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Abstract
K201 has previously been shown to reduce diastolic contractions in vivo during β-adrenergic stimulation and elevated extracellular calcium concentration ([Ca^sup 2+^]^sub o^). The present study characterised the effect of K201 on electrically stimulated and spontaneous diastolic sarcoplasmic reticulum (SR)-mediated Ca^sup 2+^ release and contractile events in isolated rat cardiomyocytes during β-adrenergic stimulation and elevated [Ca^sup 2+^]^sub o^. Parallel experiments using confocal microscopy examined spontaneous diastolic Ca^sup 2+^ release events at an enhanced spatiotemporal resolution. 1.0 μmol/L K201 in the presence of 150 nmol/L isoproterenol (ISO) and 4.75 mmol/L [Ca^sup 2+^]^sub o^ significantly decreased the amplitude of diastolic contractions to ~16% of control levels. The stimulated free Ca^sup 2+^ transient amplitude was significantly reduced, but stimulated cell shortening was not significantly altered. When intracellular buffering was taken into account, K201 led to an increase in action potential-induced SR Ca^sup 2+^ release. Myofilament sensitivity to Ca^sup 2+^ was not changed by K201. Confocal microscopy revealed diastolic events composed of multiple Ca^sup 2+^ waves (2-3) originating at various points along the cardiomyocyte length during each diastolic period. 1.0 μmol/L K201 significantly reduced the (a) frequency of diastolic events and (b) initiation points/diastolic interval in the remaining diastolic events to 61% and 71% of control levels respectively. 1.0 μmol/L K201 can reduce the probability of spontaneous diastolic Ca^sup 2+^ release and their associated contractions which may limit the propensity for the contractile dysfunction observed in vivo.[PUBLICATION ABSTRACT]