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Vol. 287, Issue 2, 720-724, November 1998

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

Daniel S. Fletcher, Mari Rios Candelore, Danica Grujic1, Bradford B. Lowell1, Silvi Luell, Vedrana S. Susulic2 and D. Euan Macintyre

Department of Pharmacology, Merck & Co., Rahway, New Jersey

The effects of beta-3 adrenergic receptor (beta 3-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 beta 3-AR (beta 3-AR[KO]) or having beta 3-AR in white and brown adipose tissue only (beta 3-AR[WAT+BAT]). After s.c. administration of 3 mg/kg of the selective, rodent specific beta 3-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 beta 3-AR[KO] mice. Treatment of WT mice with SR 56811A, a beta 3-AR agonist that exhibited a relatively lower affinity for rodent beta 3-AR in vitro, did not affect GI motility or plasma glycerol levels in WT or beta 3[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 beta 3-AR[KO] mice. These results are consistent with a postulated role for beta 3-AR in regulation of GI motility in the mouse. However, treatment of beta 3-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 beta 3-AR agonist may exert its effects on the GI tract indirectly, through an unknown signaling mechanism activated by agonism of beta 3-AR in adipose tissue.

0022-3565/98/2872-0720$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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