Reperfusion-induced Ventricular Arrhythmias Research Articles

Pacing-induced delayed protection against arrhythmias is attenuated by aminoguanidine, an inhibitor of nitric oxide synthase.

1. Cardiac pacing, in anaesthetized dogs, protects against ischaemia and reperfusion-induced ventricular arrhythmias when this is initiated 24 h after the pacing stimulus. Now we have examined whether this delayed cardioprotection afforded by cardiac pacing is mediated through nitric oxide. 2. Twenty-two dogs were paced (4 x 5 min periods at 220 beats min(-1)) by way of the right ventricle, 24 h prior to a 25 min period of coronary artery occlusion. Nine of these dogs were given the inhibitor of induced nitric oxide synthase, aminoguanidine (50 mg kg(-1) i.v.), 0.5 h prior to coronary artery occlusion. Sham-operated non-paced dogs with and without aminoguanidine treatment served as controls. 3. Pacing markedly (P<0. 05) reduced arrhythmia severity (ventricular fibrillation, VF, during occlusion 15%; survival from the combined ischaemia-reperfusion insult 62%) compared to control, sham-operated, unpaced dogs (VF during occlusion 58%; survival 17%). This protection was attenuated by the administration of aminoguanidine prior to coronary artery occlusion (survival from the combined ischaemia-reperfusion insult 11%, which was significantly (P<0.05) less than in the paced dogs not given aminoguanidine and similar to the controls). Aminoguanidine had no significant effects on coronary artery occlusion when given to dogs that had not been paced. In the dose used aminoguanadine transiently elevated systemic arterial pressure by a mean of 20 mmHg and reduced heart rate by a mean of 22 beats min(-1). 4. These results suggest that nitric oxide, probably derived from induced nitric oxide synthase, contributes significantly to the delayed cardioprotection afforded by cardiac pacing.

Ischemia/reperfusion-induced arrhythmias in anaesthetized rats: a role of Na + and Ca 2+ influx

We hypothesized that by limiting the Na + and Ca 2+ loading by a blocker/inhibitor of the Na + channel (lidocaine), Na + overload (R56865: N-[1-[4-(4-fluorophenoxy)butyl]-4-piperidinyl]- N-methyl-2-benzothiazolamine), Ca 2+ channel (verapamil), Na +–H + exchange (ethylisobutyl amiloride) or of Na +–Ca 2+ exchange (No. 7943: 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulfonate), it should be possible to reduce ischemia/reperfusion-induced arrhythmias. To test this hypothesis, we used anaesthetized rats subjected to 5 min of coronary artery occlusion followed by 10 min of reperfusion to study antiarrhythmic effects of above compounds on reperfusion-induced ventricular premature beats, ventricular tachycardia, and reversible and irreversible ventricular fibrillation. Compound or saline was administered as an intravenous bolus injection at 5 min before ischemia. Pretreatment with lidocaine (5 mg/kg), verapamil (0.63 mg/kg), R56865 (0.63 mg/kg) or ethylisobutyl amiloride (1.25 mg/kg) significantly reduced or abolished all types of ventricular arrhythmias. However, pretreatment with verapamil was associated with second or third degree heart block in 3 out of 12 animals. Pretreatment with No. 7943 did not significantly influence the ischemia/reperfusion-induced ventricular arrhythmias. The present results suggest that both intracellular Na +- and Ca 2+-loading play important roles in reperfusion-induced ventricular arrhythmias and the inhibition of Na +–Ca 2+ exchange to limit Ca 2+ loading probably does not play any important role in ischemia/reperfusion-induced arrhythmias in anaesthetized rats.

Estrogen diminishes postischemic hydroxyl radical production.

Reperfusion of blood flow to an ischemic myocardium is imperative to survival; ironically, it may also manifest several pathophysiological conditions. The most important of these are reperfusion arrhythmias and tissue injury and/or death. The mechanisms involved in reperfusion arrhythmias remain to be fully elucidated; however, increasing evidence indicates that reperfusion-induced arrhythmias are a free radical-mediated phenomenon. Acute administration of conjugated equine estrogen to dogs attenuates ischemia- and reperfusion-induced arrhythmias. The cardioprotective effect of estrogens in postmenopausal women is well documented, and recent studies suggest that estrogens possess strong antioxidant properties, with equine estrogens most potent. In this study we show that administration of conjugated equine estrogen to fully anesthetized dogs abolishes the burst of .OH radicals typically produced on reperfusion of the myocardium. This indicates that estrogen might attenuate reperfusion-induced ventricular arrhythmias by virtue of its antioxidant properties, suggesting a novel cardioprotective effect of the hormone.

