CISAPRIDE AND STRUCTURAL ANALOGS SELECTIVELY ENHANCE 5-HYDROXYTRYPTAMINE (5-HT)-INDUCED PURINERGIC NEUROTRANSMISSION IN THE GUINEA-PIG PROXIMAL COLON

In the guinea pig proximal colon, 5-hydroxytryptamine (5-HT) stimulate s neuronal 5-HT1-like receptors to induce relaxations that are mediate d by nitric oxide and ATP. In the current study, the effects of cisapr ide and structural analogs on these 5-HT-induced relaxations were inve stigated. In the continuous presence of ketanserin (0.3 mu M) and trop isetron (3 mu M) to block contractions via 5-HT,,, 5-HT, and 5-HT, rec eptors, 5-HT induced relaxations that yielded a biphasic concentration -response curve. Cisapride (0.1-1 mu M) enhanced the second phase of t he concentration-response curve to 5-HT by about 20% to 40%, whereas f rom 0.3 mu M onwards, it inhibited the first phase. Also in the presen ce of cisapride (0.3 mu M), tetrodetoxin (0.3 mu M) abolished the rela xations to 5-HT. Cisapride (0.3 mu M) did not affect the concentration -response curves to isoprenaline, nitroglycerin, nitroprusside or exog enous ATP, which demonstrated its specificity. The 5-HT relaxation-enh ancing effects of cisapride were not mimicked by phentolamine (1 mu M) , NAN-190 (0.03 mu M), spiperone (1 mu M), citalopram (0.3 mu M), paro xetine (0.3 mu M), pargyline (100 mu M) or SDZ 205-557 (0.3 mu M). In the presence of the inhibitor of nitric oxide synthesis, NG-nitro-L-ar ginine (100 mu M), cisapride (0.3 mu M) still enhanced the remaining r elaxations to 5-HT (2-3-fold). However, in the presence of the P-2-pur inoceptor antagonist suramin (300 mu M), cisapride did not enhance the relaxations to 5-HT. In the presence of N-G-nitro-L-arginine, the cis apride-enhanced relaxations to 5-HT were inhibited by about 90% by sur amin. 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.