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

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Abstract
—This study was designed to investigate the interaction between the NO/l-arginine pathway and the α2-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 α2-adrenoceptor agonist) induced an endothelium-dependent relaxation of eNOS− but not WT arteries preconstricted either with phenylephrine or serotonin. In the presence of Nω-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 α2-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 α2-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 α2-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, α2-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 α2-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.