β3-adrenoceptors in human detrusor muscle
β3-adrenoceptors in human detrusor muscle
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DOI：
10.1016/s0090-4295(01)01635-1
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发表时间：
2002-05-01
期刊：
影响因子：
2.1
通讯作者：
Yamaguchi, O
中科院分区：
文献类型：
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作者：
Yamaguchi, O
逼尿肌含有 β 肾上腺素受体 (β-AR)，在大多数物种中已发现 2 种亚型 - β(1)-AR 和 β(2)-AR。虽然 β(2)-AR 通过激活腺苷酸环化酶在肌肉松弛中发挥重要作用，但有证据表明，第三种亚型 β(3)-AR 与内源性儿茶酚胺的代谢功能有关，可介导人逼尿肌的松弛。 β(3)-AR 信使 RNA (mRNA) 在人膀胱组织中占主导地位，其中 97% 的总 β-AR mRNA 为 β(3)-AR 亚型，仅 1.5% 和 1.4% 为 β(1)-AR 和 β(2)-AR 亚型。 从功能上讲，选择性 β(3)-AR 激动剂可放松人离体逼尿肌，而选择性beta(1)-AR/beta(2)-AR 激动剂则不会。异丙肾上腺素诱导的松弛可被选择性 β(3)-AR 拮抗剂抑制，但不会被选择性 β(1)-AR 或 β(2)-AR 拮抗剂抑制。在动物模型中，β(3)-AR 激动剂可增加膀胱容量，并且仅具有微弱的心血管副作用。尽管这一证据表明β(3)-AR激动剂可用于治疗膀胱过度活动症，但在动物模型中鉴定出β(3)-AR激动剂作为抗肥胖剂的临床试验表明存在震颤和心动过速的副作用。开发对人β(3)-AR具有高选择性的化合物，通过使用转染人β(1)-AR、β(2)-AR和β(3)-AR基因的细胞系的筛选技术来鉴定，可以缓解此类问题。初步发现，49%（43 名特发性逼尿肌不稳定患者中的 21 名）存在 β(3)-AR 基因的色氨酸 64 精氨酸突变（这可能是一种有用的遗传标记），有证据表明 β(3)-AR 是治疗膀胱过度活动症的治疗靶点。
The detrusor muscle contains beta-adrenoceptors (beta-AR), and 2 subtypes-beta(1)-AR and beta(2)-AR-have been identified in most species. Although beta(2)-AR has an important role in muscle relaxation via activation of adenylate cyclase, evidence suggests that a third subtype beta(3)-AR, which is implicated in metabolic functions of endogenous catecholamines, mediates relaxation of human detrusor muscle. There is a predominant expression Of beta(3)-AR messenger RNA (mRNA) in human bladder tissue, with 97% of total beta-AR mRNA being represented by the beta(3)-AR subtype and only 1.5% and 1.4% by the beta(1)-AR and beta(2)-AR subtypes, respectively, Functionally, selective beta(3)-AR agonists relax human isolated detrusor, whereas selective beta(1)-AR/beta(2)-AR agonists do not. Isoproterenol-induced relaxation is inhibited by selective beta(3)-AR antagonists but not by selective beta(1)-AR or beta(2)-AR antagonists. In animal models, beta(3)-AR agonists increase bladder capacity and have only weak cardiovascular side effects. Although this evidence points toward the clinical utility of beta(3)-AR agonists as therapy for overactive bladder, clinical trials Of beta(3)-AR agonists identified in animal models as antiobesity agents indicate side effects of tremor and tachycardia. Development of compounds with high selectivity for the human beta(3)-AR, identified by screening techniques using cell lines transfected with the human beta(1)-AR, beta(2)-AR, and beta(3)-AR genes, may mitigate such problems. Together with the preliminary finding that 49% (21 of 43) of patients with idiopathic detrusor instability have a tryptophan 64 arginine mutation of the beta(3)-AR gene, which may be a useful genetic marker, evidence points toward beta(3)-AR being a therapeutic target for treatment of overactive bladder disorder.