A selective NK-2 antagonist blocks the increase of canine colonic tone and ileal contractions induced by the NK-2 selective receptor agonist, [beta Ala8] neurokinin A-(4-10)

Background: The regulatory roles of tachykinins in intestinal motor function may be clarified by use of novel, stable and selective antagonists 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 agonist [beta Ala8] neurokinin A-(4-10).

Methods: Experiments were performed in three conscious female dogs. Proximal colonic tone was recorded by a barostat and intraluminal pressures were recorded in the terminal ileum. 10, 15 and 20 cm orad to the ileocaecal junction. In separate experiments, and in a random sequence, dogs received an i.v. injection of the NK-2 antagonist SR48968, 10, 100, 1000 micrograms/kg, followed after 30 min by 2 micrograms/kg of the agonist [beta Ala8] neurokinin A-(4-10). Experiments were replicated twice in each dog.

Results: The NK-2 agonist increased colonic tone, and SR48968 antagonized these effects in a dose-dependent fashion (Spearman's rank, r = 0.86; P < 0.01); antagonism 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 the interdigestive motor complex, [beta Ala8] neurokinin A-(4-10) increased ileal contractions: pre-treatment with SR48968 blocked this increase in ileal motility. When given during phase III, [beta Ala8] neurokinin A-(4-10) interrupted the motility front; this effect was not antagonized by SR48968.

Conclusions: SR48968 antagonizes the increase in 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. SR48968 may be useful for investigating the physiological role of tachykinins on the gastrointestinal tract.