INVOLVEMENT OF NEUROKININS IN THE NONCHOLINERGIC RESPONSE TO ACTIVATION OF 5-HT3 AND 5-HT4 RECEPTORS IN GUINEA-PIG ILEUM

1 The involvement of neurokinins in the non-cholinergically-mediated c ontractile response induced by stimulation of 5-HT3 and 5-HT4 receptor s has been examined in the longitudinal muscle-myenteric plexus prepar ation of the guinea-pig ileum. 2 The 5-HT3 receptor agonist, 2-methyl- 5-hydroxytryptamine (2-methyl-5-HT), showed a lower potency in this pr eparation than the more selective 5-HT4 receptor agonist 5-methoxytryp tamine. The effect of bath drugs was markedly reduced by atropine. 3 S ubstance P (SP) and neurokinin B (NKB) produced biphasic concentration -response curves in the preparation. Neurokinin A (NKA), the NK1 recep tor agonist, [Sar(9),Met(O-2)11]SP and the NK3 receptor agonist, senkt ide yielded monophasic concentration-response curves. 4 After desensit ization of the NK1 receptor with SP or [Sar(9),met(O-2)11]SP, in the p resence of atropine, the contractile response to 2-methyl-5-HT was ent irely blocked, Desensitization of NK3 receptors with NKB, also in the presence of atropine, fully suppressed the 5-HT4 receptor-mediated con traction evoked by 5-methoxytryptamine. 5 In preparations prelabelled with [H-3]-choline, SP produced a concentration-dependent increase in tritium overflow, an index of [H-3]-acetylcholine release, while an in verse relationship was found with NKB. At low neurokinin concentration s, the releasing effect of NKB was much more marked. 6 It is suggested that in the response to 5-HT3 receptor stimulation, there is a role f or SP and acetylcholine. NKB appears to be preferentially involved in the release of acetylcholine elicited by stimulation of 5-HT4 receptor s.