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 d iastolic dilation. To test the hypothesis that Ca2+ release from sarco plasmic reticulum (SR) is important in initiation of such stretch-indu ced arrhythmias (SLAs), we studied effects of ryanodine in an isolated canine heart model. Arrhythmias were induced by a computerized ventri cular volume servo-pump system that transiently increased left ventric ular volume by precise amounts (Delta V) during diastole. The probabil ity of eliciting an SIA (P-SIA) was compared at the minimum Delta V th at resulted in P-SIA of greater than or equal to 90% under baseline co nditions. Block of SR Ca2+ release with 10(-5) M ryanodine in 11 ventr icles produced mild inhibition of SIAs, reducing P-SIA by 19.4% (P = 0 .039). Because ryanodine produces leakage of SR Ca2+ at low concentrat ion and block of SR Ca2+ release at high concentration, ryanodine conc entration was varied from 10(-9) to 10(-5) M in six ventricles. Ryanod ine had minimal effect on P-SIA over this concentration range. In six ventricles with elevated intracellular Ca2+ produced by pretreatment w ith 0.1-0.3 mu M strophanthidin, 10(-5) M ryanodine did not significan tly reduce P-SIA. Probability of inducing ventricular pairs or nonsust ained ventricular tachycardia was greater in strophanthidin-treated ve ntricles than in controls, but induction of these repetitive ventricul ar beats in the strophanthidin group was virtually abolished by additi on of 10(-5) M ryanodine. We conclude that release of SR Ca2+ via ryan odine-sensitive channels slightly enhances ventricular sensitivity to induction of SIAs, but this process is not critical to initiation of S IAs, because ryanodine did not completely abolish such arrhythmias. Th is might occur by Ca2+-induced release of SR Ca2+, where triggering Ca 2+ is transported via sarcolemmal stretch-activated channels. Oscillat ory release of SR Ca2+ appears to be critical, however, in induction o f repetitive ventricular beats by stretch under conditions of intracel lular Ca2+ overload, because high-grade ventricular arrhythmias are bl ocked by ryanodine.