NEUROKININ RECEPTORS IN THE GUINEA-PIG ILEUM

Experiments were performed in the longitudinal muscle strip of the gui nea pig ileum to characterize the receptors involved in the contractil e response of this preparation to neurokinins. Antagonists for the NK- 1 (CP 96345, CP 99994) and NK-2 (SR 48968) receptors, atropine for NK- 3 receptors, as well as diphenhydramine (histamine H-1 receptor antago nist) and indometacin (cyclooxygenase inhibitor) were used to determin e the relative contribution of neurokinin receptors and some endogenou s agents to the myotropic effects of substance P (SP) and neurokinin r eceptor selective agonists. The present findings indicate that the thr ee neurokinin receptor types take part in the contractile activities o f SP-related peptides. NK-1 receptors, probably localized in the smoot h muscle, are inhibited only by the two CP compounds and not by atropi ne or the other agents. NK-2 receptors contribute to the contraction b y 5-10% and are blocked by SR 48968. NK-3 receptors act indirectly thr ough the release of acetylcholine from the myenteric plexus, since act ivities of [MePhe(7)]NKB and senktide are blocked by atropine. Septide behaves as a selective NK-1 receptor agonist and does not show any di fference with SP, except for higher sensitivity to CP antagonists. The same is observed with Ac[Arg(6),Sar(9),Met(O-2)(11)]SP(6-11), another NK-1-selective fragment. Discrepancies between antagonist pA(2) value s obtained against undeca- and hexapeptide agonists are interpreted as due to a stronger binding affinity of undecapeptide agonists as compa red with the hexapeptides. Results of binding assays confirm data from the literature by showing that undecapeptide agonists have higher aff inities than hexapeptides, particularly septide, and such discrepancie s (with the biological assays) can also be explained by the reduction or absence of the cationic charge at the N terminal of septide.