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

Abstract

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 Ca2+ current ( I Ca,L). During RP, baseline and peak intracellular Ca2+ concentration ([Ca2+]i) increased markedly. After RP, Ca2+ transients were similar to control. The effects of RP on cell shortening were not prevented by 1 μM calpain inhibitor I, 25 μMl- 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 [Ca2+] (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-β. Exposure to phorbol ester (200 nM phorbol 12-myristate 13-acetate) inhibited cell shortening (−46 ± 7%). Western blots indicated that cat myocytes express PKC-α, -δ, and -ε as well as PKC-β. These findings suggest that brief RP of ventricular myocytes depresses contractility at the myofilament level via Ca2+/PKC-dependent signaling. These findings may provide insight into the mechanisms of contractile dysfunction that follow paroxysmal tachyarrhythmias.