A FURTHER ANALYSIS OF THE CONTRACTION INDUCED BY ACTIVATION OF CHOLECYSTOKININ-A RECEPTORS IN GUINEA-PIG ISOLATED ILEUM LONGITUDINAL MUSCLEMYENTERIC PLEXUS

The activity of a selective cholecystokinin (CCK)-A receptor agonist, N-acetyl derivative of A71623 -[2-methylphenylamino-carbonil])-Asp-(NM e)Phe-NH2) was investigated in the guinea pig isolated ileum longitudi nal muscle myenteric plexus. NAA caused both a phasic and tonic contra ction at all concentrations tested (1-1000 nM). The selective CCK-A an tagonist L-364,718 (Devazepide) antagonized both types of contraction with a pK(B) of 10.10 and 9.95, respectively. The CCK-B selective anta gonist L-365,260 H-1,4-benzodiazepine-3yl)-N-(3-methylphenyl)-urea) wa s inactive up to a concentration of 30 nM. Atropine at 300 nM and 1000 nM reduced the maximal response of NAA by only 17% and 50%, respectiv ely. The selective neurokinin (NK)-1 antagonists GR 82334 ([D-pro(9)[S piro-gamma-Lactam] Leu(10), Trp(11)]-Phys(1-11)(9)) at 300 and 1000 nM and (+/-) CP-96,345 [(2S, 3S)-cis-2-(diphenylmethyl)-N- [(2-methoxyph enyl)-methyl] -1-azabiciclo[2.2.2]octan-3-amine] at 10 nM were inactiv e or partially active. When atropine and GR 82334 or (+/-) CP-96,345 w ere combined, they produced a dose-dependent synergistic inhibition of both phasic and tonic contractions induced by NAA. The selective NK-3 receptor agonist senktide induced both phasic and tonic contractions that were blocked by tetrodotoxin. In the presence of atropine and GR 82334, both 300 nM, a synergistic depression of the response to senkti de similar to that observed for the agonist NAA was disclosed. The NK- 1 receptor agonist, substance P methylester, induced both a phasic and tonic contractions that were not blocked by tetrodotoxin or atropine. Moreover, the NK-2 selective agonist GR 64349 ([Lys(3),Gly(8),R-Lacta m-Leu(9)]NKA(3-10)) induced contractions that were not blocked by the NK-2 selective antagonist L-659,837 (Cyclo(Gln-Trp-Phe-(R)Gly[ANC-2] L eu-Met). It is hypothesized that NAA acts by releasing both acetylchol ine and substance P. The latter activates a postjunctional NK-1 recept or and a prejunctional NK-3 receptor, which in turn releases acetylcho line and substance P.