Vabicaserin Hydrochloride

5-Hydroxytryptamine (5-HT) can enhance human ureteral contractions. However, the mediating receptors have not been clarified. This study sought to further characterize the mediating receptors using several selective antagonists and agonists. Human distal ureters were obtained from 96 patients undergoing cystectomy. The mRNA expression levels of 5-HT receptors were examined using RT-qPCR experiments. The phasic contractions of ureter strips, either spontaneous or evoked with neurokinin, were recorded in an organ bath. Among the 13 5-HT receptors, 5-HT_2A and 5-HT_2C receptors showed the highest mRNA expression levels. 5-HT (10^-7-10^-4 M) increased the frequency and baseline tension of phasic contractions in a concentration-dependent manner. However, a desensitization effect was observed. The 5-HT_2C receptor selective antagonist, SB242084 (10,30,100 nM), shifted the 5-HT concentration-response curves (frequency and baseline tension) rightward with a pA2 value of 8.05 and 7.75, respectively. 5-HT_2C receptor selective agonist, vabicaserin, increased contraction frequency with an Emax of 35% of 5-HT. 5-HT_2A receptor selective antagonist, volinanserin (1,10,100 nM), only reduced baseline tension with a pA2 of 8.18. The selective antagonists of 5-HT_1A, 1B, 1D, 2B, 3, 4, 5, 6, and 7 had no antagonism. Blockade of voltage-gated sodium channels, α1-adrenergic receptors, adrenergic neurotransmission, and neurokinin-2 receptors using tetrodotoxin, tamsulosin, guanethidine, and Men10376, respectively, and desensitization of sensory afferents using capsaicin (100 μM), significantly reduced 5-HT effects. We conclude that 5-HT enhanced ureteral phasic contractions mainly by activating 5-HT_2C and 5-HT_2A receptors. Sympathetic nerve and sensory afferents partly contributed to 5-HT effects. 5-HT_2C and 5-HT_2A receptors could be promising targets for ureteral stone expulsion.