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

摘要

class="enumerated" style="list-style-type:decimal">The relaxant effects of isoprenaline may result from activation of another β-adrenoceptor subtype in addition to β1 and β2. This study evaluated the role of a third β-adrenoceptor subtype, β3, in β-adrenoceptor-induced relaxation of rat thoracic aorta by isoprenaline.Isoprenaline produced a concentration-dependent relaxation of phenylephrine pre-contracted rings of the thoracic aorta (pD2=7.46±0.15; Emax=85.9±3.4%), which was partially attenuated by endothelium removal (Emax=66.5±6.3%) and administration of the nitric oxide (NO) synthase inhibitor, L-N^G-monomethyl arginine (L-NMMA) (Emax=61.3±7.9%).In the presence of nadolol, a β1- and β2-adrenoceptor antagonist, isoprenaline-induced relaxation persisted (Emax=55.6±5.3%), but occurred at higher concentrations (pD2=6.71±0.10) than in the absence of nadolol and lasted longer.Similar relaxant effects were obtained with two β3-adrenoceptor agonists: SR 58611 (a preferential β3-adrenoceptor agonist), and CGP 12177 (a partial β3-adrenoceptor with β1- and β2-adrenoceptor antagonistic properties). SR 58611 caused concentration-dependent relaxation (pD₂=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 β₃-adrenoceptor antagonist. The relaxation induced by SR 58611 was associated with a 1.7 fold increase in tissue cyclic GMP content.Both relaxation and the cyclic GMP increase induced by SR 58611 were greatly reduced by endothelium removal and in the presence of L-NMMA.We conclude that in the rat thoracic aorta, β₃-adrenoceptors are mainly located on endothelial cells, and act in conjuction with β₁- and β₂-adrenoceptors to mediate relaxation through activation of an NO synthase pathway and subsequent increase in cyclic GMP levels.