A pharmacological investigation of synthetic substance P on the isolated guinea-pig ileum.

1. The pharmacological properties of synthetic substance P have been studied on the guinea-pig ileum and compared with those of acetylcholine and other agonists. 2. The effects of synthetic substance P in the presence of atropine, hexamethonium, mepyramine and certain of the drugs which antagonize serotonin are in close agreement with those reported for the naturally occurring peptide. 3. The spasmogenic action of substance P is not mediated by cholinergic mechanisms or release of prostaglandins, and does not appear to involve release of serotonin. The inability of tetrodotoxin to attenuate responses to substance P suggests that its spasmogenic action is not elicited through neural mechanisms. Thus, it is likely that substance P acts directly on the smooth muscle of the ileum. 4. Since substance P is present in the brain and can depolarize neurones, it may be a neurotransmitter. A screening of various centrally acting drugs, whose mechanisms of action are unclear, was undertaken to seek possible interactions with substance P. Pimozide was the most potent in depressing responses to substance P but none of the drugs caused the specific antagonism which would assist in elucidating a possible physiological role for substance P.