MECHANISMS OF ACTION OF CHOLECYSTOKININ IN THE CANINE GASTROINTESTINAL-TRACT - ROLE OF VASOACTIVE-INTESTINAL-PEPTIDE AND NITRIC-OXIDE

This study defined the cholecystokinin (CCK)/gastrin receptor subtypes at which CCK octapeptide (CCK8) and gastrin 17 (G(17)) act on motor f unctions of the intact canine gastrointestinal tract. In the antrum, s tudies of tachyphylaxis and effects of antagonists showed that i.a. G( 17) acted through CCKB receptors to activate contractions, whereas CCK , acted through A and 8 receptor subtypes to produce contractions. In the duodenum, i.a. G(17) caused dose-dependent inhibition of electrica l field-stimulated contractions, apparently by release of nitric oxide [blocked by N-nitro-L-arginine (L-NNA) or N-G-L-arginine methyl ester ]. These inhibitory effects were abolished by YMO22 (a CCKB antagonist ) but not by L-364,718 (a CCKA antagonist). However, i.a. CCK8 increas ed electrical field-stimulated contractions and L-364,718 reversed thi s effect. In isolated perfused segments of distal intestine, CCK8 caus ed inhibition and excitation and released vasoactive intestinal peptid e (VIP) into the venous effluent. CCK tetrapeptide and G(17) had incon sistent effects. Excitation and VIP release were inhibited by L-364,71 8. L-NNA potentiated excitatory responses and abolished inhibitory res ponses. Tetrodotoxin and atropine abolished and hexamethonium reduced excitatory responses to CCK8, but C-NNA restored contractions after at ropine treatment. Hexamethonium or L-NNA (but not atropine) reduced VI P release; CCK8 still enhanced it. L-364,718 abolished hexamethonium-r esistant contractions and VIP release. Thus, CCK/gastrin peptides act on neural receptors in intact canine gastrointestinal tract. In antrum , activation of neural CCKA or CCKB receptors initiates contractions. In intestine, CCKA receptors at pre- and postjunctional sites in enter ic nerves mediate acetylcholine and VIP release. CCKB receptors mediat e release of an inhibitory mediator, apparently nitric oxide, from pos tjunctional sites.