CISAPRIDE AND A STRUCTURAL ANALOG, R-76186, AND 5-HYDROXYTRYPTAMINE(4) (5-HT(4)) RECEPTOR AGONISTS ON THE GUINEA-PIG COLON ASCENDENS

The purpose of this study was to investigate whether the effects of cisapride and its close structural analogue R 76186 on the isolated guinea-pig colon ascendens, are mediated through 5-HT4 receptors. Both cisapride and R 76186 induced contractions in a concentration-dependent fashion, giving monophasic concentration-response curves (cisapride: EC50 = 1.1 X 10(-7) M, maximum effect = 40.3% of methacholine-induced (3 X 10(-7) M) contractions; R76186: EC50 = 2.4 X 10(-8) M, maximum effect = 52.1%). Blockade of either 5-HT2 or 5-HT3 receptors did not affect the responses to cisapride. However, tropisetron (in 5-HT4 receptor-blocking concentrations), and DAU 6285 and SDZ 205-557, two novel selective 5-HT4 receptor antagonists, depressed the concentration-response curve to cisapride (to about 50%), and the curve to R 76186 was shifted to the right. The apparent pA2 values were 6.6 (tropisetron), 6.3 (DAU 6285), and 7.5 (SDZ 205-557). However, none of these antagonisms was purely competitive as higher concentrations of these antagonists depressed the curve to R76186. Desensitization of the 5-HT4 receptor with 5-methoxytryptamine (5-MeOT) inhibited the responses to cisapride, and abolished those to R76186. The contractions to cisapride and R76186 were sensitive to mutual antagonism, depressing their concentration-response curves. Conclusions: Both cisapride and R76186 mediate their contractile effects in the guinea-pig colon ascendens through agonism at the 5-HT4 receptor, though cisapride also uses a non-5-HT mechanism. R76186 is a selective and potent 5-HT4 receptor agonist.