K201 (JTV-519) alters the spatiotemporal properties of diastolic Ca 2+ release and the associated diastolic contraction during β-adrenergic stimulation in rat ventricular cardiomyocytes

Abstract

K201 has previously been shown to reduce diastolic contractions in vivo during β-adrenergic stimulation and elevated extracellular calcium concentration ([Ca 2+] o). The present study characterised the effect of K201 on electrically stimulated and spontaneous diastolic sarcoplasmic reticulum (SR)-mediated Ca 2+ release and contractile events in isolated rat cardiomyocytes during β-adrenergic stimulation and elevated [Ca 2+] o. Parallel experiments using confocal microscopy examined spontaneous diastolic Ca 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 2+] o significantly decreased the amplitude of diastolic contractions to ∼16% of control levels. The stimulated free Ca 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 2+ release. Myofilament sensitivity to Ca 2+ was not changed by K201. Confocal microscopy revealed diastolic events composed of multiple Ca 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 2+ release and their associated contractions which may limit the propensity for the contractile dysfunction observed in vivo. © The Author(s) 2011.