These studies test the hypothesis that the generation of colonic slow waves can be modulated by stimulation of intrinsic enteric nerves and attempt to identify a neurotransmitter that may be responsible for this change in slow-wave activity. Isolated segments from the mid-colon of the cat generated regular, continuous slow waves at 6.5±1.1 cpm. Activation of the intrinsic nerves by electrical field stimulation transiently reduced the rate of slow-wave generation to 4.7±0.7 cpm (P<0.001). The response to electrical stimulation was blocked by tetrodotoxin and α-chymotrypsin. The following antagonists were not effective in blocking the response: atropine, hexamethonium, phenoxybenzamine, propranolol, methysergide, naloxone, or imidazole. Vasoactive intestinal polypeptide (5×10−7 M) decreased slow wave frequency to 4.5±0.4 cpm. Vasoactive intestinal polypeptide (VIP) fragment 10-28 inhibited the effect of electrical field stimulation but also decreased the slow-wave frequency. VIP-immunoreactive nerves were much more abundant in the plexus submucosus extremus than in the circular muscle of the muscularis externa. Thus, pacemakers for colonic slow waves may be modulated by intrinsic colonic nerves, and vasoactive intestinal polypeptide may be the neurotransmitter responsible for this modulation.