IS THE ATYPICAL BETA-RECEPTOR IN THE RAT STOMACH FUNDUS THE RAT BETA(3) RECEPTOR

The rat gastric fundus is known to possess an ''atypical'' beta-adrene rgic receptor that mediates relaxation to isoproterenol. The purpose o f this study was to characterize the relationship between this ''atypi cal'' beta receptor in the rat stomach and the cloned rat beta(3) rece ptor by taking advantage of highly selective pharmacological and molec ular biological probes of the beta(3) receptor. Nuclease protection an alysis of RNA from the rat gastric fundus identified beta(3) receptor mRNA whose levels in the stomach were exceeded only by those in adipos e tissue. Pharmacological analysis of the recombinant rat beta(3) rece ptor expressed in Chinese hamster ovary cells indicated low affinity o f propranolol with a K-i value of 2.3 mu M. Therefore, 0.3 mu M propra nolol was chosen as a concentration that would completely block beta(1 ) and beta(2) receptors (K-i = 1-5 nM) but would leave beta(3) recepto rs largely intact in the rat stomach fundus. In the presence of propra nolol, several beta-adrenergic receptor agonists relaxed the rat stoma ch fundus with a rank potency order of ]-amino]-propyl]1,3-benzodioxol e-2,2-dicarboxylate (CL316,243) > isoproterenol > norepinephrine = epi nephrine = 3[(1,1-dimethylethyl)amino]-2-hydroxylproproyl]1,3 dihydro- 2H-benzimidazol-2-one hydrochloride (CGP12177) > clenbuterol > terbuta line > pindolol. Isoproterenol, norepinephrine and epinephrine were fu ll agonists, whereas ]-amino]-propyl]1,3-benzodioxole-2,2-dicarboxylat e was only a partial agonist with 66% intrinsic activity relative to i soproterenol. These same beta agonists were also studied for their abi lity to stimulate adenylyl cyclase activity in Chinese hamster ovary c ells expressing the cloned rat beta(3) receptor. For this series of be ta receptor agonists, the relaxant activity in the rat stomach fundus, as measured by potency (EC(50)) or intrinsic activity (maximal respon se), correlated well with the ability of these agonists to activate th e recombinant rat beta(3) receptor. Thus the present studies provide m olecular and pharmacological evidence that the ''atypical'' beta recep tor in the rat stomach fundus that mediates relaxation is the beta(3) receptor.