title: Extracellular superoxide dismutase is a major determinant of nitric oxide bioavailability: in vivo and ex vivo evidence from ecSOD-deficient mice.
abstract: The bioavailability of nitric oxide (NO) within the vascular wall is limited by superoxide anions (O2.-). The relevance of extracellular superoxide dismutase (ecSOD) for the detoxification of vascular O2.- is unknown. We determined the involvement of ecSOD in the control of blood pressure and endothelium-dependent responses in angiotensin II-induced hypertension and renovascular hypertension induced by the two-kidney, one-clip model in wild-type mice and mice lacking the ecSOD gene. Blood pressure was identical in sham-operated ecSOD+/+ and ecSOD-/- mice. After 6 days of angiotensin II-treatment and 2 and 4 weeks after renal artery clipping, blood pressure was significantly higher in ecSOD-/- than ecSOD+/+ mice. Recombinant ecSOD selectively decreased blood pressure in hypertensive ecSOD-/- mice, whereas ecSOD had no effect in normotensive and hypertensive ecSOD+/+ mice. Compared with sham-operated ecSOD+/+ mice, sham-operated ecSOD-/- mice exhibited attenuated acetylcholine-induced relaxations. These responses were further depressed in vessels from clipped animals. Vascular O2.-, as measured by lucigenin chemiluminescence, was higher in ecSOD-/- compared with ecSOD+/+ mice and was increased by clipping. The antioxidant tiron normalized relaxations in vessels from sham-operated and clipped ecSOD-/-, as well as from clipped ecSOD+/+ mice. In contrast, in vivo application of ecSOD selectively enhanced endothelium-dependent relaxation in vessels from ecSOD-/- mice. These data reveal that endogenous ecSOD is a major antagonistic principle to vascular O2.-, controlling blood pressure and vascular function in angiotensin II-dependent models of hypertension. ecSOD is expressed in such an abundance that even in situations of high oxidative stress no relative lack of enzyme activity occurs.
authors.affiliation: Institut für Kardiovaskuläre Physiologie, Funktionsbereich Nephrologie, Klinikum der J.W.-Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Jung
authors.forename: Stefan L
authors.initials: SL
authors.lastname: Marklund
authors.forename: Helmut
authors.initials: H
authors.lastname: Geiger
authors.forename: Thierry
authors.initials: T
authors.lastname: Pedrazzini
authors.forename: Rudi
authors.initials: R
authors.lastname: Busse
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D002374:Catalase / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology / Q000503:physiopathology; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D006978:Hypertension, Renovascular / Q000378:metabolism / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D011994:Recombinant Proteins; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D013481:Superoxides; D000804:Angiotensin II; D009599:Nitroprusside; D010656:Phenylephrine; D009569:Nitric Oxide; D002374:Catalase; D013482:Superoxide Dismutase; D000109:Acetylcholine