Inhibitory effects of SR 58611A on canine colonic motility: evidence for a role of β3‐adrenoceptors

Abstract

1 In order to clarify whether atypical or β-adrenoceptors can modulate canine colonic motility in vivo, we studied the effects of SR 58611A (a selective agonist for atypical β-adrenoceptors) alone and after pretreatment with β-adrenoceptor antagonists on colonic motility in the conscious dog. The gastrocolonic response (postprandial increase in motility) was monitored by means of electrodes and strain-gauge force transducers chronically implanted along the distal colon. In some experiments, heart rate was also measured. The possible role of β³-adrenoceptors in mediating the effects of SR 58611A was also tested in vitro in circular muscle strips taken from the canine distal colon. 2 Intravenous infusion of SR 58611 A, ritodrine or isoprenaline at doses inducing the same degree of tachycardia inhibited the gastrocolonic response to a different extent, with SR 58611A and ritodrine being more effective than isoprenaline. 3 In a dose-response study, SR 58611A was more potent in inhibiting colonic motility than in inducing tachycardia: the ED₃₅ values for inhibition of colonic motility and induction of tachycardia were 23 and 156 μg kg⁻¹, i.v., respectively. 4 The inhibitory effect of SR 58611A 100 μg kg⁻¹, i.v., on the gastrocolonic response was reversed by alprenolol (non-selective β-adrenoceptor antagonist), but resistant to CGP 20712A (β₁-adrenoceptor antagonist) or ICI 118551 (β₂-adrenoceptor antagonist). 5 In vitro, SR 58611A concentration-dependently relaxed circular muscle strips, an effect that was competitively antagonized by alprenolol with a pA₂ value of 7.1, but resistant to CGP 20712A (100 nM), ICI 118551 (100 nM) or tetrodotoxin (1 μm). 6 The present study provides strong functional evidence for a role of atypical or β₃-adrenoceptors in the modulation of canine colonic motility both in vivo and in vitro by an inhibitory effect most likely at the smooth muscle level.