Published online before print June 2, 2003, doi: 10.1161/01.HYP.0000078357.92682.EC
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(Hypertension. 2003;42:49.)
© 2003 American Heart Association, Inc.
Scientific Contribution |
Endothelin Antagonism on Aldosterone-Induced Oxidative Stress and Vascular Remodeling
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.
Correspondence to Ernesto L. Schiffrin, MD, PhD, FRCPC, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec, Canada H2W 1R7. E-mail schiffe{at}ircm.qc.ca
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.
Key Words: mineralocorticoids • receptors, endothelin • arteries • resistance • extracellular matrix • free radicals
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