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

Abstract

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 Ϫ mice, nϭ14) and from their wild-type controls (WT mice, nϭ46) was studied in isometric conditions in the presence of indomethacin (blocker of cyclooxygenase). Oxymetazoline (OXY, 0.01 to 30 mol/L; a selective ␣ 2 -adrenoceptor agonist) induced an endothelium-dependent relaxation of eNOS Ϫ but not WT arteries preconstricted either with phenylephrine or serotonin. In the presence of N -nitro-L-arginine (l-NNA, 100 mol/L), an inhibitor of NOS, OXY induced an endotheliumdependent relaxation of WT mesenteric arteries. l-NNA had no effect on the relaxation caused by OXY in eNOS Ϫ 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 Ϫ and WT arteries was inhibited. OXY-induced relaxation was restored on readdition of methylene blue (1 mol/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 mol/L), suggesting the involvement of an endothelium-derived hyperpolarizing factor that activates Ca 2ϩ -activated K ϩ 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. (Circ Res. 1998;82:1323-1329.) Key Words: nitric oxide Ⅲ ␣ 2 -adrenoceptor Ⅲ vasodilation T he ␣ 2 -adrenoceptors are widely distributed in the cardiovascular system. Whereas activation of presynaptic ␣ 2 -adrenoceptors decreases sympathetic activity, 1,2 activation of smooth muscle ␣ 2 -adrenoceptors induces contraction.3,4 ␣ 2 -Adrenoceptors are also functionally expressed on the vascular endothelium. Their activation induces relaxation of isolated arteries from various vascular beds. [5][6][7] Most of the data gathered involving ␣ 2 -adrenoceptor-induced relaxation have been obtained from studies performed in large conductance vessels. 6,8 A few studies, however, have focused on the mechanisms coupling ␣ 2 -adrenoceptor activation and relaxation of resistance arteries, which are clearly different from those identified in ...

Gender-Specific Alteration of Adrenergic Responses in Small Femoral Arteries From Estrogen Receptor-β Knockout Mice

“…15 Despite enhanced constriction to PE, the similarity of responses to NE in ER␤KO and WT males suggested that ER-dependent modulation of ARs occurs to prevent enhanced NE constriction in ER␤KO males. Whereas PE constricts solely via ␣ 1 -AR on VSM cell, NE may modulate vasoconstriction via endothelial ␣ 2 -AR and release of endotheliumderived factors, 12,28,29 predominantly NO, 30 the contribution of which decreases with diminishing artery size. [31][32][33] Indeed, we found no evidence for endothelial ␣ 2 -AR-mediated dilatation in small femoral arteries from either ER␤KO or WT because NE responses were not significantly different before and after incubation with endothelial NOS and COX inhibitors.…”

Possible Role of Efnb1 Protein, a Ligand of Eph Receptor Tyrosine Kinases, in Modulating Blood Pressure

“…Ex Vivo Vessel Constriction-Vessel constriction was studied ex vivo as described previously (21). Mesenteric artery segments (2 mm in length) of third order branches (exterior diameter, 125-150 m) were stripped off the endothelium and mounted on 20-m tungsten wires in small vessel myographs, stretched to optimal tension, and maintained in physiological saline solution (130 mM NaCl, 4.7 mM KCl, 1.18 mM KH 2 PO 4 , 1.17 mM MgSO 4 , 1.17 mM NaHCO 3 , 1.6 mM CaCl 2 , 0.023 mM EDTA, 10 mM glucose aerated with 12% O 2 , 5% CO 2 , 83% N 2 , pH 7.4) at 37°C.…”

Involvement of Guanylate Cyclase and K+ Channels in Relaxation Evoked by Ferulate Nitrate in Rat Aorta Artery

“…Contractions elicited by phenylephrine involve α-adrenergic receptor-operated intracellular Ca 2+ release, Ca 2+ influx through receptor-operated Ca 2+ channels, and increase in the Ca 2+ sensitivity (27,28). Stimulation of α-adrenoceptors increases both the Ca 2+ sensitivity of contractile elements and the cytosolic Ca 2+ level (29).…”