Effect of ryanodine on the initiation and perpetuation of stretch-induced arrhythmias in isolated canine ventricle
Jobe, R.L.; Taylor, L.K.; Wang, Z.; Berger, C.M.; Stacy, G.P.; Hansen, D.E.
American Journal of Physiology 267(5 Pt 2): H1736-H1744
1994
ISSN/ISBN: 0002-9513 PMID: 7526710 Document Number: 428287
Ventricular arrhythmias can be initiated by a mechanism of transient diastolic dilation. To test the hypothesis that Ca-2+ release from sarcoplasmic reticulum (SR) is important in initiation of such stretch-induced arrhythmias (SIAs), 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 (AV) during diastole. The probability of eliciting an SIA (PsA) was compared at the minimum AV that resulted in PsA of gtoreq 90% under baseline conditions. Block of SR Ca-2+ release with 10-5 M ryanodine in 11 ventricles produced mild inhibition of SIAs, reducing PsA by 19.4% (P = 0.039). Because ryanodine produces leakage of SR Ca-2+ at low concentration and block of SR Ca-2+ release at high concentration, ryanodine concentration was varied from 10-9 to 10-5 M in six ventricles. Ryanodine had minimal effect on PsA over this concentration range. In six ventricles with elevated intracellular Ca-2+ 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 Ca-2+ 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 Ca-2+-induced release of SR Ca-2+, where triggering Ca-2+ is transported via sarcolemmal stretch-activated channels. Oscillatory release of SR Ca-2+ appears to be critical, however, in induction of repetitive ventricular beats by stretch under conditions of intracellular Ca-2+ overload, because high-grade ventricular arrhythmias are blocked by ryanodine.