INHIBITORY EFFECTS OF SR 58611A ON CANINE COLONIC MOTILITY - EVIDENCEFOR A ROLE OF BETA(3)-ADRENOCEPTORS

1 In order to clarify whether atypical or beta(3)-adrenoceptors can mo dulate canine colonic motility in vivo, we studied the effects of SR 5 8611A (a selective agonist for atypical beta-adrenoceptors) alone and after pretreatment with beta-adrenoceptor antagonists on colonic motil ity in the conscious dog. The gastrocolonic response (postprandial inc rease in motility) was monitored by means of electrodes and strain-gau ge force transducers chronically implanted along the distal colon. In some experiments, heart rate was also measured. The possible role of b eta(3)-adrenoceptors in mediating the effects of SR 58611A was also te sted in vitro in circular muscle strips taken from the canine distal c olon. 2 Intravenous infusion of SR 58611A, ritodrine or isoprenaline a t doses inducing the same degree of tachycardia inhibited the gastroco lonic response to a different extent, with SR 58611A and ritodrine bei ng more effective than isoprenaline. 3 In a dose-response study, SR 58 611A was more potent in inhibiting colonic motility than in inducing t achycardia: the ED(35) values for inhibition of colonic motility and i nduction of tachycardia were 23 and 156 mu g kg(-1), i.v., respectivel y. 4 The inhibitory effect of SR 58611A 100 mu g kg(-1), i.v., on the gastrocolonic response was reversed by alprenolol (non-selective beta- adrenoceptor antagonist), but resistant to CGP 20712A (beta(1)-adrenoc eptor antagonist) or ICI 118551 (beta(2)-adrenoceptor antagonist). 5 I n vitro, SR 58611A concentration-dependently relaxed circular muscle s trips, an effect that was competitively antagonized by alprenolol with a pA(2) value of 7.1, but resistant to CGP 20712A (100 nM), ICI 11855 1 (100 nM) or tetrodotoxin (1 mu M). 6 The present study provides stro ng functional evidence for a role of atypical or beta(3)-adrenoceptors in the modulation of canine colonic motility both in vivo and in vitr o by an inhibitory effect most likely at the smooth muscle level.