Search

To investigate and to compare the protective action of verapamil, nifedipine and diltiazem on the acutely infarcting myocardium, we studied effects on cellular damage and mechanical function in the isolated working rat heart preparation subjected to left main coronary artery ligation. First, the fall in the ventricular fibrillation threshold (VFT) was diminished by all three agents, but non-specific effects of these agents were operating at least in part. All three compounds afforded substantial dose-dependent reduction of lactate dehydrogenase release, which was taken as an index of cellular damage, and preserved ATP stores in the infarcting myocardium. The range of effective concentrations was small and close to doses which produced atrioventricular conduction disturbances (verapamil, diltiazem) or LV pump failure (nifedipine). It is argued that these concentrations may be therapeutically relevant, whereas the concentration of a beta-adrenoceptor antagonist agent required comparably to inhibit enzyme release was supra-therapeutic (metoprolol 10(-4) M). There are substantial differences between such animal models and the situation in acute myocardial infarction in man, where preliminary data show benefits both for beta-adrenergic blockade by sotalol and for calcium antagonism by nifedipine.

Antiarrhythmic and hemodynamic effects of the calcium channel antagonist verapamil were compared with those of tiapamil, a congener, in open-chest pigs with anterior descending coronary artery ligation. Tiapamil (6 mg/kg i.v.) decreased the incidence of ventricular fibrillation to 4 of 10 versus 22 of 25 in controls (p less than 0.05) and maintained left ventricular dP/dtmax after ligation (predrug value: 2,312 +/- 112 mm Hg/sec; 20 minutes after ligation: 2,139 +/- 229 mm Hg/sec). Tiapamil increased blood flow in the peripheral ischemic zone (24 +/- 3.2% vs. 16.9 +/- 1.6% of preligation value in controls, p less than 0.05) as well as in the peri-ischemic and nonischemic zones (153.9 +/- 12.7% and 186.3 +/- 17.1%, respectively; both p less than 0.0001 vs. 97.9 +/- 5% and 91.3 +/- 4.7% in controls). Verapamil (0.6 mg/kg i.v.) decreased the incidence of ventricular fibrillation to 0 of 7 versus 22 of 25 in controls (p less than 0.005); left ventricular dP/dtmax decreased from 2,062 +/- 144 to 1,060 +/- 168 mm Hg/sec (p less than 0.0001). Verapamil did not change blood flow in the peripheral, peri-ischemic, or nonischemic zones. Thus, tiapamil, and not verapamil, decreased ischemic ventricular fibrillation while maintaining left ventricular mechanical function. Verapamil congeners warrant further evaluation as antiarrhythmic agents in acute myocardial ischemia.

This study investigates the possible role of oscillatory release of calcium from sarcoplasmic reticulum in the genesis of ventricular arrhythmias during acute myocardial ischemia and reperfusion in isolated rat hearts. We used ryanodine and caffeine, which are known to modulate the oscillatory release of calcium from sarcoplasmic reticulum. During 30 minutes of left main coronary artery ligation, all 13 control hearts developed ventricular premature beats (number of beats, 225 +/- 51) and ventricular tachycardia (duration, 123 +/- 21 seconds); five hearts developed ventricular fibrillation. In a separate series of experiments, reperfusion after 15 minutes of coronary artery ligation caused ventricular fibrillation to occur within 15 seconds in all 12 hearts. Ryanodine (10(-9) to 10(-7) M) abolished ventricular arrhythmias during coronary artery ligation and prevented reperfusion ventricular fibrillation. Ryanodine (10(-9), 10(-8), and 10(-7) M) caused 15%, 23%, and 74% decreases in the maximal rate of rise of left ventricular pressure development and 20%, 32%, and 85% decreases in the maximal rate of fall of left ventricular pressure development, respectively, prior to coronary artery ligation. During acute myocardial ischemia, ryanodine 10(-9) M maintained and 10(-8) M impaired left ventricular function; 10(-7) M caused left ventricular failure. Coronary perfusion rate did not increase during ischemia. Antiarrhythmic activity occurred independent of preservation of high energy phosphates, reduction in tissue lactate, or tissue cyclic adenosine monophosphate in the ischemic myocardium. Caffeine 10(2) M decreased the incidence of ventricular arrhythmias during ischemia and upon reperfusion; protection occurred coincident with development of diastolic contracture. Caffeine increased ischemic tissue cyclic adenosine monophosphate content and worsened tissue energy status.(ABSTRACT TRUNCATED AT 250 WORDS)