title: Altered vascular reactivity in mice made hypertensive by nitric oxide synthase inhibition.
abstract: This study tested the hypothesis that nitric oxide (NO) synthase inhibition in mice would result in hypertension characterized by increased agonist-induced vasoconstrictor responsiveness and attenuated endothelium-dependent vasodilation. Administration of N-nitro-L-arginine (L-NNA), an NO synthase inhibitor (1 g/L, 4 weeks), via drinking water to mice resulted in significant elevations in blood pressure. Phenylephrine-induced contraction was significantly increased in aortic rings from L-NNA-treated mice compared with rings from control mice. Aortic rings from control mice showed a concentration-dependent relaxation to acetylcholine whereas those obtained from L-NNA-treated mice showed a biphasic response, contracting at lower concentrations while relaxing at higher concentrations. Aortic rings from L-NNA-treated mice had decreased relaxation to acetylcholine and increased sensitivity to sodium nitroprusside compared with control rings. The relaxation induced by an NO-independent soluble guanylyl cyclase activator was not different between groups. In aortic rings from control and L-NNA-treated mice pre-contracted with phenylephrine, the administration of L-NNA to the organ bath caused additional and sustained contraction. When compared with the contraction induced by phenylephrine, L-NNA-induced contraction in aorta from control mice was significantly higher than that in aorta from L-NNA-treated mice. We conclude that mice treated with L-NNA develop hypertension and that a reduction in NO availability is responsible for the changes observed in vascular reactivity.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. elinder@mail.mcg.edu
authors.forename: A Elizabeth
authors.initials: AE
authors.lastname: Linder
authors.forename: David S
authors.initials: DS
authors.lastname: Weber
authors.forename: Steven E
authors.initials: SE
authors.lastname: Whitesall
authors.forename: Louis G
authors.initials: LG
authors.lastname: D'Alecy
authors.forename: R Clinton
authors.initials: RC
authors.lastname: Webb
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000201:enzymology / Q000503:physiopathology; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000201:enzymology / Q000503:physiopathology*; D066298:In Vitro Techniques; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000503:physiopathology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D007191:Indazoles; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D009599:Nitroprusside; D010656:Phenylephrine; D019335:Nitroarginine; D019001:Nitric Oxide Synthase; D000109:Acetylcholine