A COMPARISON OF THE STIMULATORY EFFECTS OF METOCLOPRAMIDE AND CINITAPRIDE IN THE GUINEA-PIG ISOLATED ILEUM

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Abstract
The pharmacological effects of a new benzamide derivative, cinitapride, were compared to those of metoclopramide in guinea-pig isolated ileum and longitudinal smooth muscle-myenteric plexus preparations treated with propranolol (3 .mu.M). Cinitapride (EC50 = 0.74 .mu.M) was 6 times more potent than metoclopramide (EC50 = 4.69 .mu.M) in enhancing the twitch response of co-axially stimulated preparations and 11 times more potent in eliciting contractions in non-stimulated tissues, their respective EC50 values being 0.58 .mu.M and 6.52 .mu.M. These contractile effects of cinitapride and metoclopramide amounted to approximately 25% of the maximum response of the tissues to acetylcholine (1 .mu.M). Neither cinitapride nor metoclopramide, in concentrations up to 10 .mu.M, significantly affected concentration-response curves to exogenous acetylcholine or 5-hydroxytryptamine but both drugs elicited a concentration-dependent potentiation of the ileium responses to a fixed concentration (10 .mu.M) of the ganglion stimulant dimethylphenylpiperazinium (DMPP). Analysis of the twitch-enhancing and contractile effects of cinitapride using a variety of drugs suggested that a common, prejunctional locus of action upon the cell bodies or axons of postganglionic, parasympathetic neurons of the myenteric plexus is involved in both of these responses. In hexamethonium (100 .mu.M) and methysergide (0.1 .mu.M)-treated longitudinal smooth muscle preparations desensitization or blockade of 5-hydroxytryptamine receptors using high concentrations of the same agonist (30 .mu.M) or quipazine, (10 .mu.M) or the putative antagonists cocaine (30 .mu.M) or tubocurarine (10 .mu.M), produced small inhibitions (.simeq. 20%) of the contractile response to metoclopramide and cinitapride but did not affect twitch responses to these drugs. Cinitapride is a more potent stimulant of guinea-pig intestinal smooth muscle than metoclopramide in vitro although the mechanism of action of both drugs appears to be similar and involves a prejunctional enhancement of acetylcholine release from intramural cholinergic neurons. Attempts to implicate a prejunctional facilitatory 5-hydroxytryptamine receptor in the mediation of the stimulant effects of these drugs were not conclusive and additional studies are required to fully explore this possibility.