Role of beta-3-adrenoceptor in catecholamine-induced relaxations in gastric fundus from control and diabetic rats

The contribution of beta-adrenoceptor subtypes to the catecholamine-mediated relaxations in gastric fundus from control and streptozotocin (STZ)-induced diabetic rats were investigated. Isolated organ bath studies and molecular techniques were used to characterize the beta-adrenoceptor subtypes mediating relaxation of rat gastric fundus. Isoprenaline-mediated relaxation was not significantly changed by nadolol (beta(1)-/beta(2)-adrenoceptor antagonist; 1 micromol/l) but only shifted to the right by SR59230A (3-(2-ethylphenoxy)-1-[[(1S)-1,2,3,4-tetrahydronaphth-1-yl]amino]-(2S)-2-propanol oxalate salt, 0.1-1 micromol/l), a selective beta(3)-adrenoceptor antagonist, in a competitive manner. Relaxant responses to noradrenaline were antagonized in a concentration-dependent manner by SR59230A (0.1-1 micromol/l), but not by metoprolol (selective beta(1)-adrenoceptor antagonist; 0.1-1 micromol/l) and ICI-118551 (1-[2,3-(dihydro-7-methyl-1Hinden- 4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride, selective beta(2)-adrenoceptor antagonist; 0.1-1 micromol/l). SR59230A (1 micromol/l) also caused a significant rightward shift in fenoterol-induced relaxation while ICI-118551 (1 micromol/l) did not have any effect. Selective beta(3)-adrenoceptor agonist, BRL37344 ([4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy]acetic acid), caused biphasic relaxation which was not affected by nadolol (1 micromol/l). SR59230A (1 micromol/l) abolished only the first phase of BRL37344 response. beta(1)-, beta(2)- and beta(3)-adrenoceptor mRNA expressions have been detected in a similar intensity in gastric fundus from control rats. Experimental diabetes caused a significant decrease in E(max) and pD(2) values of isoprenaline and noradrenaline. Diabetes also reduced E(max) but not pD(2) value of the first component of BRL37344-induced relaxation response. The band intensity of mRNA transcript of beta(3)-adrenoceptor was reduced in diabetics while no alteration has been found for beta(1)- and beta(2)-adrenoceptor mRNA transcripts between groups. These results show that functional beta-adrenoceptor subtype involved in catecholamine-mediated relaxations is beta(3)-adrenoceptor, and its function and mRNA expression are decreased in diabetes.