Naftopidil inhibits 5-hydroxytryptamine-induced bladder contraction in rats

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• 作者：Takumi Sakai ; Ken-ichi Kasahara ; ^{kasahara.kc@om.asahi-kasei.co.jp} ; Ken-ichi Tomita ; Ichiro Ikegaki ; Hiroshi Kuriyama
• 关键词：Naftopidil ; ¦Á1-adrenoceptor antagonist ; 5-HT2A receptor ; 5-HT2B receptor ; Storage symptoms
• 刊名：European Journal of Pharmacology
• 出版年：2013
• 出版时间：30 January, 2013
• 年：2013
• 卷：700
• 期：1-3
• 页码：194-200
• 全文大小：317 K

文摘

Naftopidil is an ¦Á_1D and ¦Á_1A subtype-selective ¦Á₁-adrenoceptor antagonist that has been used to treat lower urinary tract symptoms of benign prostatic hyperplasia. In this study, we investigated the effects of naftopidil on 5-hydroxytryptamine (5-HT)-induced rat bladder contraction (10^?8-10^?4 M). Naftopidil (0.3, 1, and 3 ¦ÌM) inhibited 5-HT-induced bladder contraction in a concentration-dependent manner. On the other hand, other ¦Á₁-adrenoceptor antagonists, tamsulosin, silodosin or prazosin, did not inhibit 5-HT-induced bladder contraction. The 5-HT-induced bladder contraction was inhibited by both ketanserin and 4-(4-fluoronaphthalen-1-yl)-6-propan-2-ylpyrimidin-2-amine (RS127445), serotonin 5-HT_2A and 5-HT_2B receptor antagonists, respectively. In addition, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and ¦Á-methyl-5-HT, 5-HT_2A and 5-HT₂ receptor agonists, respectively, induced bladder contraction. The 5-HT-induced bladder contraction was not inhibited by N-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-pyridin-2-yl-cyclohexanecarboxamide (WAY-100635), [1-[2[(methylsulfonyl)amino]ethyl]-4-piperidinyl]methyl-1-methyl-1H-indole-3-carboxylate (GR113808) or (R)-3-[2-[2-(4-methylpiperidin-1-yl)ethyl]pyrrolidine-1-sulphonyl]phenol (SB269970), 5-HT_1A, 5-HT₄ and 5-HT₇ receptor antagonists, respectively. Naftopidil inhibited both the 5-HT_2A and 5-HT₂ receptor agonists-induced bladder contractions. Naftopidil binds to the human 5-HT_2A and 5-HT_2B receptors with pKi values of 6.55 and 7.82, respectively. These results suggest that naftopidil inhibits 5-HT-induced bladder contraction via blockade of the 5-HT_2A and 5-HT_2B receptors in rats. Furthermore, 5-HT-induced bladder contraction was enhanced in bladder strips obtained from bladder outlet obstructed rats, with this contraction inhibited by naftopidil. The beneficial effects of naftopidil on storage symptoms such as urinary frequency and nocturia in patients with benign prostatic hyperplasia may be due, in part, to the blockade of the 5-HT_2A and 5-HT_2B receptors in the bladder.