Studies on the role of protein kinase C in cardiac contractility

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In guinea pig left atria, endothelin-1 (ET-1) produced a concentrationdependent positive inotropic effect. ET-1 at concentrations of 10 nM and higher caused a dual-component positive inotropic effect composed of an initial increasing phase (early component) and a second greater positive inotropic phase (late component). The early component was correlated to the ET-1-induced prolongation of action potential duration in the time course and was inhibited by nifedipine, indicating that the early component may be attributed to the increased calcium influx during the prolonged action potential duration. The late component was preferentially suppressed by pretreatment with the protein kinase C inhibitors, H-7 and staurosporine. ET-1 was found to stimulate phosphoinositide hydrolysis as measured by ^3H-inositol monophosphate accumulation and to activate protein kinase C. These results suggest that stimulation of phosphoinositide hydrolysis and subsequent activation of protein kinase C may play a key role in establishment of the late component. Since ET-1 significantly enhanced the postrest contraction which reflects indirectly the amount of calcium stored in the sarcoplasmic reticulum and the late component was markedly inhibited by ryanodine, one of the potential mechanisms by which protein kinase C activation regulates cardiac contractility may be related to the function of the sarcoplasmic reticulum.