. Magnesium is known to be a natural calcium antagonist [13]. Its calcium antagonistic action is multifunctional, including inhibition of voltage dependent L-type calcium channel [36], suppression of Na+/Ca2+ exchanging system [37], inhibition of calcium release from sarcoplasmic reticulm (SR) [38], potentiation of calcium sequestration into SR [39] and suppression of calcium binding to specific site of troponin C [40]. Although it was not a study on the myocardial infarct size, Ferrari et al. [41] reported that magnesium reduces mitochondrial calcium overload and protects myocardial injury in isolated rabbit hearts. It is conceivable that the magnesium–calcium interaction mechanism may also affect myocardial infarct size limiting effect of magnesium in rabbits.

Magnesium deficiency has been reported to increase the infarct size [42]. Several beneficial effects of magnesium other than infarct size limiting effect have been proposed in myocardial infarction: coronary vasodilation [43], inhibition of catecholamine release [44], and inhibition of platelet aggregation protecting against thrombosis [45]. It is noteworthy that magnesium supplementation is inexpensive, easy to administer, and relatively free of side effects [46].

In conclusion, magnesium administration has an infarct size limiting effect independent of its effects on energy sparing and incidence of arrhythmias in myocardial infarction in rabbits. The infarct size limiting effect of magnesium is attributable, at least in part, to augmentation of adenosine mechanism.

Time for primary review 14 days.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

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