Amelioration of ischemia- and reperfusion-induced myocardial injury by 17beta-estradiol: role of nitric oxide and calcium-activated potassium channels.

17Beta-estradiol increases the production of nitric oxide (NO) and prostacyclin and opens Ca2+-activated K+ (K(Ca)) channels. Whether these effects of 17beta-estradiol reduce infarct size and the incidence of ventricular arrhythmia was investigated in dogs subjected to myocardial ischemia and reperfusion. Infarct size was measured in open-chest dogs after 90 minutes' occlusion of the left anterior descending coronary artery and a subsequent 6 hours of reperfusion. Infusion of 17beta-estradiol into the coronary artery was initiated 10 minutes before coronary occlusion and continued until after 1 hour of reperfusion, with the exception of the occlusion period. The difference in NO concentration between coronary venous and arterial blood 10 minutes after the onset of reperfusion was significantly greater in dogs treated with 17beta-estradiol (10 ng x kg(-1) x min(-1)) than in control animals. Infarct size (13.1+/-3.0% versus 43.7+/-5.4% of the area at risk) and the incidence of ventricular arrhythmia during ischemia and reperfusion periods were significantly reduced in the 17beta-estradiol group. Both N(G)-nitro-L-arginine methyl ester (an inhibitor of NO synthase) and iberiotoxin (a blocker of K(Ca) channels) reduced both the infarct size-limiting effect (infarct size, 29.3+/-3.0% and 31.7+/-2.1%, respectively) and the antiarrhythmic effect of 17beta-estradiol; indomethacin (an inhibitor of cyclooxygenase) did not attenuate the beneficial effects of 17beta-estradiol. 17Beta-estradiol reduced both myocardial infarct size and the occurrence of ischemia- and reperfusion-induced ventricular arrhythmias, which appear to be mediated by NO and the opening of K(Ca) channels in canine hearts.

Ischemia- and reperfusion-induced ventricular arrhythmias in dogs: effects of estrogen.

The purpose of this investigation was to determine if exogenous estrogen could attenuate the ventricular arrhythmias caused by myocardial ischemia and reperfusion. Conjugated equine estrogen, administered as an intravenous bolus injection (100 micrograms) to anesthetized, instrumented beagles of both genders, significantly attenuated the incidence of ventricular arrhythmias during a 20-min period of ischemia (2 +/- 1 vs. 19 +/- 16% ectopy) and in the first 5 min of reperfusion (15 +/- 9 vs. 69 +/- 20% ectopy). By 15-20 min of ischemia, ventricular salvos and nonsustained ventricular tachycardia were frequently observed in nontreated dogs. One dog in this group fibrillated during ischemia. In contrast, estrogen-treated dogs exhibited only an occasional ventricular premature beat during the same period of ischemia. When compared with baseline values, the percent ectopy during ischemia in estrogen-treated dogs was insignificant. During reperfusion, nontreated dogs displayed severe, life-threatening arrhythmias such as sustained ventricular tachycardia. In two of these dogs ventricular tachycardia deteriorated to ventricular fibrillation. In comparison, estrogen-treated dogs displayed only innocuous ventricular arrhythmias during reperfusion, i.e., ventricular premature beats, ventricular salvos, and ventricular bigeminy. In addition to the effect of estrogen on arrhythmias, there was a gradual increase in coronary blood flow on reperfusion in estrogen-treated dogs. This effect of estrogen was preceded by a significantly higher coronary perfusion pressure during ischemia (31 +/- 2 vs. 18 +/- 4 mmHg, P < 0.05). In conclusion, our findings suggest that antiarrhythmic effects of estrogen treatment might stabilize ventricular rhythmicity during ischemia and reperfusion.

Attenuation by R 56865, a novel cytoprotective drug, of regional myocardial ischemia- and reperfusion-induced electrocardiographic disturbances in anesthetized rabbits.

