on June 2, 2003
Hypertension. 2003
Published online before print June 2, 2003, doi: 10.1161/01.HYP.0000078357.92682.EC
Published online before print June 2, 2003, doi: 10.1161/01.HYP.0000078357.92682.EC
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Submitted on March 11, 2003
From the Canadian Institutes of Health Research (CIHR) Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal (IRCM), University of Montreal, Montreal, Quebec, Canada. * To whom correspondence should be addressed. E-mail: schiffe{at}ircm.qc.ca.
Abstract--Endothelin A (ETA) receptor blockade has prevented vascular remodeling in aldosterone and salt-induced hypertension. To evaluate effects of the ETA receptor antagonist, BMS 182874, compared with the aldosterone antagonist, spironolactone, on vascular remodeling in aldosterone-infused rats not exposed to a high salt diet, Sprague-Dawley rats were infused subcutaneously with aldosterone (0.75 µg/h) and treated with BMS 182874 (40 mg · kg-1 · d-1), spironolactone, or hydralazine (both 25 mg · kg-1 · d-1) while receiving a normal salt diet for 6 weeks. Aldosterone increased systolic BP (P<0.01), plasma endothelin (3.33±0.32 versus 1.85±0.40 pmol/L in control, P<0.05), systemic oxidative stress as shown by plasma thiobarbituric acid-reacting substances and vascular nicotinamide adenine dinucleotide phosphate (NADPH) activity. Aldosterone increased small artery media thickness (17.7±0.9 versus 13.6±0.8 µm in control, P<0.05) and media/lumen ratio (7.6±0.4 versus 5.5±0.4% in control, P<0.05), with growth index of 21% indicating hypertrophic remodeling. Laser confocal microscopy showed increased collagen and fibronectin deposition and intercellular adhesion molecule-1 (ICAM-1) content in the vessel wall of aldosterone-infused rats. The 3 treatments lowered BP, although hydralazine was slightly less effective. BMS 182874 and spironolactone decreased oxidative stress, normalized the hypertrophic remodeling, decreased collagen and fibronectin deposition, and reduced ICAM-1 abundance in the vascular wall of aldosterone-infused rats, whereas hydralazine only reduced NADPH activity in aorta but did not affect the remaining parameters. Vascular remodeling of small arteries occurs in aldosterone-infused rats exposed to a normal salt diet and may be mediated in part by ET-1 via stimulation of ETA receptors. Endothelin blockade may exert beneficial effects on vascular remodeling, fibrosis, oxidative stress, and adhesion molecule expression in aldosterone-induced hypertension.
Revised on March 26, 2003
Endothelin Antagonism on Aldosterone-Induced Oxidative Stress and Vascular Remodeling
Qian Pu;
Key words: mineralocorticoids • receptors, endothelin • arteries • resistance • extracellular matrix • free radicals
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