Enhancement of gastric mucosal blood flow by beta-3 adrenergic agonists prevents indomethacin-induced antral ulcer in the rat.

Indomethacin (32 mg/kg s.c.) produced mainly antral ulcers in refed rats but almost exclusively corpus erosions in fasted rats. Subcutaneous doses of a nonselective beta (isoproterenol), a selective beta-2 (salbutamol) and selective beta-3 adrenergic agonists CBRL35135, (R*,R*)-(+/-)-methyl 4-[2-[2-hydroxy-2-(3-chlorophenyl)ethylamino]propyl] phenoxyacetate hydrobromide; CL316,243, disodium (R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxy-ethyl]- amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate; SR58611A, ethyl[(7S)-7-[(2R)-(2(3-chlorophenyl)-2-hydroxyethylamino]5,6,7, 8-tetrahydronaphthalen-2-yloxy]acetate hydrochloride) dose-dependently attenuated the antral ulcers, and their activities were in the order of BRL35135 (ED50 = 0.03 mg/kg) > CL316,243 (ED50 = 0.04 mg/kg) > SR58611A (ED50 = 0.2 mg/kg) > isoproterenol (ED50 = 0.4 mg/kg) > salbutamol (ED50 = 6 mg/kg). Whereas only isoproterenol, salbutamol and BRL35135 significantly attenuated the corpus erosions and reduced gastric acid secretion in pylorus-ligated rats. In in vitro, all the beta agonists enhanced the beating rate of guinea pig atria (beta-1 action) and inhibited spontaneous contractions of rat uterus (beta-2 action) and colon (beta-3 action). There was found a statistically significant correlation between the IC50 values of the drugs on the colon and ED50 values on the indomethacin-induced antral ulcers (r = 0.97). In addition, the beta agonists excepting salbutamol increased antral gastric mucosal blood flow in rats anesthetized with halothane, and the activities were arranged in the potency order of inhibiting colon motility.(ABSTRACT TRUNCATED AT 250 WORDS)