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


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-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.


CONCLUSIONS
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.
Li
Lixin
L
Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824-1317, USA.
Fink
Gregory D
GD
Watts
Stephanie W
SW
Northcott
Carrie A
CA
Galligan
James J
JJ
Pagano
Patrick J
PJ
Chen
Alex F
AF
D000818:Animals; D001794:Blood Pressure; D002339:Carotid Arteries / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D003900:Desoxycorticosterone; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology*; D006973:Hypertension / Q000097:blood / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D019255:NADPH Oxidases / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000502:physiology; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000502:physiology*; D012083:Renin / Q000097:blood; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics; D013481:Superoxides / Q000032:analysis / Q000378:metabolism*; D014161:Transduction, Genetic; D014969:Xanthine Oxidase / Q000502:physiology
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D013481:Superoxides; D003900:Desoxycorticosterone; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; D012083:Renin