Cisapride and a structural analogue, R 76,186, are 5-hydroxytryptamine4 (5-HT4) 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 76,186 on the isolated guinea-pig colon ascendens, are mediated through 5-HT4 receptors. Both cisapride and R 76,186 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; R 76,186: 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 76,186 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 R 76,186. Desensitization of the 5-HT4 receptor with 5-methoxytryptamine (5-MeOT) inhibited the responses to cisapride, and abolished those to R 76,186. The contractions to cisapride and R 76,186 were sensitive to mutual antagonism, depressing their concentration-response curves.


CONCLUSIONS
Both cisapride and R 76,186 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. R 76,186 is a selective and potent 5-HT4 receptor agonist.
Briejer
M R
MR
Department of Human and Animal Physiology, Wageningen Agricultural University, The Netherlands.
Akkermans
L M
LM
Meulemans
A L
AL
Lefebvre
R A
RA
Schuurkes
J A
JA
D010129:4-Aminobenzoic Acid / Q000494:pharmacology; D000818:Animals; D020117:Cisapride; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D062366:para-Aminobenzoates
D010880:Piperidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D062366:para-Aminobenzoates; C082038:R 76186; C072790:2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino)ethyl ester; D012701:Serotonin; D010129:4-Aminobenzoic Acid; D020117:Cisapride