Failure of antiarrhythmic drugs to prevent experimental reperfusion ventricular fibrillation.

Abstract

SUMMARY Ninety-nine adult mongrel dogs underwent acute ligation of the proximal left anterior descending coronary artery. Thirty minutes later, the occlusion was released to evaluate the effectiveness of five antiarrhythmic protocols in eliminating reperfusion ventricular fibrillation. The five protocols included: protocol 1 -i.v. lidocaine, preligation and prerelease (n = 19); protocol 2 i.v. lidocaine, prereperfusion only (n = 22); protocol 3 chronic, oral, daily amiodarone for 2 weeks preligation (n = 19); protocol 4 -i.v. procainamide, preligation and prereperfusion (n = 21); and protocol 5 i.v. verapamil, prereperfusion (n = 18). Each regimen was evaluated with respect to the incidence of reperfusion ventricular fibrillation in dogs that survived to reperfusion, and the results were compared to 77 control dogs that underwent identical coronary artery occlusion and release procedures without drug therapy. The incidence of reperfusion ventricular fibrillation was as follows: protocol I -seven of 15 dogs (47%); protocol 2 -six of 18 (33%); protocol 3 11 of 16 dogs (69%); protocol 4-eight of 17 dogs (47%); and protocol 5-10 of 17 dogs (59%), compared with 36 of 60 (60%) in control dogs.Using chi-square analysis, protocol 2 was beneficial (p < 0.05). The dogs were then stratified into high-and low-risk subgroups based on the arrhythmic events of the antecedent coronary artery ligation periods, and predictive risk indexes for the occurrence of reperfusion ventricular fibrillation were developed. The MantelHaenszel method of statistical analysis revealed that none of these protocols resulted in a statistically significant reduction in the incidence of reperfusion ventricular fibrillation. Thus, use of these predictive indexes plus appropriate statistical methods has revealed, unexpectedly, limitations in the efficacy of a spectrum of antiarrhythmic agents in preventing reperfusion ventricular fibrillation.CANINE coronary artery occlusion and reperfusion models have been studied extensively as a means for understanding the life-threatening ventricular arrhythmias that occur after myocardial ischemia and infarction. However, as useful as these canine models have been in revealing electrophysiologic mechanisms, their use as models for evaluating anti-

Effects of the New Class III Antiarrhythmic Drug MS-551 and d-Sotalol on Canine Coronary Ligation-Reperfusion Ventricular Arrhythmias

“…However, when pentobarbital sodium was used as an anesthetic, d-sotalol as well as MS-551 were effective in suppressing the VF. Although the rate of occurrence of reperfusion VF was not high (59% in all 32 control beagles of the present study) and variable as has already been reported (21), the suppression of VF by these drugs might be related to the prolongation of the refractory period. It is because new class III antiarrhythmic drugs are reported not to suppress either cardiac Na or Ca channels and thus had no antiarrhythmic effects on automaticity arrhythmias such as those produced by two-stage coronary ligation or digitalis in dogs (6).…”

“…d-Sotalol was infused intravenously at a speed of 10 mg/kg/hr. Since the incidence of occurrence of coronary ligationreperfusion arrhythmias is known to be quite variable (21), experiments were randomized using a pair of beagles (by coin-flip); one received the drug infusion, and the other received 0.9% NaCI (saline) infusion. The speed of infusion was 1 ml/min.…”

Verapamil prevents slowing of transmural conduction and suppresses arrhythmias in an isolated guinea pig ventricular model of ischemia and reperfusion.

“…However, several recent studies in in situ hearts and isolated tissues have suggested that both reentry and oscillatory afterpotentials (delayed afterdepolarizations) may be involved in the generation of these arrhythmias, [7][8][9][10] Verapamil, a slow channel inhibitor, has been demonstrated to be effective in preventing arrhythmias in experimental ischemia.11-15 However, contradictory observations have been reported with respect to verapamil's efficacy in preventing reperfusion arrhythmias. 4,[16][17][18][19][20] The mechanisms by which verapamil might suppress reperfusion arrhythmias are even less clear. Verapamil was found to suppress reperfusion-induced oscillatory From The goals of the present investigation were to evaluate the potential efficacy of verapamil against reperfu-sion-induced arrhythmias in this model and to determine the electrophysiological actions that accompany antiarrhythmic efficacy.…”

Effects of dazoxiben on arrhythmias and ventricular fibrillation induced by coronary artery occlusion and reperfusion in anaesthetised greyhounds.

“…These "reperfusion arrhythmias" are particularly severe and frequently fatal since they often progress to ventricular fibrillation. They also seem to be resistant to standard antiarrhythmic therapy (Naito, et al, 1981), suggesting that their aetiology may vary from that of arrhythmias observed during myocardial ischaemia. Since thromboxane has been implicated in coronary vasospasm in patients with variant angina (Lewy etal., 1979) it may also be involved in the reperfusion arrhythmias which can occur when spasm is reversed.…”