We investigated the antiischemic and antiarrhythmic effects of R 56865 in pentobarbital-anesthetized, open-chest rabbits subjected to 10 min regional myocardial ischemia and 20 min reperfusion, using two experimental protocols. In the first, R 56865 (0.02-0.16 mg/kg) was administered as a bolus intravenous (i.v.) injection 5 min before ligation of a branch of the left circumflex coronary artery (LCX); in the second, the drug, at the highest dose studied (0.16 mg/kg), was injected by the same route during ischemia, 5 min after coronary artery ligation. Ischemia-induced ST segment increase and reperfusion-induced ventricular arrhythmias were determined in lead II of the four-limb ECG. Mean carotid arterial pressure and heart rate (HR) were also measured. When given before ischemia, R 56865 dose-dependently prevented ischemia-induced ST segment increase and reperfusion arrhythmias. The antiischemic and antiarrhythmic dose-response curves were superimposable, suggesting a common mechanism of action. R 56865 (0.16 mg/kg) fully attenuated ischemia-induced ST segment shift and ventricular arrhythmias on reperfusion. These protective effects were not associated with systemic hypotension or bradycardia. When high-dose R 56865 (0.16 mg/kg) was given during ischemia, ST segment shift and ventricular arrhythmias on reperfusion were not attenuated. The results strongly suggest that R 56865 affords protection against the deleterious effects of moderate ischemia by mechanisms not associated with an indirect reduction of cardiac work. R 56865 may elicit cardioprotection directly in ischemic tissue.

The protection by ischemic preconditioning against myocardial ischemia- and reperfusion-induced arrhythmias is not mediated by ATP-sensitive potassium channels in rats.

Single or multiple brief periods of myocardial ischemic preconditioning (PC) limits ischemia- and reperfusion-induced arrhythmias. This study tested whether PC protects against ischemia/reperfusion-induced arrhythmias and, if so, whether the protective effect was mediated by the opening of ATP-sensitive (KATP) channels. In protocol 1, the effects of PC (three cycles of 2 minutes of coronary occlusion and 5 minutes of reperfusion) on the development of arrhythmias after a coronary occlusion of 5, 10, or 20 minutes followed by 10 minutes of reperfusion were studied in rats. In protocol 2, solvent or a KATP channel blocker (glyburide [0.64 mg/kg body weight delivered intravenously]) was administered 5 minutes before PC. In a second group, glyburide was administered immediately after PC. In a third group, solvent, glyburide, or a KATP channel opener (pinacidil [0.16 mg/kg delivered intravenously]) was administered 5 minutes before coronary occlusion for 5 minutes without PC. In protocol 1, PC significantly reduced the ischemia-induced ventricular premature beats (VPBs) and ventricular tachycardia (VT), and it abolished ischemia-induced ventricular fibrillation (VF) during 10 or 20 minutes of coronary artery occlusion. PC also significantly reduced reperfusion-induced ventricular arrhythmias after 5 or 10 minutes of coronary artery occlusion; this effect of PC, however, was lost during reperfusion after 20 minutes of coronary occlusion. In protocol 2, PC again produced a marked reduction in reperfusion-induced arrhythmias and abolished the incidence of VPBs during 5 minutes of ischemia as well as the incidence of irreversible VF during reperfusion, whereas glyburide did not block the protective effect of PC on ischemia- and reperfusion-induced arrhythmias. Glyburide administered in non-PC animals did not reduce ischemia- and reperfusion-induced arrhythmias, nor did pinacidil. The protective effect of PC was not attenuated by glyburide. These results suggest that the protective effect of PC in ischemia- and reperfusion-induced arrhythmias is not likely to be related to activation of KATP potassium channels during ischemia in rats.

R 83 572, A [formula omitted] inhibitor, prevents ischemia- and reperfusion-induced ventricular arrhythmias: In vivo studies in the rats

R 83 572, A [formula omitted] inhibitor, prevents ischemia- and reperfusion-induced ventricular arrhythmias: In vivo studies in the rats

