Cardiac alternans closely linked to calcium dysregulation is a crucial risk factor for fatal arrhythmia causing especially sudden death. Calcium overload is well-known to activate Ca-dependent protein kinase C (PKC); however, the effects of PKC on arrhythmogenic cardiac alternans have not yet been investigated. This study aimed to determine the contributions of PKC activities in cardiac alternans associated with calcium cycling disturbances. In the present study, action potential duration alternans (APD-ALT) induced by high free intracellular calcium ([Ca]) exerted not only in a calcium concentration-dependent manner but also in a frequency-dependent manner. High [Ca]-induced APD-ALT was suppressed by not only BAPTA-AM but also nifedipine. On the other hand, PKC inhibitors BIM and Gö 6976 eliminated high [Ca]-induced APD-ALT, and PKC activator PMA was found to induce APD-ALT at normal [Ca] condition. Furthermore, BIM effectively prevented calcium transient alternans (CaT-ALT) and even CaT disorders caused by calcium overload. Moreover, BIM not only eliminated electrocardiographic T-wave alternans (TWA) caused by calcium dysregulation, but also lowered the incidence of ventricular arrhythmias in isolated hearts. What's more, BIM prevented the expression of PKC α upregulated by calcium overload in high calcium-perfused hearts. We firstly found that pharmacologically inhibiting Ca-dependent PKC over-activation suppressed high [Ca]-induced cardiac alternans. This recognition indicates that inhibition of PKC activities may become a therapeutic target for the prevention of pro-arrhythmogenic cardiac alternans associated with calcium dysregulation.
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