Nagashima M, Hattori Y, Akaishi Y, Tohse N, Sakuma I, Kitabatake A, Kanno M
Department of Pharmacology, Hokkaido University School of Medicine, Sapporo, Japan.
Am J Physiol. 1996 Oct;271(4 Pt 2):H1423-32. doi: 10.1152/ajpheart.1996.271.4.H1423.
Stimulation of alpha 1-adrenoceptors produces a positive inotropic effect in rat and rabbit ventricular myocardium via different mechanisms, the prolongation of action potential duration (APD) exclusively in the former and an increase in myofibrillar Ca2+ sensitivity in large part in the latter. This study was designed to determine whether the two inotropic mechanisms are mediated by different alpha 1-adrenoceptor subtypes. In rat papillary muscles, the positive inotropic effect and APD prolongation induced by phenylephrine (in the presence of propranolol) were inhibited by WB-4101, but not affected by chlorethylclonidine (CEC). WB-4101, but not CEC, blocked the phenylephrine-induced inhibition of the transient outward current (Ito) in rat ventricular cells. On the other hand, WB-4101 and CEC each antagonized the positive inotropic effect of phenylephrine in rabbit papillary muscles. However, the phenylephrine-induced APD prolongation observed in rabbit papillary muscles was blocked only by WB-4101. These results indicate that the WB-4101 sensitive alpha 1-adrenoceptor subtype mediates the positive inotropism that is correlated with the APD prolongation resulting from Ito reduction, whereas the CEC-sensitive subtype mediates the positive inotropism that is probably associated with increased myofibrillar Ca2+ sensitivity. Radioligand binding studies with [3H] prazosin showed a similar ratio of alpha 1A-to alpha 1B-adrenoceptor subtypes in rat and rabbit ventricular myocardium, implying that the different degree of contribution of each action mechanism to the overall inotropic effect in the two species cannot be explained by distribution of the alpha 1-adrenoceptor subtypes.
刺激α1 - 肾上腺素能受体通过不同机制在大鼠和兔心室肌中产生正性肌力作用，在前者中是单纯延长动作电位时程（APD），而在后者中很大程度上是增加肌原纤维对Ca2+的敏感性。本研究旨在确定这两种正性肌力机制是否由不同的α1 - 肾上腺素能受体亚型介导。在大鼠乳头肌中，苯肾上腺素（在普萘洛尔存在下）诱导的正性肌力作用和APD延长被WB - 4101抑制，但不受氯乙可乐定（CEC）影响。WB - 4101而非CEC阻断了苯肾上腺素诱导的大鼠心室细胞瞬时外向电流（Ito）的抑制。另一方面，WB - 4101和CEC均拮抗苯肾上腺素在兔乳头肌中的正性肌力作用。然而，在兔乳头肌中观察到的苯肾上腺素诱导的APD延长仅被WB - 4101阻断。这些结果表明，WB - 4101敏感的α1 - 肾上腺素能受体亚型介导了与因Ito减少导致的APD延长相关的正性肌力作用，而CEC敏感的亚型介导了可能与肌原纤维Ca2+敏感性增加相关的正性肌力作用。用[3H]哌唑嗪进行的放射性配体结合研究表明，大鼠和兔心室肌中α1A与α1B - 肾上腺素能受体亚型的比例相似，这意味着两种物种中每种作用机制对整体正性肌力作用的不同贡献程度不能用α1 - 肾上腺素能受体亚型的分布来解释。
