The effects of cisapride (R 51619), a new non-dopamine-blocking gastrokinetic drug, on gastrointestinal contractility have been determined on isolated preparations of the guinea pig. On the intact gastroduodenal preparation, cisapride enhanced contractile amplitude (3.4 X 10(-7) M), improved antroduodenal coordination (EC50 = 1.9 X 10(-7) M) and antagonized gastric relaxation induced by phenylephrine, dopamine, isoproterenol, 5-hydroxytryptamine (in the presence of atropine) and periarterial nerve stimulation (IC50 range, 9.1 X 10(-7)-2.4 X 10(-6) M). Experiments with metoclopramide yielded similar results on amplitude, coordination and dopamine-induced relaxation at 5 X 10(-5), 2.2 X 10(-5) and 1.7 X 10(-5) M, respectively. On the ileum, cisapride enhanced the contractile response to electrical stimulation at low concentrations (EC50 = 9.2 X 10(-9) M) as compared with metoclopramide (EC50 = 3.3 X 10(-6) M). On this preparation, cisapride showed no direct cholinergic or nicotine-like effects and did not enhance the response to methacholine (indicative of a lack of inhibition of acetylcholinesterase-activity and of sensitization of the muscarine receptor). On the colon ascendens, cisapride induced contractions (EC50 = 3.5 X 10(-8) M) (metoclopramide, 3.5 X 10(-6) M), insensitive to atropine and only marginally inhibited by tetrodotoxin. In conclusion, cisapride effectively improves spontaneous or electrically evoked contractions of isolated preparations of the guinea pig, most likely via facilitation of the release of acetylcholine. However, the inhibition of gastric relaxation and the induction of colonic contractions in the presence of atropine indicate that, besides cholinergic neuronal pathways, other mechanisms are involved in the motor-stimulating properties of cisapride.