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

The relaxant effects of isoprenaline may result from activation of another β‐adrenoceptor subtype in addition to β 1 and β 2 . This study evaluated the role of a third β‐adrenoceptor subtype, β 3 , 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 (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 ‐N G ‐monomethyl arginine ( L ‐NMMA) (E max =61.3±7.9%). In the presence of nadolol, a β 1 ‐ and β 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. Similar relaxant effects were obtained with two β 3 ‐adrenoceptor agonists: SR 58611 (a preferential β 3 ‐adrenoceptor agonist), and CGP 12177 (a partial β 3 ‐adrenoceptor with β 1 ‐ and β 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 β 3 ‐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, β 3 ‐adrenoceptors are mainly located on endothelial cells, and act in conjuction with β 1 ‐ and β 2 ‐adrenoceptors to mediate relaxation through activation of an NO synthase pathway and subsequent increase in cyclic GMP levels.British Journal of Pharmacology (1999) 128 , 69–76; doi: 10.1038/sj.bjp.0702797