A SELECTIVE NK-2 ANTAGONIST BLOCKS THE INCREASE OF CANINE COLONIC TONE AND ILEAL CONTRACTIONS INDUCED BY THE NK-2 SELECTIVE RECEPTOR AGONIST, [BETA-ALA(8)] NEUROKININ A-(4-10)

Background: The regulatory roles of tachykinins in intestinal motor fu nction may be clarified by use of novel, stable and selective antagoni sts of neurokinin receptors. We studied the effects of the non-peptide NK-2 receptor antagonist SR48968 on canine colonic tone under resting conditions and after stimulation by the selective NK-2 receptor agoni st [beta Ala(8)] neurokinin A-(4-10). Methods: Experiments were perfor med in three conscious female dogs. Proximal colonic tone was recorded by a barostat and intraluminal pressures were recorded in the termina l ileum, 10, 15 and 20 cm orad to the ileocaecal junction. In separate experiments, and in a random sequence, dogs received an i.v. injectio n of the NK-2 antagonist SR48968, 10, 100, 1000 mu g/kg, followed afte r 30 min by 2 mu g/kg of the agonist [beta Ala(8)] neurokinin A-(4-10) . Experiments were replicated twice in each dog. Results: The NK-2 ago nist increased colonic tone, and SR48968 antagonized these effects in a dose-dependent fashion (Spearman's rank, r = 0.86; P < 0.01); antago nism was complete at the highest dose. SR48968 alone had no effect on colonic tone and ileal motility. When given during phase I or II of th e interdigestive motor complex, [beta Ala(8)] neurokinin A-(4-10) incr eased ileal contractions; pre-treatment with SR48968 blocked this incr ease in ileal motility. When given during phase III, [beta Ala(8)] neu rokinin A-(4-10) interrupted the motility front; this effect was not a ntagonized by SR48968. Conclusions: SR48968 antagonizes the increase i n canine colonic tone and ileal motility induced by activation of NK-2 receptors. However, SR48968 by itself had no effect on the control of colonic tone and ileal motility under unstimulated conditions. SR4896 8 may be useful for investigating the physiological role of tachykinin s on the gastrointestinal tract.