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 beta 3-adrenoceptors can modulate canine colonic motility in vivo, we studied the effects of SR 58611A (a selective agonist for atypical beta-adrenoceptors) alone and after pretreatment with beta-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 beta 3-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 58611A, 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 micrograms kg-1, i.v., respectively. 4. The inhibitory effect of SR 58611A 100 micrograms kg-1, i.v., on the gastrocolonic response was reversed by alprenolol (non-selective beta-adrenoceptor antagonist), but resistant to CGP 20712A (beta 1-adrenoceptor antagonist) or ICI 118551 (beta 2-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 microM). 6. The present study provides strong functional evidence for a role of atypical or beta 3-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.

Localization of the β(beta)3‐adrenoceptor in the human gastrointestinal tract: an immunohistochemical study

“…Our human β 3 ‐adrenoceptor immuno‐localization findings and the evidence of others that supports localization of this receptor on the smooth muscle of the rat jejunum, 2 colon, 3 stomach, 14 oesophagus, 20 the guinea pig caecum 21 and the dog colon, 22 suggest species‐common receptor functions for the β 3 ‐adrenoceptor protein in the mammalian gastrointestinal tract. The β 3 ‐adrenoceptor agonist SR58611A has recently been shown to inhibit gastric acid secretion in the cat stomach 23 …”

Lack of responses to a beta3-adrenergic agonist in lipoatrophic A-ZIP/F-1 mice.

“…Evidence suggesting a direct action of the ␤ 3 agonist on the gastrointestinal tract includes the identification of ␤ 3 -adrenergic receptors throughout the gastrointestinal tract (35,36) and the observation that ␤ 3 agonists inhibit in vitro colon contraction bioassays (37). On the other hand, a ␤ 3 agonist slows intestinal motility in mice lacking all ␤ 3 receptors except those in adipose tissue (23).…”

Functional Evidence for the Presence of β₃-Adrenoceptors in the Guinea Pig Common Bile Duct and Colon

“…These studies showed a much larger population of p2-with respect to Pi-adrenoceptors, while Pv-adrenoceptors could not be detected, most probably because of the weak affinity of the ligand used. Thus, when considering p-adrenoceptors from a functional point of view, the guinea pig colon is similar to the rat and dog colon, two species where pi-adrenoceptor agonists can inhibit colonic motility both in vitro [14,40] and in vivo [40,41]. The functional relevance of the inhibitory effect observed with SR 58611A can also be argued by the observation that the compound blocked the occurrence of an orga nized, propulsive motor event such as the peristaltic reflex.…”