Mechanical activity was recorded from muscle preparations isolated from the guinea-pig stomach. Neurotensin (10(-11) M to 10(-7) M) produced dose-dependent tonic contractions and showed a higher affinity but lower efficiency compared to acetylcholine (ACH). Atropine and tetrodotoxin had no effect on the neurotensin responses. Blockade of prostaglandin (PG) synthesis by indomethacin or cortisone (5 X 10(-6) M) shifted to the right the dose-response curve for neurotensin (NT) and significantly reduced the NT maximum responses. The data suggest the involvement of PG-mechanisms in the myogenic effect of neurotensin. The electrically-induced, atropine-sensitive contractions (5 to 10 Hz, 0.3 to 0.5 ms) of the muscle strips were inhibited by NT (10(-11) M to 10(-9) M). This inhibition was overcome by yohimbine (10(-6) M) or prostaglandin F2a. It is concluded that NT modulates cholinergic neurotransmission in gastric smooth muscle probably via presynaptically located adrenoceptors.