Cyclic AMP-independent relaxation mediated by β 3-adrenoceptors on guinea pig gastrointestine

Abstract

In this study, we investigated the signal transduction pathway involved in β 3-adrenoceptor-mediated relaxations of guinea pig gastric fundus and duodenum. In the presence of β 1- and β 2-adrenoceptor blockade, the potency (pD 2 value) of catecholamines ((−)-isoprenaline, (−)-noradrenaline and (−)-adrenaline) and β 3-adrenoceptor agonists (( R*, R*)-(±)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxyacetic acid sodium (BRL37344) and (±)-[4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2 H-benzimidazol-2-one] hydrochloride ((±)-CGP12177A)) to induce relaxation was not affected by the adenylate cyclase inhibitor, 9-(tetrahydro-2-furanyl)-9 H-purin-6-amine (SQ-22,536, 100 μM). Catecholamines induced an elevation of cyclic AMP and SQ-22,536 significantly abolished the responses of gastric fundus. However, cyclic AMP levels were unaltered by the β 3-adrenoceptor agonists in gastric fundus and by the five agonists in duodenum. Furthermore, the relaxant responses to catecholamines and to β 3-adrenoceptor agonists were unaffected by the cyclic AMP-dependent protein kinase inhibitor, N-(2-[ p-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide (H-89, 10 μM) in gastric fundus. These results suggest that β 3-adrenoceptor-induced relaxation is mediated through both cyclic AMP-dependent and cyclic AMP-independent pathways in gastric fundus and through a cyclic AMP-independent pathway in duodenum.