Williamson K L, Broadley K J
Arch Int Pharmacodyn Ther. 1987 Feb;285(2):181-98.
Positive inotropic responses to selective alpha-adrenoceptor agonists of isolated paced left atria and chronotropic responses of isolated spontaneously beating right atria of rats were examined. After establishing a cumulative concentration-response curve to isoprenaline, and washout, a concentration-response curve for phenylephrine, methoxamine, cirazoline, amidephrine or UK 14,304 was constructed in the presence of beta-adrenoceptor blockade by propranolol. The 4 alpha 1-selective agonists produced positive inotropic responses, the order of maximum effectiveness being methoxamine greater than phenylephrine greater than cirazoline greater than amidephrine. In terms of EC50 values, methoxamine was the least potent, the other 3 agonists having approximately equivalent potencies. The alpha 2-selective agonist UK 14,304 had no inotropic activity. Weak positive chronotropic activity occurred with phenylephrine, methoxamine and amidephrine; cirazoline exerted only negative chronotropy and UK 14,304 was without effect. Phenylephrine was examined in the absence or presence of prazosin (3 nM) or propranolol (1 microM). Propranolol failed to affect the concentration-response curve for left atrial tension, but prazosin displaced the curve to the right. This indicates that the inotropic responses obtained in the absence of antagonists were mediated solely via alpha-adrenoceptors. After displacement by prazosin there was a further shift by propranolol, suggesting the presence of a beta-adrenoceptor-mediated component at higher concentrations of phenylephrine. The right atrial rate responses to phenylephrine were unaffected by prazosin, but abolished by propranolol; beta-adrenoceptors only are therefore involved in this response. The pA2 values for antagonism of methoxamine-induced increases in left atrial tension by the alpha 1- and alpha 2-selective antagonists prazosin (9.05 +/- 0.06) and idazoxan (6.37 +/- 0.05), respectively, were consistent with the responses being mediated via alpha-adrenoceptors of the alpha 1-subtype. The pA2 value for prazosin was similar to that obtained for antagonism of methoxamine-induced contractions of rat aortic spirals (8.83 +/- 0.13).
研究了大鼠离体起搏左心房对选择性α-肾上腺素能受体激动剂的正性肌力反应以及离体自发搏动右心房的变时反应。在建立对异丙肾上腺素的累积浓度-反应曲线并冲洗后，在普萘洛尔阻断β-肾上腺素能受体的情况下构建去氧肾上腺素、甲氧明、可乐定、酰胺福林或UK 14,304的浓度-反应曲线。4种α1选择性激动剂产生正性肌力反应，最大效能顺序为甲氧明＞去氧肾上腺素＞可乐定＞酰胺福林。就半数有效浓度（EC50）值而言，甲氧明的效力最低，其他3种激动剂的效力大致相当。α2选择性激动剂UK 14,304无正性肌力活性。去氧肾上腺素、甲氧明和酰胺福林出现微弱的正性变时活性；可乐定仅产生负性变时作用，UK 14,304无作用。在无或有哌唑嗪（3 nM）或普萘洛尔（1 μM）存在的情况下研究了去氧肾上腺素。普萘洛尔未能影响左心房张力的浓度-反应曲线，但哌唑嗪使曲线右移。这表明在无拮抗剂时获得的正性肌力反应仅通过α-肾上腺素能受体介导。在被哌唑嗪置换后，普萘洛尔使曲线进一步右移，提示在较高浓度的去氧肾上腺素时存在β-肾上腺素能受体介导的成分。去氧肾上腺素对右心房率的反应不受哌唑嗪影响，但被普萘洛尔消除；因此只有β-肾上腺素能受体参与此反应。α1和α2选择性拮抗剂哌唑嗪（9.05±0.06）和咪唑克生（6.37±0.05）拮抗甲氧明引起的左心房张力增加的pA2值与反应通过α1亚型的α-肾上腺素能受体介导一致。哌唑嗪的pA2值与拮抗甲氧明引起的大鼠主动脉螺旋条收缩的pA2值（8.83±0.13）相似。
