Naftopidil inhibits 5-hydroxytryptamine-induced bladder contraction in rats.

Abstract Naftopidil is an α 1D and α 1A subtype-selective α 1 -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 μM) inhibited 5-HT-induced bladder contraction in a concentration-dependent manner. On the other hand, other α 1 -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 α-methyl-5-HT, 5-HT 2A and 5-HT 2 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-1 H -indole-3-carboxylate (GR113808) or ( R )-3-[2-[2-(4-methylpiperidin-1-yl)ethyl]pyrrolidine-1-sulphonyl]phenol (SB269970), 5-HT 1A , 5-HT 4 and 5-HT 7 receptor antagonists, respectively. Naftopidil inhibited both the 5-HT 2A and 5-HT 2 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.