Diabetes and susceptibility to reperfusion-induced ventricular arrhythmias

Studies using chemically-induced models of diabetes have shown the diabetic myocardium to exhibit abnormalities in cellular ion transport, which may affect susceptibility to reperfusion-induced arrhythmias. We studied the incidence of reperfusion-induced ventricular tachycardia (VT) and fibrillation (VF) in isolated hearts from rats with streptozotocin-induced diabetes and from age-matched and weight-matched control rats ( n = 12 per group). Following 5 min of regional ischaemia, reperfusion resulted in a similarly low incidence of arrhythmias in all three groups. Following 10 min of regional ischaemia, the incidence of VT was 92, 100 and 92%, and the incidence of VF was 75, 92 and 92% in diabetic, age-matched control and weight-matched control groups, respectively (NS). However, among those hearts which exhibited VF, the incidence of sustained (≥120 s) VF was 73 and 55% in age-matched and weight-matched control groups, respectively, and 0% in the diabetic group ( P<0.05 vs both controls). The mean duration of VF in the diabetic group was reduced from 201 ± 33 and 171 ± 36 s in age-matched and weight-matched control groups, respectively, to 9 ± 3 s ( P<0.05). Thus, streptozotocin-induced diabetes in the rat does not result in an increased susceptibility to reperfusion-induced arrhythmias. To the contrary, hearts from diabetic rats are less susceptible to potentially lethal arrhythmias during reperfusion. Likely contributory factors to this phenomenon include (i) increased myocardial content of free radical scavenging enzymes, (ii) prolonged action potential duration, and (iii) reduced activity of sarcolemmal Na + H + and Na + Ca 2+ exchange processes, all of which have previously been reported in similar models of diabetes.

Time course and interrelation of reperfusion-induced ST changes and ventricular arrhythmias in acute myocardial infarction

With the increasing use of thrombolytic therapy, the presence and time course of reperfusion-induced ventricular arrhythmias and ST-segment changes have become of particular interest. Technical improvements in bipolar Holter monitoring offer the opportunity to record both parameters continuously and simultaneously. Time course and interaction of both parameters in dependence on the onset of thrombolysis and time of reperfusion were investigated in 30 patients with acute myocardial infarction. Reperfusion was achieved in 20 patients after 49 ± 23 minutes and in another 2 patients after 120 minutes (73%, group A). Vascular occlusion persisted in 8 patients for >24 hours (group B). Sudden ST-segment changes (>0.2 mV/15 min) in the bipolar leads indicated reperfusion in 7 of 22 patients (32%). Idioventricular rhythms, most frequent in reperfused patients (group A: 18 of 22 patients, mean 121 beats/hour), were unspecific reperfusion markers (group B: 5 of 8 patients, 1 beat/hour) unless frequent (p < 0.05) or longer lasting, repetitive (p < 0.01) episodes were considered. Premature ventricular beats and couplets (p < 0.05) were also most frequent in group A (peak frequency 3 to 5 hours after thrombolysis). Ventricular tachycardia observed in 21 of 22 patients (95%) in group A and in 3 of 8 (38%) in group B (p < 0.01) attained their peak frequency 7 to 9 hours after thrombolysis. They occurred most often in anterior myocardial infarction and were often preceded by frequent singular premature beats (r = 0.78). In summary, (1) sudden ST-segment changes in the bipolar leads rarely but reliably predict the time of reperfusion, (2) ventricular tachycardias are most likely late after thrombolysis and thus make prolonged corresponding supervision advisable, and (3) the frequency rather than the type of ventricular arrhythmia is useful to noninvasively predict coronary reperfusion.

Reduction of reperfusion-induced ventricular arrhythmias by salicylic acid

Reduction of reperfusion-induced ventricular arrhythmias by salicylic acid

The role of oxygen free radicals and extracellular calcium ions in reperfusion-induced arrhythmias.

To examine the role of oxygen free radicals and extracellular calcium ions in reperfusion-induced ventricular arrhythmias, we evaluated the effects of hypoxic reperfusion, oxygen free radical scavengers, allopurinol and hypocalcemic reperfusion on reperfusion-induced ventricular arrhythmias. The hearts of male Sprague-Dawley rats were perfused in the working heart mode. Whole heart ischemia was induced for 15 min and then reperfused. Rats were divided into 5 groups: control group, scavenger group, allopurinol group, hypoxia group and hypocalcemia group. Scavenger, hypoxic and hypocalcemic perfusions were undertaken only during the period of perfusion. The incidence of reperfusion-induced ventricular fibrillation (Vf) was reduced in the scavenger group (100% to 38%) and the hypoxia group (100% to 50%). Spontaneous reversion of Vf to regular sinus rhythm was recognized in the hypoxia and hypocalcemia groups. In conclusion, oxygen free radicals would play an important role in the genesis of the reperfusion arrhythmias, and extracellular calcium concentration would also play an important role in sustaining the reperfusion arrhythmias. Notably, hypoxic reperfusion had protective effects on both processes.

