title: Endothelin antagonism on aldosterone-induced oxidative stress and vascular remodeling.
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 microg/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 microm 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.
authors.affiliation: Canadian Institutes of Health Research Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, 110 Pine Avenue West, Montreal, Quebec, Canada H2W 1R7.
authors.forename: Qian
authors.initials: Q
authors.lastname: Pu
authors.forename: Mario Fritsch
authors.initials: MF
authors.lastname: Neves
authors.forename: Agostino
authors.initials: A
authors.lastname: Virdis
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
authors.forename: Ernesto L
authors.initials: EL
authors.lastname: Schiffrin
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure; D003619:Dansyl Compounds / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000097:blood / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism; D006321:Heart / Q000033:anatomy & histology; D006830:Hydralazine / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000033:anatomy & histology / Q000166:cytology; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D019255:NADPH Oxidases / Q000378:metabolism; D009929:Organ Size; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D013148:Spironolactone / Q000494:pharmacology*; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D003619:Dansyl Compounds; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D000451:Mineralocorticoid Receptor Antagonists; D044022:Receptor, Endothelin A; D017392:Thiobarbituric Acid Reactive Substances; D014665:Vasodilator Agents; D018799:Intercellular Adhesion Molecule-1; C085754:5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide; D006830:Hydralazine; D013148:Spironolactone; D000450:Aldosterone; D019255:NADPH Oxidases