Electropharmacological analysis of the signal transduction mechanisms of the delayd rectifier potassium channel of heart cells.

本研究旨在探讨直接激活腺苷酸环化酶对豚鼠心室细胞l型Ca^<2+> (I_<Ca>)和延迟整流K^+电流（I_K）的差异调节。异丙肾上腺素在相同的阈值浓度下，同时增加I_K和I_<Ca>，但水溶性福斯柯林衍生物NKH477在较低的阈值浓度下增加I_K，而不是增加I_<Ca>。另一方面，β -1肾上腺素受体的选择性刺激比I_K更敏感地引起I_<Ca>的增加。这些结果表明，通过腺苷酸环化酶和环amp依赖性蛋白激酶介导的从β -肾上腺素受体到I_<Ca>和I_K通道的简单信号转导途径不足以解释这些差异。因此，我们认为I_<Ca>和I_K通道在β肾上腺素受体刺激过程中可能受到不同程度的调节。我们还在培养的人主动脉内皮细胞中研究了负载荧光Ca^<2+>指示物fura-2的细胞内游离Ca^<2+>浓度（[Ca^<2+>]_i）响应组胺和ATP持续升高的机制。结果表明，[Ca^<2+>]_i持续升高是由于细胞外Ca^<2+>对Cl^-敏感进入人主动脉内皮细胞所致。

This study was designed to investigate the differential modulation of the L-type Ca^<2+> (I_<Ca>) and the delayd rectifier K^+ current (I_K) by direct activation of adenylate cyclase in guinea pig ventricular cells. Isoproterenol equally and simultaneously increased both I_<Ca> and I_K in a same threshold concentration, but a water soluble forskolin derivative, NKH477, increased I_K at lower threshold concentrations than that for increasing I_<Ca>. Selective stimulation of beta-1 adrenoceptors, on the other hand, elicited an increase in I_<Ca> more sensitively than I_K. These results suggest that a simple signal transduction pathway from beta adrenoceptors to I_<Ca> and I_K channels mediated through adenylate cyclase and cyclic AMP-dependent protein kinase is not sufficient to explain these differences. It is, therefore, concluded that I_<Ca> and I_K channels could be differentially regulated during beta adrenoceptor stimulation.Mechanisms responsible for the sustained elevation in intracellular free Ca^<2+> concentration ([Ca^<2+>]_i) in response to histamine and ATP were also studied in cultured human aortic endothelial cells loaded with the fluorescent Ca^<2+> indicator fura-2. Results indicate that the sustained elevation of [Ca^<2+>]_i is resulted from the Cl^--sensitive entry of extracellular Ca^<2+> in human aortic endothelial cells.