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(Circulation. 2003;107:1053.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
From the Department of Pharmacology and Toxicology (L.L., G.D.F., S.W.W., C.A.N., J.J.G, A.F.C.) and the Neuroscience Program (G.D.F., J.J.G, A.F.C.), Michigan State University, East Lansing; and the Hypertension and Vascular Research Division (P.J.P.), Henry Ford Hospital, Detroit, Mich.
Correspondence to Alex F. Chen, MD, PhD, FAHA, Department of Pharmacology and Toxicology, B403 Life Sciences Building, Michigan State University, East Lansing, MI 48824-1317. E-mail chenal{at}msu.edu
Background Angiotensin IIinduced hypertension is associated with NAD(P)H oxidasedependent superoxide production in the vessel wall. Vascular superoxide level is also increased in deoxycorticosterone acetate (DOCA)salt hypertension, which is associated with a markedly depressed plasma renin activity because of sodium retention. However, the mechanisms underlying superoxide production in low-renin hypertension are undefined.
Methods and Results This study investigated (1) whether and how endothelin-1 (ET-1), which is increased in DOCA-salt hypertensive rats, contributes to arterial superoxide generation and (2) the effect of gene transfer of manganese superoxide dismutase and endothelial nitric oxide synthase. Both superoxide and ET-1 levels were significantly elevated in carotid arteries of DOCA-salt rats compared with that of the sham-operated controls. ET-1 concentration-dependently stimulated superoxide production in vitro in carotid arteries of normotensive rats. The increase in arterial superoxide in both ET-1treated normotensive and DOCA-salt rats was reversed by a selective ETA receptor antagonist, ABT-627, the flavoprotein inhibitor diphenyleneiodonium, and the NADPH oxidase inhibitor apocynin but not by the nitric oxide synthase inhibitor N
-L-arginine methyl ester or the xanthine oxidase inhibitor allopurinol. Furthermore, in vivo blockade of ETA receptors significantly reduced arterial superoxide levels, with a concomitant decrease of systolic blood pressure in DOCA-salt rats. Ex vivo gene transfer of manganese superoxide dismutase or endothelial nitric oxide synthase also suppressed superoxide levels in carotid arteries of DOCA-salt rats.
Conclusions These findings suggest that ET-1 augments vascular superoxide production at least in part via an ETA/NADPH oxidase pathway in low-renin mineralocorticoid hypertension.
Key Words: endothelin NADPH oxidase superoxide hypertension
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