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

The purpose of this study is to determine the effects of brief rapid pacing (RP; similar to 200-240 beats/min for similar to5 min) on contractile func tion in ventricular myocytes. RP was followed by a sustained inhibition of peak systolic cell shortening (-44 +/- 4%) that was not due to changes in d iastolic cell length, membrane voltage, or L-type Ca2+ current (I-Ca,I-L). During RP, baseline and peak intracellular Ca2+ concentration ([Ca2+](i)) i ncreased markedly. After RP, Ca2+ transients were similar to control. The e ffects of RP on cell shortening were not prevented by 1 muM calpain inhibit or I, 25 muM L-N-5-(1-iminoethyl)-orthinthine, or 100 muM 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 cheleryt hrine (2-4 muM), a protein kinase C (PKC) inhibitor, or LY379196 (30 nM), a selective inhibitor of PKC-beta. Exposure to phorbol ester (200 nM phorbol 12-myristate 13-acetate) inhibited cell shortening (-46 +/- 7%). Western b lots indicated that cat myocytes express PKC-alpha,-delta, and -epsilon as well as PKC-beta. These findings suggest that brief RP of ventricular myocy tes depresses contractility at the myofilament level via Ca2+/PKC-dependent signaling. These findings may provide insight into the mechanisms of contr actile dysfunction that follow paroxysmal tachyarrhythmias.