Intestinal segments obtained from guinea pig ileum were set up in an organ bath to record peristaltic responses to distension by a pressure rise in the lumen. The effects of drugs applied in the bathing medium on the peristaltic responses were examined. Sodium nitroprusside (10(-9) M to 10(-5) M) stimulated the peristaltic reflex. Nitroglycerin (10(-7) M) was similarly effective in stimulating the peristalsis. A permeable cyclic GMP, 8-bromo cyclic GMP (2.5 x 10(-4) M), mimicked the action of these compounds. Methylene blue (10(-5) M) blocked the nitroprusside-induced stimulation of the peristalsis, but not the effect of 8-bromo cyclic GMP. Sodium nitroprusside did not change the baseline tension of the circular muscle, and it enhanced neither the contractile response to electrical direct stimulation nor the cholinergic transmission to the circular muscle. These results suggest that nitric oxide is formed from the nitrocompounds in mechanosensitive neurons in the intestine and causes activation of guanylate cyclase by which the level of intracellular cyclic GMP is elevated, and cyclic GMP acts to make the stretch receptors more sensitive. As nitric oxide is derived from the enteric vascular bed or neurons, its importance as a modulator of peristaltic activity in the intestine is discussed.