title: Nitric oxide inhibits alpha2-adrenoceptor-mediated endothelium-dependent vasodilation.
abstract: This study was designed to investigate the interaction between the NO/L-arginine pathway and the alpha2-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 micromol/L; a selective alpha2-adrenoceptor agonist) induced an endothelium-dependent relaxation of eNOS- but not WT arteries preconstricted either with phenylephrine or serotonin. In the presence of Nomega-nitro-L-arginine (l-NNA, 100 micromol/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 alpha2-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 alpha2-adrenoceptor-mediated relaxation of eNOS- and WT arteries was inhibited. OXY-induced relaxation was restored on readdition of methylene blue (1 micromol/L, inhibitor of guanylate cyclase), suggesting that cGMP may be the mechanism of inhibition of the alpha2-adrenergic pathway in the presence of NO. Finally, OXY-mediated relaxation was blocked by tetraethylammonium (1 mmol/L) but not glibenclamide (1 micromol/L), suggesting the involvement of an endothelium-derived hyperpolarizing factor that activates Ca2+-activated K+ channels. In conclusion, alpha2-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 alpha2-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.
authors.affiliation: Institut de Cardiologie de Montréal, Centre de Recherche, Quebec, Canada. thorin@icm.umontreal.ca
authors.forename: E
authors.initials: E
authors.lastname: Thorin
authors.forename: P L
authors.initials: PL
authors.lastname: Huang
authors.forename: M C
authors.initials: MC
authors.lastname: Fishman
authors.forename: J A
authors.initials: JA
authors.lastname: Bevan
mesh_terms: D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000502:physiology*; D004789:Enzyme Activation; D006162:Guanylate Cyclase / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000502:physiology; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D015221:Potassium Channels / Q000187:drug effects; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D019789:Tetraethylammonium / Q000494:pharmacology; D014664:Vasodilation
chemical_list: D015221:Potassium Channels; D018341:Receptors, Adrenergic, alpha-2; D009569:Nitric Oxide; D019789:Tetraethylammonium; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D006162:Guanylate Cyclase; D006152:Cyclic GMP