title: Beta-3 adrenergic receptor agonists cause an increase in gastrointestinal transit time in wild-type mice, but not in mice lacking the beta-3 adrenergic receptor.
abstract: The effects of beta-3 adrenergic receptor (beta3-AR) agonists on gastrointestinal (GI) motility, as reported by stomach retention and intestinal transit of radiolabelled charcoal, were compared in wild-type (WT) mice and in transgenic mice lacking beta3-AR (beta3-AR[KO]) or having beta3-AR in white and brown adipose tissue only (beta3-AR[WAT+BAT]). After s.c. administration of 3 mg/kg of the selective, rodent specific beta3-AR agonists BRL 35135, CL 316, 243 or ICI 198,157, WT mice exhibited a significant decrease in the extent of movement of radiotracer through the stomach and intestines, indicative of decreased GI motility. These compounds also caused an increase in plasma glycerol levels in the WT mice, suggesting that increased lipolysis in adipose tissue had been evoked. None of these compounds had an effect on GI motility or evoked lipolysis in the beta3-AR[KO] mice. Treatment of WT mice with SR 56811A, a beta3-AR agonist that exhibited a relatively lower affinity for rodent beta3-AR in vitro, did not affect GI motility or plasma glycerol levels in WT or beta3[KO] mice when administered s.c. at 3 mg/kg. Clonidine, an alpha-2 adrenergic receptor agonist, used as a positive control in these GI studies, caused a decrease in GI motility in both WT and beta3-AR[KO] mice. These results are consistent with a postulated role for beta3-AR in regulation of GI motility in the mouse. However, treatment of beta3-AR[WAT+BAT] mice with 3 mg/kg BRL 35135 resulted in elevated plasma glycerol levels, as well as increased stomach retention and decreased intestinal transit of radiotracer. These results suggest that this beta3-AR agonist may exert its effects on the GI tract indirectly, through an unknown signaling mechanism activated by agonism of beta3-AR in adipose tissue.
authors.affiliation: Department of Pharmacology, Merck & Co., Rahway, New Jersey, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Fletcher
authors.forename: M R
authors.initials: MR
authors.lastname: Candelore
authors.forename: D
authors.initials: D
authors.lastname: Grujic
authors.forename: B B
authors.initials: BB
authors.lastname: Lowell
authors.forename: S
authors.initials: S
authors.lastname: Luell
authors.forename: V S
authors.initials: VS
authors.lastname: Susulic
authors.forename: D E
authors.initials: DE
authors.lastname: Macintyre
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D005772:Gastrointestinal Transit / Q000187:drug effects*; D005990:Glycerol / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D010627:Phenethylamines / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000235:genetics; D022702:Receptors, Adrenergic, beta-3
chemical_list: D000318:Adrenergic beta-Agonists; D010627:Phenethylamines; D011943:Receptors, Adrenergic, beta; D022702:Receptors, Adrenergic, beta-3; C063157:BRL 35135; D003000:Clonidine; D005990:Glycerol