Endothelin-1 increases vascular superoxide via endothelin(A)-NADPH oxidase pathway in low-renin hypertension

• Published in: Circulation (New York, N.Y.) N.Y.), 2003-02, Vol.107 (7), p.1053-1058
• Main Authors: Li, Lixin, Fink, Gregory D, Watts, Stephanie W, Northcott, Carrie A, Galligan, James J, Pagano, Patrick J, Chen, Alex F
• Format: Article
• Language: English
• Subjects: Animals; Blood Pressure; Carotid Arteries - chemistry; Carotid Arteries - drug effects; Carotid Arteries - metabolism; Desoxycorticosterone; Endothelin Receptor Antagonists; Endothelin-1 - metabolism; Endothelin-1 - pharmacology; Hypertension - blood; Hypertension - chemically induced; Hypertension - enzymology; Hypertension - metabolism; Male; NADPH Oxidases - physiology; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase - physiology; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptors, Endothelin - physiology; Renin - blood; Signal Transduction; Superoxide Dismutase - genetics; Superoxides - analysis; Superoxides - metabolism; Transduction, Genetic; Xanthine Oxidase - physiology
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000051459.74466.46

Angiotensin II-induced hypertension is associated with NAD(P)H oxidase-dependent 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. 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-1-treated normotensive and DOCA-salt rats was reversed by a selective ET(A) receptor antagonist, ABT-627, the flavoprotein inhibitor diphenyleneiodonium, and the NADPH oxidase inhibitor apocynin but not by the nitric oxide synthase inhibitor N(omega)-L-arginine methyl ester or the xanthine oxidase inhibitor allopurinol. Furthermore, in vivo blockade of ET(A) 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. These findings suggest that ET-1 augments vascular superoxide production at least in part via an ET(A)/NADPH oxidase pathway in low-renin mineralocorticoid hypertension.