Faculty of Pharmaceutical Sciences from Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
J Pharm Pharmacol. 2013 Sep;65(9):1337-46. doi: 10.1111/jphp.12105. Epub 2013 Jul 30.
Our main objectives were to investigate the affinity properties of endothelial and muscular α1D -adrenoceptors and to characterize the cross-talk between endothelial α1D -adrenoceptors and β2 -adrenoceptors in rat carotid.
Relaxation and contraction concentration-response curves for phenylephrine (α1 -adrenergic agonist) were obtained in carotid rings in absence or presence of increasing concentrations of BMY7378 (α1D -adrenergic antagonist), combined or not with increasing concentration of ICI-118,551 (β2 -adrenergic antagonist). Schild analysis was used to estimate the affinity constant from pA2 values of BMY7378.
BMY7378 produced an unsurmountable antagonism on phenylephrine-induced relaxation but a surmountable antagonism on phenylephrine-induced contraction. BMY7378 potency was higher in inhibiting the relaxation than the contraction induced by phenylephrine because the rightward shifts induced by BMY7378 were greater in the relaxation. The apparent pA2 value for BMY7378 in phenylephrine-induced relaxation was greater than in contraction. When combined with ICI-118,551, BMY7378 yielded a surmountable antagonism on phenylephrine-induced relaxation and presented a pA2 value similar to that obtained in phenylephrine-induced contraction.
Endothelial α1D -adrenoceptors, which mediates rat carotid relaxation, present high ligand affinity because of the cross-talk with β2 -adrenoceptors, which explains the higher potency of phenylephrine in inducing relaxation than contraction and the atypical unsurmountable antagonism produced by BMY7378 on phenylephrine-induced relaxation.
我们的主要目的是研究内皮和肌 α1D -肾上腺素能受体的亲和特性，并描述大鼠颈动脉内皮 α1D -肾上腺素能受体与 β2 -肾上腺素能受体之间的串扰。
在不存在或存在增加浓度的 BMY7378（α1D -肾上腺素能拮抗剂）的情况下，获得了苯肾上腺素（α1 -肾上腺素能激动剂）对颈动脉环的松弛和收缩浓度-反应曲线，并且结合或不结合增加浓度的 ICI-118,551（β2 -肾上腺素能拮抗剂）。使用 Schild 分析从 BMY7378 的 pA2 值估算亲和常数。
BMY7378 对内源性去甲肾上腺素诱导的松弛产生不可逾越的拮抗作用，但对内源性去甲肾上腺素诱导的收缩产生可逾越的拮抗作用。BMY7378 抑制苯肾上腺素诱导的松弛比收缩的作用更强，因为 BMY7378 引起的右移在松弛中更大。在苯肾上腺素诱导的松弛中，BMY7378 的表观 pA2 值大于在收缩中。当与 ICI-118,551 联合使用时，BMY7378 对内源性去甲肾上腺素诱导的松弛产生可逾越的拮抗作用，并呈现出与在苯肾上腺素诱导的收缩中获得的相似的 pA2 值。
介导大鼠颈动脉松弛的内皮 α1D -肾上腺素能受体由于与 β2 -肾上腺素能受体的串扰而具有高配体亲和力，这解释了苯肾上腺素在诱导松弛方面比收缩方面的作用更强，以及 BMY7378 对内源性去甲肾上腺素诱导的松弛产生的非典型不可逾越的拮抗作用。
