Studies on the role of protein kinase C in cardiac contractility

在豚鼠左心房，内皮素-1(ET-1)产生浓度依赖性正性变力作用。10 nM及以上浓度的ET-1可引起双成分正性肌力效应，包括一个初始的增强期(早期成分)和第二个更大的正性肌力阶段(晚期成分)。早期成分与ET-1引起的动作电位时程延长有关，并被硝苯地平抑制，提示早期成分可能与动作电位时程延长时钙内流增加有关。蛋白激酶C抑制剂H-7和星形孢菌素可优先抑制后一组分。通过~3H-肌醇一磷酸蓄积测定，发现ET-1刺激磷脂酰肌醇水解物和激活蛋白激酶C。这些结果提示，刺激磷脂酰肌醇水解物和随后激活蛋白激酶C可能在晚期成分的建立中起关键作用。由于ET-1显著增强间接反映肌浆网钙储存量的静息后收缩，而兰诺定明显抑制晚期成分，因此蛋白激酶C激活调节心肌收缩能力的可能机制之一可能与肌浆网的功能有关。

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.