Studies on the role of protein kinase C in cardiac contractility

在豚鼠左心房中，内皮素-1 (ET-1) 产生浓度依赖性正性肌力作用。浓度为 10 nM 或更高的 ET-1 引起双成分正性肌力作用，由初始增加阶段（早期成分）和第二个更大的正性肌力阶段（晚期成分）组成。早期成分与 ET-1 诱导的动作电位持续时间延长相关，并被硝苯地平抑制，表明早期成分可能归因于动作电位持续时间延长期间钙流入增加。晚期成分通过蛋白激酶 C 抑制剂 H-7 和十字孢菌素预处理优先受到抑制。发现 ET-1 刺激磷酸肌醇水解（通过 ^3H-肌醇单磷酸积累测量）并激活蛋白激酶 C。这些结果表明，刺激磷酸肌醇水解和随后激活蛋白激酶 C 可能在后期组分的建立中发挥关键作用。由于ET-1显着增强静息后收缩，间接反映了肌浆网中钙的储存量，而晚期成分被兰尼定显着抑制，因此蛋白激酶C激活调节心肌收缩力的潜在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.