Pharmacologic modifications of reperfusion arrhythmias in the dog in vivo: possible relation to limitation of the extent of infarction

To study the effects of pharmacologic interventions on reperfusion-induced arrhythmias, open chest anesthetized dogs were subjected to occlusion of a coronary artery for 3 hours followed by reperfusion for 3 hours. Electrocardiograms were recorded with a two-channel monitor with the subsequent recordings submitted to computer-assisted analysis. The extent of myocardial infarction was measured by staining with triphenyl tetrazolium chloride. Mexiletine (12 mg/kg) and verapamil (0.9 mg/kg) were given, starting at 120 min of coronary occlusion and continued until the end of experiments. Dibunol (60 mg/kg) was administered at 120 min of ischemia. Dibunol and dibunol together with verapamil reduced the extent of infarction (to 62 ± 6% and 53 ± 4% of the zone at risk, respectively; compared to 77 ± 3% of the zone at risk in the control group, P < 0.05) while verapamil alone and mexiletine did not. There were 5 fatal episodes of ventricular fibrillations in 23 dogs, together with other malignant arrhythmias when occlusion was released in the control group. Mexiletine and verapamil prevented these episodes of ventricular fibrillation during reperfusion while dibunol, and dibunol together with verapamil, did not. Apart from fibrillations, mexiletine eliminated ventricular tachycardias, in contrast to the other drugs, which did not. Mexiletine and verapamil alone prevented ventricular premature beats while dibunol, and dibunol with verapamil, exacerbated their generation. The failure of these agents to prevent episodes of ventricular fibrillation, and the exacerbation of ventricular tachycardias and ventricular premature beats in those groups with a reduced extent of infarction, has led us to propose that a link may exist between the extent of limitation of infarction and the occurrence of reperfusion-induced ventricular arrhythmias.

Prevention of reperfusion-induced ventricular arrhythmias in isolated rat heart with magnesium

The effects of magnesium (from 1.2 to 7.2 mM) were investigated in isolated perfused rat heart subjected to coronary artery ligation and reperfusion. Increasing magnesium concentrations, of the medium containing 3.00 mM of calcium, induced a significant bradycardia and a protective effect towards reperfusion arrhythmias. A significant correlation was found between the heart rate and the antiarrhythmic activity of increasing magnesium concentrations. The effects of high magnesium concentration (4.8 mM) were also investigated after labelling of internal stores of noradrenaline with [3H]noradrenaline. Without any marked change in the pattern of release of radioactivity, a significant reduction of the sudden release of radioactivity was observed during the reperfusion. However, magnesium did not change the uptake of noradrenaline by the heart. Our results suggest that the antiarrhythmic effect of magnesium might be of importance in the clinical treatment of myocardial ischemia.

Effect of alprazolam on ischemia and reperfusion-induced ventricular arrhythmias in the isolated perfused rat heart.

The effects of the triazolobenzodiazepine anxiolytic, alprazolam, on the incidence of ischemia- and reperfusion-induced ventricular arrhythmias was studied in the isolated buffer-perfused rat heart. Administration of alprazolam before and after myocardial ischemia resulted in a dosage-dependent reduction in the incidence and duration of reperfusion-induced ventricular fibrillation and was significant at a concentration of 1 X 10(-3) mol/l alprazolam. This cardioprotective effect was not extended to ischemia-induced ventricular dysrhythmias. In conclusion, our findings provide evidence that benzodiazepine drugs are able to provide a cardioprotective effect in the experimental setting of myocardial ischemia followed by coronary reperfusion.

Pathophysiology of myocardial ischemia: importance of platelet-vessel wall interactions.

Clinical and experimental evidence for important interactions between platelets and vascular endothelium under conditions of myocardial ischemia is briefly summarized. The clinical evidence for a role of platelets in myocardial ischemia includes studies indicating alterations in platelet behavior and the therapeutic benefit of some antiplatelet drugs. Experimental evidence suggesting the importance of platelets in ischemia includes reductions in transmyocardial platelet number under these conditions, the cyclical reductions in coronary blood flow that result from intermittent intravascular platelet aggregation, and the relationship between induced platelet aggregation and cardiac arrhythmias. Evidence strongly suggesting the importance of platelet emboli and thromboxane generation as a major cause of reperfusion-induced ventricular arrhythmias is outlined.

