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

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) (100 nM) (n = 15) greatly steepened the restitution curves (S_max > 1) (p < .01) at each site compared to the control group (n = 15). Furthermore, treatment with PMA also induced larger spatial dispersions of S_max (p < .05) and decreased the thresholds of the VA and APD alternans (p < .01). However, perfused with the PKC inhibitor, bisindolylmaleimide (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 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 S_max 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.