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(Hypertension. 2003;42:811.)
© 2003 American Heart Association, Inc.

Scientific Contributions

ET_A Receptor Blockade Decreases Vascular Superoxide Generation in DOCA-Salt Hypertension

Glaucia E. Callera; Rhian M. Touyz; Simone A. Teixeira; Marcelo N. Muscara; Maria Helena C. Carvalho; Zuleica B. Fortes; Dorothy Nigro; Ernesto L. Schiffrin; Rita C. Tostes

From the Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo (G.E.C., S.A.T., M.N.M., M.H.C.C., Z.B.F., D.N., R.C.T.), Sao Paulo, Brazil, and Clinical Research Institute of Montreal, University of Montreal (R.M.T., E.L.S.), Montreal, Canada.

Correspondence to Rita C.A. Tostes, University of Sao Paulo, Institute of Biomedical Science, Pharmacology Department, Av. Lineu Prestes, 1524, Sao Paulo, SP, 05508-900 Brazil. E-mail rtostes{at}usp.br

Development and progression of end-organ damage in hypertension have been associated with increased oxidative stress. Superoxide anion accumulation has been reported in deoxycorticosterone acetate (DOCA)-salt hypertension, in which endothelin-1 plays an important role in cardiovascular damage. We hypothesized that blockade of ET_A receptors in DOCA-salt rats would decrease oxidative stress. Both systolic blood pressure (SBP, 210±9 mm Hg; P<0.05) and vascular superoxide generation in vivo were increased in DOCA-salt (44.9±10.3% of ethidium bromide–positive nuclei; P<0.05) versus control uninephrectomized (UniNx) rats (118±3 mm Hg; 18.5±3%, respectively). In DOCA-salt rats, the ET_A antagonist BMS 182874 (40 mg/kg per day PO) lowered SBP (170±4 versus UniNx, 120±3 mm Hg) and normalized superoxide production (21.7±6 versus UniNx, 11.9±7%). Vitamin E (200 mg/kg per day PO) decreased superoxide formation in DOCA-salt rats (18.8±7%) but did not alter SBP. Oxidative stress in nonstimulated circulating polymorphonuclear cells (PMNs) or in PMNs treated with zymosan, an inducer of superoxide release, was similar in DOCA-salt and UniNx groups. Superoxide formation by PMNs was unaffected by treatment with BMS 182874. Western blot analysis showed increased nitrotyrosine-containing proteins in mesenteric vessels from DOCA-salt compared with UniNX. Treatment with either BMS 182874 or vitamin E abolished the differences in vascular nitrotyrosine-containing proteins between DOCA-salt and UniNX. Maximal relaxation to acetylcholine was decreased in DOCA-salt aortas (75.8±4.2% versus UniNx, 95.4±1.9%, P<0.05). BMS 182874 treatment increased acetylcholine-induced relaxation in DOCA-salt aortas to 93.5±4.5%. These in vivo findings indicate that increased vascular superoxide production is associated with activation of the endothelin system through ET_A receptors in DOCA-salt hypertension, in apparently blood pressure–independent fashion.

Key Words: endothelin • receptors, endothelin • deoxycorticosterone • hypertension, arterial • oxidative stress

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