The alpha 1-adrenergic receptor that mediates smooth muscle contraction in human prostate has the pharmacological properties of the cloned human alpha 1c subtype.
The alpha 1-adrenergic receptor that mediates smooth muscle contraction in human prostate has the pharmacological properties of the cloned human alpha 1c subtype.
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发表时间：
1994-04
影响因子：
3.6
通讯作者：
C. Forray;J. Bard;J. Wetzel;G. Chiu;E. Shapiro;R. Tang;H. Lepor;P. Hartig;R. Weinshank;T. Branchek
中科院分区：
文献类型：
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作者：
C. Forray;J. Bard;J. Wetzel;G. Chiu;E. Shapiro;R. Tang;H. Lepor;P. Hartig;R. Weinshank;T. Branchek
分子克隆研究揭示了α 1-肾上腺素能受体的三种亚型的存在。然而，任何个体亚型与其在体内的功能作用之间的联系仍然难以捉摸。为了弥合分子生物学和病理生理学之间的差距，我们选择了一个模型平滑肌系统，人前列腺，并研究了α 1亚型在该组织中的作用。为了确定哪种α 1肾上腺素能受体亚型介导人前列腺的收缩反应，我们首先研究了三种克隆的人α 1亚型（α 1a/d，α 1b和α 1c）的药理学特性。哌唑嗪、特拉唑嗪、多沙唑嗪、阿夫唑嗪和阿巴喹对人α 1亚型无选择性。WB-4101和5-甲基乌拉地尔的效力等级顺序为α 1c > α 1a/d >> α 1b。吲哚拉明和（+）-尼古地平对α 1c-肾上腺素能受体具有选择性，对α 1a/d或α 1b亚型的亲和力至少低10倍。发现SK&F104856对α 1a/d受体亚型的效力比对α 1b-或α 1c-肾上腺素能受体的效力高6倍。我们接下来测定了这些拮抗剂在体外抑制苯肾上腺素诱导的人前列腺组织收缩的效力。吲哚拉明、5-甲基乌拉地尔和SK&F104856抑制收缩反应和取代克隆的人α 1c亚型的[3 H]哌唑嗪的效力相似。我们的数据表明，介导人类前列腺平滑肌收缩的α 1受体具有克隆的人类α 1c肾上腺素能受体的药理学特性。本研究的结果表明，选择性α 1c-肾上腺素能受体拮抗剂可能是临床上更有效和更好的耐受性药物，用于治疗症状性良性前列腺增生。
Molecular cloning studies have revealed the existence of three subtypes of alpha 1-adrenergic receptors. However, the link between any individual subtype and its functional role in the body has remained elusive. In an effort to bridge the gap between molecular biology and pathophysiology, we have chosen a model smooth muscle system, the human prostate, and investigated the role of alpha 1 subtypes in this tissue. To determine which alpha 1-adrenergic receptor subtype mediates the contractile response of the human prostate, we first studied the pharmacological properties of three cloned human alpha 1 subtypes (alpha 1a/d, alpha 1b, and alpha 1c). Prazosin, terazosin, doxazosin, alfuzosin, and abanoquil showed no selectivity for the human alpha 1 subtypes. WB-4101 and 5-methylurapidil showed a rank order of potency of alpha 1c > alpha 1a/d >> alpha 1b. Indoramin and (+)-niguldipine were selective for the alpha 1c-adrenergic receptor, with at least 10-fold lower affinity at either alpha 1a/d or alpha 1b subtypes. SK&F104856 was found to be 6-fold more potent at the alpha 1a/d receptor subtype than at alpha 1b- or alpha 1c-adrenergic receptors. We next determined the potency of these antagonists to inhibit the phenylephrine-induced contraction of human prostatic tissue in vitro. The potencies of indoramin, 5-methylurapidil, and SK&F104856 to inhibit the contractile response and to displace [3H]prazosin from the cloned human alpha 1c subtype were similar. Our data suggest that the alpha 1 receptor that mediates the contraction of human prostate smooth muscle has the pharmacological properties of the cloned human alpha 1c-adrenergic receptor. The findings of the present study suggest that selective alpha 1c-adrenergic receptor antagonists may be clinically more efficacious and better tolerated agents for the treatment of symptomatic benign prostatic hyperplasia.