The pharmacological effects of a new
benzamide derivative
cinitapride, have been compared to those of
metoclopramide in guinea-pig isolated ileum and longitudinal smooth muscle-myenteric plexus preparations treated with
propranolol (3 microM).
Cinitapride (EC50 = 0.74 microM) was 6 times more potent than
metoclopramide (EC50 = 4.69 microM) 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 microM and 6.52 microM. These contractile effects of
cinitapride and
metoclopramide amounted to approximately 25% of the maximum response of the tissues to
acetylcholine (1 microM). Neither
cinitapride nor
metoclopramide, in concentrations up to 10 microM, significantly affected concentration-response curves to exogenous
acetylcholine or
5-hydroxytryptamine but both drugs elicited a concentration-dependent potentiation of the ileum responses to a fixed concentration (10 microM) 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 neurones of the myenteric plexus is involved in both of these responses. In
hexamethonium (100 microM) and
methysergide (0.1 microM)-treated longitudinal smooth muscle preparations desensitization or blockade of
5-hydroxytryptamine receptors using high concentrations of the same agonist (30 microM) or
quipazine (10 microM) or the putative antagonists
cocaine (30 microM) or
tubocurarine (10 microM) produced small inhibitions (congruent to 20%) of the contractile responses to
metoclopramide and
cinitapride but did not affect twitch responses to these drugs. It is concluded that
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 neurones. 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.