August 12, 2003Open Access
View Full PaperET A Receptor Blockade Decreases Vascular Superoxide Generation in DOCA-Salt Hypertension
Key Result
ETA receptor blockade with BMS 182874 normalized vascular superoxide production in DOCA-salt hypertensive rats (21.7% vs 44.9% in untreated DOCA-salt rats).
Structured PICO
Does ETA receptor blockade decrease vascular superoxide generation and blood pressure in DOCA-salt hypertensive rats?
P
Population
Deoxycorticosterone acetate (DOCA)-salt hypertensive rats and control uninephrectomized (UniNx) rats
I
Intervention
ETA antagonist BMS 182874 (40 mg/kg per day PO) or Vitamin E (200 mg/kg per day PO)
C
Comparator
Untreated DOCA-salt rats and control uninephrectomized (UniNx) rats
O
Outcome
Systolic blood pressure and vascular superoxide generation in vivosurrogate
ETA receptor blockade with BMS 182874 decreases vascular superoxide production and improves endothelial function in DOCA-salt hypertension, suggesting endothelin-1 mediates oxidative stress via ETA receptors.
Main Result
Absolute Event Rate: 21.7% vs 44.9%
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.