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In the guinea pig proximal colon, 5-hydroxytryptamine (5-HT) stimulates neuronal 5-HT1-like receptors to induce relaxations that are mediated by nitric oxide and ATP. In the current study, the effects of cisapride and structural analogs on these 5-HT-induced relaxations were investigated. In the continuous presence of ketanserin (0.3 microM) and tropisetron (3 microM) to block contractions via 5-HT2A, 5-HT3 and 5-HT4 receptors, 5-HT induced relaxations that yielded a biphasic concentration-response curve. Cisapride (0.1-1 microM) enhanced the second phase of the concentration-response curve to 5-HT by about 20% to 40%, whereas from 0.3 microM onwards, it inhibited the first phase. Also in the presence of cisapride (0.3 microM), tetrodotoxin (0.3 microM) abolished the relaxations to 5-HT. Cisapride (0.3 microM) did not affect the concentration-response curves to isoprenaline, nitroglycerin, nitroprusside or exogenous ATP, which demonstrated its specificity. The 5-HT relaxation-enhancing effects of cisapride were not mimicked by phentolamine (1 microM), NAN-190 (0.03 microM), spiperone (1 microM), citalopram (0.3 microM), paroxetine (0.3 microM), pargyline (100 microM) or SDZ 205-557 (0.3 microM). In the presence of the inhibitor of nitric oxide synthesis, NG-nitro-L-arginine (100 microM), cisapride (0.3 microM) still enhanced the remaining relaxations to 5-HT (2-3-fold). However, in the presence of the P2-purinoceptor antagonist suramin (300 microM), cisapride did not enhance the relaxations to 5-HT. In the presence of NG-nitro-L-arginine, the cisapride-enhanced relaxations to 5-HT were inhibited by about 90% by suramin. We conclude that in the guinea pig colon, cisapride selectively facilitates the suramin-sensitive, ATP-mediated part of the relaxation to 5-HT via an unidentified effect on intramural nerves.