SUBSTANCE-P ENTERIC NEURONS MEDIATE NON-COLINERGIC TRANSMISSION TO THE CIRCULAR MUSCLE OF THE GUINEA-PIG INTESTINE

The sites of action and possible roles of substance P in contracting the circular muscle of the guinea-pig ileum were studied using 2 analogs of substance P that act as antagonists of some of its actions. These are D-Arg1, D-Pro2, D-Trp7,9, Leu11-substance P and D-Pro2, D-Trp7,9-substance P, referred to by the single letter amino acid codes for the substituting amino acids as (RPWWL)-SP and (PWW)-SP, respectively. Records of circular muscle activity were taken from strips of intensive free of mucosa and submucosa and form rings with all layers of intestine intact. Substance P as equally effective in contracting the circular muscle strips as it was in contacting the longitudinal muscle. The contractions of strips were not blocked by hyoscine (2 .times. 10-6 M) or tetrodotoxin (6 .times. 10-7 M), but were substantially reduced by (RPWWL)-SP (6.7 .times. 10-6 M) or (PWW)-SP (2 .times. 10-5 M). In contrast, contractions of the circular muscle of whole rings of intestine elicited by low concentrations of substance P (4 .times. 10-7 M) were blocked by hyoscine or tetrodotoxin but not reduced by the sequence P antagonists in the concentrations referred to above. These observations indicate that the antagonists are effective at receptors for substance P receptors on enteric cholinergic nerves. Transmural stimulation of strips of circular muscle or of intestinal rings in the presence of hyocine evoked contractions that were blocked by tetrodotoxin. These hyoscine-resistant, nerve-mediated contractions could be elicited by single pulses in the strips. The contractions were reduced to less than 20% of original amplitude by (RPWWL)-SP (6.7 .times. 10-6 M). Reflex contractions of the circular muscle recorded on the oral side of a distensions stimulus had a low-threshold, hyoscine-sensitive and a high-threshold, hyoscine-insensitive, component. The low threshold component was unaffected by the substance P antagonist whereas the high threshold component was depressed. Substance P nerve are effective in transmitting to the circular muscle, that they are final nerves in non-cholinergic excitatory reflexes, and that the substance P antagonist analogs can be used to distinguish actions of substance P at neural and muscle receptors.