Efficacy of the antidepressant iprindole against experimental arrhythmias.

The antiarrhythmic activity of iprindole was compared to that of imipramine in a variety of experimental arrhythmia models. Iprindole at 20 mg/kg i.v. showed efficacy in reverting ouabain- and aconitine-induced arrhythmias in pentobarbital anesthetized dogs, and at 15-30 mg/kg i.v. reduced the severity of the ventricular arrhythmias following acute coronary artery occlusion in anesthetized pigs. Imipramine (5-10 mg/kg i.v.) was also effective in reverting ouabain- and aconitine-induced arrhythmias, but appeared to exacerbate arrhythmias during coronary occlusion. In microelectrode experiments on isolated dog Purkinje fibers, iprindole reduced maximal upstroke velocity (Vmax) and action potential duration (characteristics of Class Ib antiarrhythmic agents) at concentrations greater than 1 microgram/ml. Significant decreases in Vmax occurred at lower iprindole concentrations when membrane potential was reduced by increasing external potassium from 4 to 10 mM, suggesting that electrical activity in depolarized cells may be selectively suppressed by iprindole. The present data indicate that iprindole may exert beneficial therapeutic effects in the treatment of cardiac arrhythmias, mediated, at least in part, through a Class I mechanism of action.

Acute coronary artery occlusion-reperfusion arrhythmias in pigs: antiarrhythmic and antifibrillatory evaluation of verapamil, nifedipine, prenylamine and propranolol.

The antiarrhythmic activity of the calcium entry blockers, verapamil, nifedipine and prenylamine, was assessed against arrhythmias occurring during 20 min of acute occlusion, or upon rapid reperfusion of the left anterior descending coronary artery (LAD) in anesthetized pigs. Propranolol, which may indirectly reduce calcium entry by blocking the facilitory action of catecholamines on slow channel conductance, was also evaluated for antiarrhythmic activity in this acute arrhythmia model. Only verapamil (0.2 mg/kg i.v.) reduced both the number of arrhythmias occurring during LAD occlusion and the incidence of ventricular fibrillation (VF) occurring after occlusion and reperfusion. Although both nifedipine (0.04-0.2 mg/kg i.v.) and propranolol (1-2 mg/kg i.v.) produced a slight but significant (P less than 0.05) dose-dependent decrease in the incidence of VF during the occlusion period only, this protection was accompanied by a significant increase in ectopic activity. The increase in ectopic activity produced by propranolol (1.0 mg/kg i.v.) persisted even in combination with verapamil (0.2 mg/kg i.v.) which given alone decreased the ectopic frequency. Prenylamine up to 5 mg/kg was without significant antiarrhythmic or antifibrillatory activity. However, unlike verapamil and nifedipine, this drug produced only slight changes in heart rate or blood pressure which suggested the presence of only minimal calcium entry blocking action on myocardial and vascular tissue at the doses we employed. Because the relative antifibrillatory efficacies of verapamil and nifedipine paralleled the relative efficacies reported for depression of atrioventricular conduction, this may implicate the slow inward current channel in the etiology of VF occurring during acute myocardial ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute coronary artery occlusion-reperfusion-induced arrhythmias in rats, dogs and pigs: antiarrhythmic evaluation of quinidine, procainamide and lidocaine.

Arrhythmias which occur following either abrupt occlusion (CO) of the left anterior descending coronary artery (LAD), or rapid reperfusion (CR) of the same, were studied in rats, dogs and pigs. We found that all rats or pigs exhibited ventricular fibrillation (VF) during CO or after CR in contrast to dogs where more than 30% survived both procedures. In rats, the distribution in the onset of non-lethal arrhythmia or VF appeared to be uniform over the CO period, while in pigs and dogs the onset times clustered into two distinct groups. Also unlike dogs and pigs, the rat frequently (75%) underwent spontaneous defibrillation. Quinidine pretreatment (10 mg/kg i.v.) proved effective in protecting all three species from VF while procainamide (20 mg/kg i.v.) was effective only in rats and dogs. Lidocaine pretreatment (10 mg/kg i.v.) was effective in preventing VF in rats, but increased the incidence of CR-induced VF in dogs and significantly (P less than 0.01) reduced the mean time to VF during CO in pigs. However, lidocaine given immediately after CO in pigs did not reduce the time to VF suggesting that lidocaine given post-infarction would not increase the risk of VF, although the drug appears to be of no therapeutic benefit during the early occlusion period. Similarities in the action of lidocaine in pigs and dogs further suggest that the mechanisms of CR-induced VF in dogs and CO-induced VF in pigs may be similar. These data also support a pivitol role of extracellular K+ accumulation of the production of early post-infarction arrhythmias. Thus, the arrhythmogenic as well as antiarrhythmic properties of the various drugs studied here may relate their known effects on potassium permeability in cell membranes.

Antiarrhythmic evaluation of verapamil, nifedipine, perhexiline and skf 525-A in four canine models of cardiac arrhythmias.

Verapamil, nifedipine, perhexiline and SKF 525-A (2-diethylaminoethyl-2,2-diphenylvalerate . HCL) were evaluated for cardiac antiarrhythmic activity by assessing their effectiveness in increasing left ventricular fibrillation threshold (FT) and antagonizing ouabain-induced arrhythmias (OA), 24 h post infarction arrhythmias (CLA) and aconitine-induced atrial arrhythmias. Calcium antagonistic doses (ID50) of each agent were approximated by intravenous titration of the amount of drug required to reduce the left ventricular contractile force by 50% in dogs pretreated with hexamethonium (10 mg/kg) to block autonomic reflexes. ID50 doses of calcium antagonists were found not to be universally effective in any single arrhythmia model while causing significant changes in heart rate, blood pressure and frequently producing death or convulsion. It is suggested that local anesthetic or 'class 1' action probably accounts for the antiarrhythmic effectiveness of SKF 525-A (7-20 mg/kg i.v.) in all four arrhythmia models and for perhexiline-induced increased FT and antagonism of CLA (15-20 mg/kg). Antiarrhythmic effectiveness of verapamil against OA may be due to calcium antagonism action.