Tohse N
Department of Pharmacology, Hokkaido University School of Medicine, Sapporo, Japan.
Hokkaido Igaku Zasshi. 1988 Sep;63(5):754-71.
In order to clarify the underlying mechanism of the inotropic effects mediated by alpha-adrenoceptor, changes of electrophysiological properties induced by alpha-adrenoceptor stimulation were investigated in rat and guinea-pig ventricular muscles. In the presence of atenolol (10 microM), phenylephrine increased dose-dependently the developed tension in rat papillary muscles. The time course of the positive inotropic effect produced by phenylephrine (10 microM) consisted of an initial transient positive inotropic phase, followed by a negative inotropic phase and then, a second positive inotropic phase. Phenylephrine also prolonged action potential duration (APD) and increased resting membrane potential (hyperpolarization). The APD prolongation was coincident with the positive inotropic phase, and the hyperpolarization of resting membrane potential developed with the negative inotropic phase and maintained irrelevantly to the following positive inotropic phase. The inotropic and electro-physiological responses by phenylephrine was blocked by prazosin (0.1 microM), but not by yohimbine (0.1 microM), indicating that the changes were mediated by alpha 1-adrenoceptors. Nifedipine (3 microM) abolished the positive inotropic effect and attenuated the APD prolongation. However, nifedipine failed to affect the negative inotropic effect and the hyperpolarization. The hyperpolarization was also observed in the quiscent muscles, and abolished by pretreatment with barium ion (0.5 mM), suggesting the increased potassium premeability by alpha-adrenoceptor stimulation. In the single cell voltage-clamp experiments, alpha-adrenoceptor stimulation was found to increase calcium current (ICa) and to decrease transient outward current (Ito). The changes of both currents explain the APD prolongation and the positive inotropic effect mediated by alpha-adrenoceptors. Protein Kinase C (C-Kinase) is suggested to be one of candidates for intracellular signal transduction systems during alpha-adrenoceptor stimulation. However, TPA, a stimulator of C-Kinase, failed to increase Ica, although it increased the delayed outward current (IK) in guinea-pig single cell, indicating that C-Kinase activation by alpha-adrenoceptors stimulation was not related to the positive inotropic effect. These results suggest that the ponitive inotropic effect mediated by alpha-adrenoceptors is evoked by an increase in Ica and a decrease in Ito, and the negative inotropic effect is related to the resting membrane potassium permeability. Both electro-physiological changes constitute the triphasic inotropic effect mediated by alpha-adrenoceptors in rat cardiac muscles.
为阐明α-肾上腺素能受体介导的变力作用的潜在机制，研究了α-肾上腺素能受体刺激在大鼠和豚鼠心室肌中诱导的电生理特性变化。在阿替洛尔（10微摩尔）存在的情况下，去氧肾上腺素剂量依赖性地增加大鼠乳头肌的收缩张力。去氧肾上腺素（10微摩尔）产生的正性变力作用的时间进程包括最初的短暂正性变力相，随后是负性变力相，然后是第二个正性变力相。去氧肾上腺素还延长动作电位时程（APD）并增加静息膜电位（超极化）。APD延长与正性变力相同时出现，静息膜电位的超极化在负性变力相时出现，并与随后的正性变力相无关地维持。去氧肾上腺素引起的变力和电生理反应被哌唑嗪（0.1微摩尔）阻断，但未被育亨宾（0.1微摩尔）阻断，表明这些变化是由α1-肾上腺素能受体介导的。硝苯地平（3微摩尔）消除了正性变力作用并减弱了APD延长。然而，硝苯地平未能影响负性变力作用和超极化。在静息肌肉中也观察到超极化，并用钡离子（0.5毫摩尔）预处理后消除，提示α-肾上腺素能受体刺激增加钾通透性。在单细胞电压钳实验中，发现α-肾上腺素能受体刺激增加钙电流（ICa）并减少瞬时外向电流（Ito）。两种电流的变化解释了APD延长和α-肾上腺素能受体介导的正性变力作用。蛋白激酶C（C激酶）被认为是α-肾上腺素能受体刺激期间细胞内信号转导系统的候选者之一。然而，TPA（一种C激酶刺激剂）虽然增加了豚鼠单细胞中的延迟外向电流（IK），但未能增加ICa，表明α-肾上腺素能受体刺激引起的C激酶激活与正性变力作用无关。这些结果表明，α-肾上腺素能受体介导的正性变力作用是由ICa增加和Ito减少引起的，负性变力作用与静息膜钾通透性有关。两种电生理变化构成了大鼠心肌中α-肾上腺素能受体介导的三相变力作用。
