Brief rapid pacing depresses contractile function via Ca2+/PKC-dependent signaling in cat ventricular myocytes

Department of Physiology, Stritch School of Medicine, Loyola University Chicago and Cardiovascular Institute, Maywood, Illinois 60153 The purpose of this study is to determine the effects of brief rapid pacing (RP; ~200-240 beats/min for ~5 min) on contractile function in ventricular myocytes. RP was followed by a sustained inhibition of peak systolic cell shortening ( 44 ± 4%) that was not due to changes in diastolic cell length, membrane voltage, or L-type Ca 2+ current ( I Ca,L ). During RP, baseline and peak intracellular Ca 2+ concentration ([Ca 2+ ] i ) increased markedly. After RP, Ca 2+ transients were similar to control. The effects of RP on cell shortening were not prevented by 1 µM calpain inhibitor I, 25 µM L - N 5 -(1-iminoethyl)-orthinthine, or 100 µM N G -monomethyl- L -arginine. However, RP-induced inhibition of cell shortening was prevented by lowering extracellular [Ca 2+ ] (0.5 mM) during RP or exposure to chelerythrine (2-4 µM), a protein kinase C (PKC) inhibitor, or LY379196 (30 nM), a selective inhibitor of PKC- . Exposure to phorbol ester (200 nM phorbol 12-myristate 13-acetate) inhibited cell shortening ( 46 ± 7%). Western blots indicated that cat myocytes express PKC- , - , and - as well as PKC- . These findings suggest that brief RP of ventricular myocytes depresses contractility at the myofilament level via Ca 2+ /PKC-dependent signaling. These findings may provide insight into the mechanisms of contractile dysfunction that follow paroxysmal tachyarrhythmias. intracellular calcium; excitation-contraction coupling; stunning; tachyarrhythmias; protein kinase C