A high concentration of indomethacin (40mu-g/ml) substantially reduced contractions of guinea-pig isolated ileum in Krebs solution to nerve stimulation with electrical pulses or nicotine. Responses to acetylcholine and histamine were also inhibited, but to a smaller extent. Low concentrations of prostaglandin E-2 (2 or 4ng/ml) mainly restored all the excitatory responses. Using a modified bathing solution (lacking in phosphate and with some other changes) indomethacin 0.36mu-g/ml selectively inhibited nerve-mediated contractions. The results explain differences in various reports, and support the possibility that prostaglandins modulate the response to cholinergic nerve activity.