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

Objective To investigate the role of protein kinase C (PKC) in action potential duration (APD) restitution and ventricular tachyarrhythmias (VA). Methods and results Rabbits hearts were isolated and prepared for Langendorff perfusion technique. The S 1 -S 2 method and dynamic S 1 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 PMA (100 nM) (n = 15) greatly steepened the restitution curves (S max >1) ( P < 0.01) at each site compared to the control group (n = 15). Furthermore, treatment with PMA also induced larger spatial dispersions of S max ( P < 0.05) and decreased the thresholds of the VA and APD alternans ( P < 0.01). However, perfused with the PKC inhibitor, BIM (500 nM) (n = 10), reversibly flattened the APD restitution curves at each site (S max < 1), decreased the spatial dispersions of S max , and increased the thresholds of APD alternans and VA. According to the results of patch-clamp, peak amplitude of L-type Ca 2+ current was significantly increased by addition of PMA compared with CTL group (P < 0.05). Antagonize this current with verapamil (n = 10) can fully inhibited the PMA induced increasing of S max and inducibility of VA and alternans. Conclusion PKC activation increased the dispersion of APD restitution and thus led to occurrence of VA, which possibly related to the increased Ca 2+ influx.