Alifedrine, a positive inotropic agent that moderately reduces the severity of ischaemia and reperfusion-induced ventricular arrhythmias

The effects of alifedrine, a positive inotropic agent, were examined in greyhounds anaesthetised with chloralose. An intravenous dose of 0.3 mg kg −1 resulted in a substantial increase in myocardial contractility (increased dP/dt max, cardiac output and stroke volume) without significantly affecting heart rate. The effects of alifedrine on the severity of arrhythmias resulting from both coronary artery occlusion and reperfusion were also determined. A mild anti-arrhythmic effect was observed during early ischaemia when the incidence of ventricular tachycardia was reduced from 90% in controls to 50% in treated dogs. There was also a significant reduction in the number of extrasystoles appearing as ventricular tachycardia (from 511 ± 138 to 151 ± 84). The total number of extrasystoles during the first 30 min of ischaemia was also reduced, although not significantly, from 846 ± 193 to 527 ± 86. Following release of a 40 min coronary artery occlusion there was a marked reduction in reperfusion-induced ventricular fibrillation from 75% in controls, to 37% in the alifedrine-treated dogs. The overall survival from the combined occlusion-reperfusion insult was increased from 20% in controls to 50%. These results suggest that alifedrine has an unusual and useful spectrum of pharmacological activity in that it combines antiarrhythmic activity with an ability to improve cardiac function.

Diltiazem and the reduction of reperfusion-induced arrhythmias in the rat: Protection is secondary to modification of ischemic injury and heart rate

We have used the isolated rat heart with transient coronary artery occlusion to investigate whether diltiazem has an anti-arrhythmic action against reperfusion-induced ventricular arrhythmias. In the first series of studies (early administration group) the drug was administered 5 min prior to the induction of regional ischemia, this resulted in a dose-dependent reduction in reperfusion-induced ventricular fibrillation. With 5 X 10(-8), 10(-7), 5 X 10(-7), 10(-6) and 5 X 10(-6) mols of diltiazem/l, total ventricular fibrillation (reversible plus irreversible) was reduced from its control incidence of 100% (12/12) to 91%, 58% (P = less than 0.05), 17% (P = less than 0.001), 0% (P = less than 0.001) and 0% (P = less than 0.001) respectively. Heart rate was also reduced in a dose-dependent manner, falling from its control value of 268 +/- 6 beats/min to less than 50% with the highest concentration of diltiazem. Coronary flow was increased in a dose-dependent manner in the diltiazem treated groups. In additional studies with an anti-arrhythmic dose of diltiazem (5 X 10(-7) mols/l), hearts were paced to their drug free control value; under these conditions the anti-arrhythmic effect of diltiazem was lost. In further studies, diltiazem (10(-7) and 5 X 10(-7) mols/l) was administered just prior to reperfusion (late administration group), no anti-arrhythmic effects were observed. In additional studies we determined whether, with early administration, diltiazem (5 X 10(-7) mols/l) exerted its anti-arrhythmic effect by altering the relationship between the vulnerability to reperfusion-induced arrhythmias and the duration of preceding ischemia. In diltiazem-free control hearts a bell-shaped profile was observed with a maximum vulnerability after 10 min of ischemia (100% incidence of reperfusion-induced ventricular fibrillation). In diltiazem-treated hearts, a bell-shaped curve was also observed, however, its optimum was shifted to the right and downwards (20 min of ischemia gave maximum vulnerability [41%] to reperfusion-induced arrhythmias). We conclude that the ability of diltiazem to protect the isolated rat heart against reperfusion-induced arrhythmias is secondary to its anti-ischemic effect and in particular to its negative chronotropic properties.

Cardioprotection with calcium antagonists by suppression of early ischaemia and reperfusion-induced arrhythmias.

This paper discusses the relevance of certain animal models for the production of ischaemia and reperfusion-induced ventricular arrhythmias to clinical problems of ischaemia, for example, sudden cardiac death. It then describes experiments in anaesthetised rats subjected to acute coronary artery occlusion in which nifedipine (administered both intravenously and orally) prevented the occurrence of ventricular fibrillation and markedly increased survival. In anaesthetised dogs, a continuous intravenous infusion of nifedipine reduced the severity and incidence of ventricular ectopic activity and also dramatically improved survival on reperfusion fro 12.5% (in the controls) to 88%. The mechanisms of this protection are discussed.