The influence of verapamil and its isomers on vulnerability to ventricular fibrillation during acute myocardial ischemia and adrenergic stimulation in isolated rat heart.
In isolated heart preparations, dl-verapamil inhibits the increased vulnerability to ventricular fibrillation and reduces myocardial tissue levels of cyclic 3'5'-adenosine monophosphate (cyclic AMP), a proposed arrhythmogenic agent. The ventricular antiarrhythmic effect of dl-verapamil may not be mediated by selective slow channel inhibition since both d(+) and l(-) isomers display equipotent activity. Three different mechanisms may contribute to the antiarrhythmic properties of dl-verapamil: calcium channel antagonism (l(-) isomer), sodium channel inhibition (d(+) isomer) and reduced cyclic AMP accumulation. In the intact animal model, coronary artery ligation is associated with increased levels of circulating catecholamines and sympathetic neural overactivity. In isolated heart preparations, it is therefore appropriate to evaluate the influence of dl-verapamil and isomers on vulnerability to ventricular fibrillation and cyclic AMP accumulation during acute myocardial ischemia with added adrenergic stimulation. We found that dl and l(-) but not d(+)-verapamil (all 1.5 X 10(-7) M) inhibited the fall in ventricular fibrillation threshold through a mechanism not involving cyclic AMP. L(-) but not d(+) verapamil inhibited Ca2+ dependent slow responses and decreased action potential duration at 90% repolarization. We propose that the ventricular antiarrhythmic property of dl and l(-) verapamil during acute regional myocardial ischemia with added adrenergic stimulation is due to inhibition of transsarcolemmal calcium influx.
D000818:Animals; D002118:Calcium / Q000378:metabolism; D003327:Coronary Disease / Q000150:complications* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism; D014693:Ventricular Fibrillation / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D014700:Verapamil / Q000494:pharmacology*
D007473:Ion Channels; D014700:Verapamil; D000242:Cyclic AMP; D002118:Calcium; D004837:Epinephrine