Activation of PKC affects the ventricular restitution properties and arrhythmogenesis through L-type Ca+ current.

Abstract

To investigate the role of protein kinase C (PKC) in action potential duration (APD) restitution and ventricular tachyarrhythmias (VAs). Rabbits hearts were isolated and prepared for Langendorff perfusion technique. The stimuli-extra-stimulus (S1-S2) method and dynamic S1 pacing protocol were performed to construct APD restitution and to induce APD alternans or VA, respectively, at 10 sites throughout the ventricular chamber. Administration of phorbol-12-myristate-13-acetate (PMA) (100nM) (n=15) greatly steepened the restitution curves (Smax>1) (p<.01) at each site compared to the control group (n=15). Furthermore, treatment with PMA also induced larger spatial dispersions of Smax (p<.05) and decreased the thresholds of the VA and APD alternans (p<.01). However, perfused with the PKC inhibitor, bisindolylmaleimide (BIM) (500nM) (n=10), reversibly flattened the APD restitution curves at each site (Smax<1), decreased the spatial dispersions of Smax, and increased the thresholds of APD alternans and VA. According to the results of patch-clamp, peak amplitude of L-type Ca2+ current was significantly increased by addition of PMA compared with control (CTL) group (p<.05). Antagonize this current with verapamil (n=10) can fully inhibited the PMA induced increasing of Smax and inducibility of VA and alternans. PKC activation increased the dispersion of APD restitution and thus led to occurrence of VA, which possibly related to the increased Ca2+ influx.