Ryanodine and caffeine prevent ventricular arrhythmias during acute myocardial ischemia and reperfusion in rat heart

Abstract

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. Our findings suggest that oscillatory release of calcium from the sarcoplasmic reticulum may play an important role in ventricular arrhythmogenesis during acute myocardial ischemia and reperfusion. Impairment of left ventricular mechanical function appears likely to preclude the use of ryanodine and caffeine in vivo as ventricular antiarrhythmic agents.