Skomedal T, Schiander I G, Osnes J B
Department of Pharmacology, University of Oslo, Norway.
J Pharmacol Exp Ther. 1988 Dec;247(3):1204-10.
The classical approach of displacing the dose-response curve by an alpha adrenoceptor blocker has most often failed to demonstrate a contribution of an alpha adrenoceptor-mediated component in the final inotropic response to norepinephrine unless the beta adrenoceptors are extensively blocked. To unmask and quantify the inotropic components in the response to norepinephrine, we took a different approach by studying reversal responses to appropriate adrenoceptor blockers in isolated paced rat papillary muscles maximally stimulated by norepinephrine. The inotropic response to norepinephrine was rapidly reversed by simultaneous addition of the beta adrenoceptor blocker timolol and the alpha adrenoceptor blocker prazosin. When the adrenoceptor blockers were added sequentially, both alpha and beta adrenoceptor-mediated components in the inotropic response to norepinephrine could be demonstrated: one beta adrenoceptor-mediated component (timolol sensitive only) that represented about 75% of the inotropic response and one alpha adrenoceptor-mediated component (prazosin sensitive only) that represented about 25% of the inotropic response. When one adrenoceptor population was eliminated by giving one of the adrenoceptor blockers before norepinephrine, the inotropic response in this situation could be completely reversed by the other adrenoceptor blocker. The expression of both alpha and beta adrenoceptor-mediated components was significantly less during concomitant receptor stimulation than when the respective receptor populations were stimulated separately. Thus, there was apparently a mutual inhibition of one component upon the other. Although the beta adrenoceptor-mediated inotropic component clearly was the dominating one, the present observations will explain the difficulties in demonstrating an alpha adrenoceptor-mediated component during unopposed beta adrenoceptor stimulation in the inotropic response to norepinephrine in earlier studies.
经典的用α肾上腺素能受体阻滞剂使剂量-反应曲线移位的方法，除非β肾上腺素能受体被广泛阻断，否则大多无法证明α肾上腺素能受体介导的成分对去甲肾上腺素最终正性肌力反应有贡献。为了揭示并量化对去甲肾上腺素反应中的正性肌力成分，我们采用了一种不同的方法，即研究在去甲肾上腺素最大刺激下的离体起搏大鼠乳头肌中对合适的肾上腺素能受体阻滞剂的翻转反应。同时加入β肾上腺素能受体阻滞剂噻吗洛尔和α肾上腺素能受体阻滞剂哌唑嗪，可迅速逆转对去甲肾上腺素的正性肌力反应。当依次加入肾上腺素能受体阻滞剂时，对去甲肾上腺素的正性肌力反应中α和β肾上腺素能受体介导的成分均可被证明：一个β肾上腺素能受体介导的成分（仅对噻吗洛尔敏感）约占正性肌力反应的75%，一个α肾上腺素能受体介导的成分（仅对哌唑嗪敏感）约占正性肌力反应的25%。当在给予去甲肾上腺素之前给予一种肾上腺素能受体阻滞剂消除其中一种受体群体时，这种情况下的正性肌力反应可被另一种肾上腺素能受体阻滞剂完全逆转。与分别刺激各自的受体群体时相比，在同时刺激受体时，α和β肾上腺素能受体介导的成分表达均显著降低。因此，显然一种成分对另一种成分有相互抑制作用。尽管β肾上腺素能受体介导的正性肌力成分显然是主要成分，但本观察结果将解释在早期研究中，在对去甲肾上腺素的正性肌力反应中，当β肾上腺素能受体无对抗刺激时，难以证明α肾上腺素能受体介导的成分的原因。
