Cisapride acts on muscarinic (glandular M2) receptors to induce contraction of isolated gastric myocytes: mediation via a calcium-phosphoinositide pathway.

The effects of cisapride on guinea pig gastric smooth muscle were characterized. Cisapride induced concentration-dependent contraction of isolated myocytes with an EC50 of 10(-11) M, which was antagonized in concentration-dependent fashion by atropine. 4-Diphenylacetoxy-N-methylpiperidine-methiodide (4-DAMP) (10(-6) M), a selective M2 glandular receptor antagonist, inhibited contraction to cisapride (10(-10) M), whereas pirenzepine, an M1 receptor antagonist, had no effect. For comparison, carbachol induced contraction with an EC50 of 5 x 10(-11) M, which was also atropine-sensitive. Cisapride-induced contraction was not blocked by methysergide (10(-6) M), a nonselective serotonin antagonist. Cisapride displaced specific binding of [3H]N-methylscopolamine at a single receptor population with a Ki of 6.51 x 10(-5) M and a Bmax of 351.0 fmol/mg protein. Cisapride (10(-6) M) evoked a 73.8 +/- 7.6% increase in inositol 1,4,5-trisphosphate at 30 sec and a maximal increase of greater than 130% at 2 min, which was significantly reduced by atropine (10(-6) M). In contrast, cisapride did not enhance or inhibit basal levels of cyclic AMP. Thus, cisapride induces contraction via specific interaction at smooth muscle M2 glandular muscarinic receptors, which is associated with inositol trisphosphate generation, but not adenylyl cyclase activation.