Nitric Oxide Inhibits ₂-Adrenoceptor–Mediated Endothelium-Dependent Vasodilation

From the Institut de Cardiologie de Montréal (E.T.), Centre de Recherche, Montréal, Canada; the Cardiovascular Research Center (P.L.H., M.C.F.), Medical Services, Massachusetts General Hospital and Harvard Medical School, Boston, Mass; and the Totman Laboratory for Human Cerebrovascular Research (J.A.B.), University of Vermont, Burlington, Vt.

Correspondence to Eric Thorin, PhD, Institut de Cardiologie de Montréal, Centre de Recherche, 5000, rue Belanger, Montréal, Quebec H1T 1C8, Canada. E-mail thorin{at}icm.umontreal.ca

Abstract—This study was designed to investigate the interaction between the NO/L-arginine pathway and the ₂-adrenoceptor–mediated endothelium-dependent vasorelaxation. Reactivity of isolated resistance mesenteric arterial segments from mice lacking the gene for constitutive endothelial NO synthase (eNOS^- mice, n=14) and from their wild-type controls (WT mice, n=46) was studied in isometric conditions in the presence of indomethacin (blocker of cyclooxygenase). Oxymetazoline (OXY, 0.01 to 30 µmol/L; a selective ₂-adrenoceptor agonist) induced an endothelium-dependent relaxation of eNOS^- but not WT arteries preconstricted either with phenylephrine or serotonin. In the presence of N-nitro-L-arginine (l-NNA, 100 µmol/L), an inhibitor of NOS, OXY induced an endothelium-dependent relaxation of WT mesenteric arteries. l-NNA had no effect on the relaxation caused by OXY in eNOS^- arterial rings. Therefore, the relaxation caused by OXY was independent of NO formation. To demonstrate the inhibitory role of NO on the ₂-adrenoceptor–mediated relaxation, subthreshold (0.1 nmol/L) to threshold (1 nmol/L) concentrations of sodium nitroprusside (donor of NO) were added to l-NNA–treated arteries before OXY challenges: in these conditions, the ₂-adrenoceptor–mediated relaxation of eNOS^- and WT arteries was inhibited. OXY-induced relaxation was restored on readdition of methylene blue (1 µmol/L, inhibitor of guanylate cyclase), suggesting that cGMP may be the mechanism of inhibition of the ₂-adrenergic pathway in the presence of NO. Finally, OXY-mediated relaxation was blocked by tetraethylammonium (1 mmol/L) but not glibenclamide (1 µmol/L), suggesting the involvement of an endothelium-derived hyperpolarizing factor that activates Ca²⁺-activated K⁺ channels. In conclusion, ₂-adrenoceptor activation caused relaxation of isolated murine mesenteric arteries that was functionally blocked by NO through a mechanism that may involve activation of the soluble guanylate cyclase and cGMP formation. The endothelium-dependent ₂-adrenoceptor–mediated relaxation is likely to be due to an endothelium-derived hyperpolarizing factor, whose release and/or production is reduced by concurrent NO formation.

Key Words: nitric oxide • ₂-adrenoceptor • vasodilation

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