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 ci sapride and its close structural analogue R 76186 on the isolated guin ea-pig colon ascendens, are mediated through 5-HT4 receptors. Both cis apride and R 76186 induced contractions in a concentration-dependent f ashion, giving monophasic concentration-response curves (cisapride: EC 50 = 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 effe ct = 52.1%). Blockade of either 5-HT2 or 5-HT3 receptors did not affec t the responses to cisapride. However, tropisetron (in 5-HT4 receptor- blocking concentrations), and DAU 6285 and SDZ 205-557, two novel sele ctive 5-HT4 receptor antagonists, depressed the concentration-response curve to cisapride (to about 50%), and the curve to R 76186 was shift ed 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 w as purely competitive as higher concentrations of these antagonists de pressed the curve to R76186. Desensitization of the 5-HT4 receptor wit h 5-methoxytryptamine (5-MeOT) inhibited the responses to cisapride, a nd abolished those to R76186. The contractions to cisapride and R76186 were sensitive to mutual antagonism, depressing their concentration-r esponse curves. Conclusions: Both cisapride and R76186 mediate their c ontractile effects in the guinea-pig colon ascendens through agonism a t the 5-HT4 receptor, though cisapride also uses a non-5-HT mechanism. R76186 is a selective and potent 5-HT4 receptor agonist.