title: ETA receptor blockade decreases vascular superoxide generation in DOCA-salt hypertension.
abstract: 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 ETA 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 ETA 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 ETA receptors in DOCA-salt hypertension, in apparently blood pressure-independent fashion.
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Glaucia E
authors.initials: GE
authors.lastname: Callera
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
authors.forename: Simone A
authors.initials: SA
authors.lastname: Teixeira
authors.forename: Marcelo N
authors.initials: MN
authors.lastname: Muscara
authors.forename: Maria Helena C
authors.initials: MH
authors.lastname: Carvalho
authors.forename: Zuleica B
authors.initials: ZB
authors.lastname: Fortes
authors.forename: Dorothy
authors.initials: D
authors.lastname: Nigro
authors.forename: Ernesto L
authors.initials: EL
authors.lastname: Schiffrin
authors.forename: Rita C
authors.initials: RC
authors.lastname: Tostes
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology; D001160:Arterioles / Q000033:anatomy & histology / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D046508:Culture Techniques; D003619:Dansyl Compounds / Q000494:pharmacology; D003900:Desoxycorticosterone; D065128:Endothelin Receptor Antagonists; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009504:Neutrophils / Q000378:metabolism; D018384:Oxidative Stress; D011506:Proteins / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D012965:Sodium Chloride; D013481:Superoxides / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D003619:Dansyl Compounds; D065128:Endothelin Receptor Antagonists; D011506:Proteins; D044022:Receptor, Endothelin A; D014665:Vasodilator Agents; D013481:Superoxides; C085754:5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide; C002744:3-nitrotyrosine; D003900:Desoxycorticosterone; D014443:Tyrosine; D012965:Sodium Chloride; D000109:Acetylcholine