TY - JOUR T1 - <em>Beta</em>-3 Adrenergic Receptor Agonists Cause an Increase in Gastrointestinal Transit Time in Wild-type Mice, But Not in Mice Lacking the <em>Beta</em>-3 Adrenergic Receptor JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 720 LP - 724 VL - 287 IS - 2 AU - Daniel S. Fletcher AU - Mari Rios Candelore AU - Danica Grujic AU - Bradford B. Lowell AU - Silvi Luell AU - Vedrana S. Susulic AU - D. Euan Macintyre Y1 - 1998/11/01 UR - http://jpet.aspetjournals.org/content/287/2/720.abstract N2 - The effects of beta-3 adrenergic receptor (β3-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 β3-AR (β3-AR[KO]) or having β3-AR in white and brown adipose tissue only (β3-AR[WAT+BAT]). After s.c. administration of 3 mg/kg of the selective, rodent specific β3-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 β3-AR[KO] mice. Treatment of WT mice with SR 56811A, a β3-AR agonist that exhibited a relatively lower affinity for rodent β3-AR in vitro, did not affect GI motility or plasma glycerol levels in WT or β3[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 β3-AR[KO] mice. These results are consistent with a postulated role for β3-AR in regulation of GI motility in the mouse. However, treatment of β3-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 β3-AR agonist may exert its effects on the GI tract indirectly, through an unknown signaling mechanism activated by agonism of β3-AR in adipose tissue. The American Society for Pharmacology and Experimental Therapeutics ER -