Investigation of 5-HT3 receptor-mediated contraction in guinea-pig distal colon.

We investigated the participation of cholinergic and tachykininergic mechanisms in 5-hydroxytryptamine (5-HT)-induced contraction via 5-HT3 receptors in longitudinal and circular muscle of guinea-pig isolated distal colon. 5-HT produced concentration-dependent contractile responses in longitudinal and circular muscle. The 5-HT3 receptor antagonists ramosetron (YM060) ((R)-5-[(1-methyl-3-indolyl) carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride), YM114 (KAE-393) ((R)-5-[(2,3-dihydro-1-indolyl)carbonyl]-4,5,6,7-tetrahydro-1 H-benzimidazole hydrochloride), ondansetron and granisetron produced a concentration-dependent shift to the right of the 5-HT concentration-response curves in both muscle. However, methysergide and GR113808 had no effect on 5-HT-induced contraction. In the longitudinal muscle, atropine concentration-dependently inhibited 5-HT-induced contraction, and tetrodotoxin abolished it. (+/-)-CP96,345 attenuated the contractile response to 5-HT, but (+/-)-SR48,968 had no effect on it. In the presence of atropine, (+/-)-CP96,345 completely blocked 5-HT-induced contraction. In the circular muscle, atropine had no effect on the contractile response to 5-HT, whereas tetrodotoxin completely suppressed it. The contractile response elicited by 5-HT in the circular muscle was not inhibited by either (+/-)-CP96,345, (+/-)-SR48,968, devazepide, L-365,260 or indomethacin. It is suggested that 5-HT acts via 5-HT3 receptors to release acetylcholine and substance P, which in turn are responsible for contraction of the longitudinal muscle. In the circular muscle, as in the longitudinal muscle, 5-HT-induced contraction is mediated by the 5-HT3 receptor. Unlike the case in longitudinal muscle, however, this contraction involves neither cholinergic nor tachykininergic transmission. It is also suggested that neither cholecystokinin (CCK) nor prostaglandins participate in 5-HT3 receptor-mediated contraction in circular muscle.