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Circulation Research. 2003
Published online before print August 21, 2003, doi: 10.1161/01.RES.0000092140.81594.A8
A more recent version of this article appeared on October 3, 2003
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Right arrow Endothelium/vascular type/nitric oxide

Submitted on May 19, 2003
Revised on August 12, 2003
Accepted on August 12, 2003

Extracellular Superoxide Dismutase Is a Major Determinant of Nitric Oxide Bioavailability. In Vivo and Ex Vivo Evidence From ecSOD-Deficient Mice

Oliver Jung ; Stefan L. Marklund ; Helmut Geiger ; Thierry Pedrazzini ; Rudi Busse ; and Ralf P. Brandes *

From the Institut für Kardiovaskuläre Physiologie (O.J., R.B., R.P.B.) and Medizinische Klinik IV (H.G.), Funktionsbereich Nephrology, Klinikum der J.W.-Goethe-Universität, Frankfurt am Main, Germany; Department of Medical Biosciences (S.L.M.), Clinical Chemistry, Umea University Hospital, Umea, Sweden; and the Division of Hypertension (T.P.), University of Lausanne Medical School, Lausanne, Switzerland.

* To whom correspondence should be addressed. E-mail: r.brandes{at}em.uni-frankfurt.de.

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 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.
Key words: superoxide dismutase • oxidative stress • angiotensin • endothelium • hypertension




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