Ford A P, Arredondo N F, Blue D R, Bonhaus D W, Jasper J, Kava M S, Lesnick J, Pfister J R, Shieh I A, Vimont R L, Williams T J, McNeal J E, Stamey T A, Clarke D E
Center for Neurobiology, Roche Bioscience, Palo Alto, California, USA.
Mol Pharmacol. 1996 Feb;49(2):209-15.
Norepinephrine (NE) contracts smooth muscle cells within the human lower urinary tract (LUT) (bladder neck, prostate, and urethra). Receptor distribution and pharmacological evidence have implicated activation of alpha 1A-adrenoceptors. We disclose the pharmacological properties of the novel, selective alpha 1A-adrenoceptor antagonist N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro- alpha,alpha-dimethyl-1H-indole-3-ethanamine hydrochloride (RS-17053) and examine critically the pharmacological identity of the alpha 1-adrenoceptor mediating contractions to NE in human LUT tissues. In several tissues from rat and cloned adrenoceptors, RS-17053 displayed high affinity for the alpha 1A-adrenoceptor (pKi and pA2 estimates of 9.1-9.9) and a 30-100-fold selectivity over the alpha 1B- and the alpha 1D-adrenoceptor subtypes (pK1 and pA2 estimates of 7.7-7.8). However, in isolated smooth muscle preparations from human LUT tissues, RS-17053 antagonized responses to NE only at high concentrations. Estimates of affinity (pA2) at alpha 1-adrenoceptors mediating NE-induced contractions were 7.5 in prostatic periurethral longitudinal smooth muscle (compared with 8.6 for prazosin), 6.9 in anterior fibromuscular stroma (prazosin, 8.9), and 7.1 in bladder neck (prazosin, 8.5). These findings indicate that contractile responses to NE in human LUT tissues are mediated by a receptor displaying pharmacological properties that are clearly different from those of the defined alpha 1A-adrenoceptor and raise the possibility that multiple forms of the alpha 1A-adrenoceptor may exist in human LUT that are discriminated by RS-17053. In this regard, the affinity estimates obtained with RS-17053 and other alpha 1-adrenoceptor antagonists in human LUT tissues are identical to those described for the putative alpha 1L-adrenoceptor.
去甲肾上腺素（NE）可使人体下尿路（LUT）（膀胱颈、前列腺和尿道）内的平滑肌细胞收缩。受体分布和药理学证据表明，α1A - 肾上腺素能受体被激活。我们揭示了新型选择性α1A - 肾上腺素能受体拮抗剂N - [2 - (2 - 环丙基甲氧基苯氧基)乙基]-5 - 氯-α,α - 二甲基-1H - 吲哚-3 - 乙胺盐酸盐（RS - 17053）的药理学特性，并严格检验介导人体LUT组织对NE收缩反应的α1 - 肾上腺素能受体的药理学特性。在大鼠的几种组织和克隆的肾上腺素能受体中，RS - 17053对α1A - 肾上腺素能受体表现出高亲和力（pKi和pA2估计值为9.1 - 9.9），对α1B - 和α1D - 肾上腺素能受体亚型具有30 - 100倍的选择性（pK1和pA2估计值为7.7 - 7.8）。然而，在人体LUT组织的离体平滑肌制剂中，RS - 17053仅在高浓度时拮抗对NE的反应。在介导NE诱导收缩的α1 - 肾上腺素能受体处的亲和力（pA2）估计值在前列腺周尿道纵行平滑肌中为7.5（哌唑嗪为8.6），在前纤维肌基质中为6.9（哌唑嗪为8.9），在膀胱颈中为7.1（哌唑嗪为8.5）。这些发现表明，人体LUT组织中对NE的收缩反应是由一种药理学特性与已定义的α1A - 肾上腺素能受体明显不同的受体介导的，并增加了人体LUT中可能存在多种可被RS - 17053区分的α1A - 肾上腺素能受体形式的可能性。在这方面，RS - 17053和其他α1 - 肾上腺素能受体拮抗剂在人体LUT组织中获得的亲和力估计值与针对假定的α1L - 肾上腺素能受体所描述的估计值相同。
