D'Agostino Gianluigi, Condino Anna M, Gallinari Paola, Franceschetti Gian P, Tonini Marcello
Department of Experimental and Applied Pharmacology, School of Pharmacy, University of Pavia, Viale Taramelli 14, I-27100 Pavia, Italy.
J Pharmacol Exp Ther. 2006 Jan;316(1):129-35. doi: 10.1124/jpet.105.092551. Epub 2005 Sep 15.
Bladder overactivity (OAB) is a chronic and debilitating lower urinary tract (LUT) disorder that affects millions of individuals worldwide. LUT symptoms associated with OAB, such as urgency and urinary incontinence, cause a hygienic and social concern to patients, but their current pharmacological treatment is largely inadequate due to the lack of uroselectivity. Although OAB etiology remains multifactorial and poorly understood, increasing evidence indicates that serotonin [5-hydroxytryptamine (5-HT)] is an endogenous substance involved in the control of micturition at central and peripheral sites. In this study, we demonstrated the presence of three distinct 5-HT receptors localized at parasympathetic nerve terminals of the human bladder by measuring electrically evoked tritiated acetylcholine release in isolated detrusor strips. These prejunctional receptors, involved in both positive and negative feedback mechanisms regulating cholinergic transmission, have been characterized by means of three highly selective 5-HT antagonists for 5-HT(4), 5-HT(7), and 5-HT(1A) receptors, namely GR113808A ([1-[2-[(-methylsulphonyl) amino] ethyl]4-piperinidyl]methyl1-methyl-1H-indole-3-carboxylate succinate), SB269970 [(R)-3-(2-(2-(4-methylpiperidin-1-yl)ethyl)pyrrolidine-1-sulfonyl)phenol hydrochloride], and WAY100635 [N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)-cyclohexane-carboxamide trichloride]. Under these conditions, we confirmed the facilitatory role of 5-HT(4) heteroreceptors on acetylcholine release and revealed for the first time the occurrence of 5-HT(7) and 5-HT(1A) heteroreceptors with a facilitatory and an inhibitory action, respectively. Our findings strengthen the novel concept for the use of recently patented selective 5-HT agonists and antagonists for the control of OAB dysfunctions associated with inflammatory conditions, although their therapeutic efficacy needs to be explored in the clinical setting.
膀胱过度活动症（OAB）是一种慢性且使人衰弱的下尿路（LUT）疾病，影响着全球数百万人。与OAB相关的下尿路症状，如尿急和尿失禁，给患者带来了卫生和社交方面的困扰，但由于缺乏尿选择性，其目前的药物治疗在很大程度上并不充分。尽管OAB的病因仍然是多因素的且了解甚少，但越来越多的证据表明，血清素[5-羟色胺（5-HT）]是一种在内脏和外周部位参与排尿控制的内源性物质。在本研究中，我们通过测量离体逼尿肌条中电诱发的氚化乙酰胆碱释放，证实了人膀胱副交感神经末梢存在三种不同的5-HT受体。这些节前受体参与调节胆碱能传递的正反馈和负反馈机制，已通过三种对5-HT(4)、5-HT(7)和5-HT(1A)受体具有高度选择性的5-HT拮抗剂进行了表征，即GR113808A（[1-[2-[（甲基磺酰基）氨基]乙基]-4-哌啶基]甲基-1-甲基-1H-吲哚-3-羧酸酯琥珀酸盐）、SB269970[（R）-3-（2-（2-（4-甲基哌啶-1-基）乙基）吡咯烷-1-磺酰基）苯酚盐酸盐]和WAY100635[N-（2-（4-（2-甲氧基苯基）-1-哌嗪基）乙基）-N-（2-吡啶基）-环己烷甲酰胺三氯化物]。在这些条件下，我们证实了5-HT(4)异受体对乙酰胆碱释放的促进作用，并首次揭示了分别具有促进作用和抑制作用的5-HT(7)和5-HT(1A)异受体的存在。我们的研究结果强化了使用最近获得专利的选择性5-HT激动剂和拮抗剂来控制与炎症相关的OAB功能障碍这一新概念，尽管它们的治疗效果需要在临床环境中进行探索。
