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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.

In the guinea-pig proximal colon, 5-hydroxytryptamine (5-HT) relaxes the longitudinal muscle by stimulating neuronal 5-HT receptors, which induces the release of nitric oxide (NO). It was investigated whether the inhibitory neurotransmitters adenosine 5'-triphosphate (ATP) and/or vasoactive intestinal polypeptide (VIP) could be involved as well. Antagonists to block the contractile response to 5-HT via 5-HT2, 5-HT3 or 5-HT4 receptors were present throughout the experiments and methacholine was administered to precontract the strips. ATP, VIP and 5-HT induced concentration-dependent relaxations, in the case of 5-HT yielding a non-monophasic concentration-response curve. Tetrodotoxin (TTX; 300 nM), NG-nitro-L-arginine (L-NNA, 100 microM) and their combination did not inhibit the relaxations induced by VIP (up to 0.3 microM) or 0.3-3 microM ATP but reduced those by 10 microM ATP. Suramin (300 microM) strongly inhibited the relaxations to ATP and VIP. L-NNA and suramin also inhibited the relaxations to 5-HT. In the presence of L-NNA (100 microM), suramin did not significantly inhibit the relaxations to 5-HT. Suramin did not affect the relaxations to isoprenaline, nitroglycerin or exogenous NO (1 microM), demonstrating its specificity. Apamin (30 nM) inhibited both the relaxations to ATP (by 70-100%) and to 5-HT; relaxations to isoprenaline were partially inhibited, indicating a non-specific component in the inhibitory action of apamin. However, relaxations to exogenous VIP (up to 0.3 microM), NO (1 microM) and to nitroglycerin were not inhibited. In the presence of L-NNA (100 microM), apamin inhibited the relaxations to 5-HT only at 30 microM. alpha, beta-methylene-ATP (alpha, beta-Me-ATP; 100 microM) did not desensitize the responses to ATP. Reactive blue 2 affected the relaxations to isoprenaline at concentrations necessary to significantly inhibit the relaxations to ATP (i.e. from 10 microM onwards). Thus, it was not possible to test either alpha, beta-Me-ATP or reactive blue 2 against the relaxations to 5-HT. alpha-Chymotrypsin (0.015 mg.ml-1) and trypsin (0.005 mg.ml-1) almost abolished the relaxations to VIP, but did not affect those to isoprenaline and 5-HT. The VIP receptor antagonists [p-Cl-D-Phe6, Leu17]VIP (1 microM) and VIP10-28 (1 and 3 microM) did not affect the concentration-response curve to VIP and were hence not tested against 5-HT. Phosphoramidon (1 microM) had no effect on the relaxations to VIP or 5-HT.(ABSTRACT TRUNCATED AT 400 WORDS)