Beta 3-adrenoceptor stimulation induces vasorelaxation mediated essentially by endothelium-derived nitric oxide in rat thoracic aorta

1 The relaxant effects of isoprenaline may result from activation of another beta-adrenoceptor subtype in addition to beta(1) and beta(2). This study evaluated the role of a third beta-adrenoceptor subtype, beta(3), in beta-adrenoceptor-induced relaxation of rat thoracic aorta by isoprenaline. 2 Isoprenaline produced a concentration-dependent relaxation of phenylephrine pre-contracted rings of the thoracic aorta (pD(2) = 7.46 +/- 0.15; E-max = 85.9 +/- 3.4%), which was partially attenuated by endothelium removal (E-max = 66.5 +/- 6.3%) and administration of the nitric oxide (NO) synthase inhibitor, L-NG-monomethyl arginine (L-NMMA:) (E-max = 61.3 +/- 7.9%). 3 In the presence of nadolol, a beta(1)- and beta(2)-adrenoceptor antagonist, isoprenaline-induced relaxation persisted (E-max = 55.6 +/- 5.3%), but occurred at higher concentrations (pD(2) = 6.71 +/- 0.10) than in the absence of nadolol and lasted longer. 4 Similar relaxant effects were obtained with two beta(3)-adrenoceptor agonists: SR 58611 (a preferential beta(3)-adrenoceptor agonist), and CGP 12177 (a partial beta(3)-adrenoceptor with beta(1)- and beta(2)-adrenoceptor antagonistic properties). SR 58611 caused concentration-dependent relaxation (pD(2) = 5.24 +/- 0.07; E-max = 59.5 +/- 3.7%), which was not modified by pre-treatment with nadolol but antagonized by SR 59230A, a beta(3)-adrenoceptor antagonist. The relaxation induced by SR 58611 was associated with a 1.7 fold increase in tissue cyclic GMP content. 5 Both relaxation and the cyclic GMP increase induced by SR 58611 were greatly reduced by endothelium removal and in the presence of L-NMMA. 6 We conclude that in the rat thoracic aorta, beta(3)-adrenoceptors are mainly located on endothelial cells, and act in conjuction with beta(1)- and beta(2)-adrenoceptors to mediate relaxation through activation of an NO synthase pathway and subsequent increase in cyclic GMP levels.