EFFECT OF RYANODINE ON THE INITIATION AND PERPETUATION OF STRETCH-INDUCED ARRHYTHMIAS IN ISOLATED CANINE VENTRICLE

Ventricular arrhythmias can be initiated by a mechanism of transient diastolic dilation. To test the hypothesis that Ca2+ release from sarcoplasmic reticulum (SR) is important in initiation of such stretch-induced arrhythmias (SLAs), we studied effects of ryanodine in an isolated canine heart model. Arrhythmias were induced by a computerized ventricular volume servo-pump system that transiently increased left ventricular volume by precise amounts (Delta V) during diastole. The probability of eliciting an SIA (P-SIA) was compared at the minimum Delta V that resulted in P-SIA of greater than or equal to 90% under baseline conditions. Block of SR Ca2+ release with 10(-5) M ryanodine in 11 ventricles produced mild inhibition of SIAs, reducing P-SIA by 19.4% (P = 0.039). Because ryanodine produces leakage of SR Ca2+ at low concentration and block of SR Ca2+ release at high concentration, ryanodine concentration was varied from 10(-9) to 10(-5) M in six ventricles. Ryanodine had minimal effect on P-SIA over this concentration range. In six ventricles with elevated intracellular Ca2+ produced by pretreatment with 0.1-0.3 mu M strophanthidin, 10(-5) M ryanodine did not significantly reduce P-SIA. Probability of inducing ventricular pairs or nonsustained ventricular tachycardia was greater in strophanthidin-treated ventricles than in controls, but induction of these repetitive ventricular beats in the strophanthidin group was virtually abolished by addition of 10(-5) M ryanodine. We conclude that release of SR Ca2+ via ryanodine-sensitive channels slightly enhances ventricular sensitivity to induction of SIAs, but this process is not critical to initiation of SIAs, because ryanodine did not completely abolish such arrhythmias. This might occur by Ca2+-induced release of SR Ca2+, where triggering Ca2+ is transported via sarcolemmal stretch-activated channels. Oscillatory release of SR Ca2+ appears to be critical, however, in induction of repetitive ventricular beats by stretch under conditions of intracellular Ca2+ overload, because high-grade ventricular arrhythmias are blocked by ryanodine.