Contractile responses to substance P and related peptides of the isolated muscularis mucosae of the guinea-pig oesophagus.

The site of action of substance P and related tachykinins with respect to isotonic contractions was examined on the isolated muscularis mucosae attached to the submucous plexus of the guinea-pig oesophagus. Substance P (greater than 30 nM) produced a concentration-dependent contraction of the muscularis mucosae (EC50 1.9 +/- 0.5 microM, n = 10). The contractions were rapid in onset (2 min or less), sustained, reversible by washing and the preparation did not show tachyphylaxis. Eledoisin and physalaemin produced similar sustained contraction of the muscularis mucosae. The order of sensitivity was eledoisin greater than substance P greater than physalaemin. Contractions induced by 1 microM of each tachykinin were not significantly modified by incubation of the tissue with substance P or eledoisin (10 microM for 30 min). The contractile responses to tachykinins were unaffected by tetrodotoxin (0.3 microM), atropine (0.3 microM), phentolamine (1 microM), chlorpheniramine (1 microM), methysergide (1 microM), baclofen (100 microM) and verapamil (10 microM), but were abolished by the incubation of the tissue with calcium-free, EGTA (0.1 mM)-containing Tyrode solution. A substance P antagonist, [D-Pro2, D-Trp7,9]-substance P (greater than 0.1 microM), produced a transient contraction of the muscularis mucosae and the smooth muscle regained its original tone within 6 to 10 min. Contractions to the tachykinins were now inhibited by the antagonist (0.1-10 microM) in a concentration-dependent manner, the order of sensitivity being physalaemin greater than substance P = eledoisin. The cholinergically mediated electrically (0.1 Hz, 0.5 ms, supramaximal voltage)-induced twitch contractions of the muscularis mucosae were not significantly modified by substance P (0.01-0.3 microM). 7 The present results indicate that substance P and related tachykinins contract the isolated muscularis mucosae of the guinea-pig oesophagus by a direct action on the smooth muscle, probably by stimulating SP-E receptors.