Effect of doxazosin on endothelial dysfunction in hypercholesterolemic/antioxidant-deficient rats.
Hypertension, hypercholesterolemia, atherosclerosis, and coronary heart disease are associated with abnormal endothelium-dependent, nitric oxide-mediated vasorelaxation. In rats, hypercholesterolemia in combination with deficiencies of vitamin E and selenium results in increased endogenous lipid oxidation and endothelial dysfunction. Two hydroxymetabolites of doxazosin, an alpha 1-adrenergic blocking antihypertensive agent, inhibit human lipid oxidation in vitro in a dose-dependent fashion. The present studies were performed to determine the effect of in vivo treatment with doxazosin on endothelial dysfunction in hypercholesterolemic/ antioxidant-deficient rats. Dahl rats were fed 1) a standard diet, 2) a high cholesterol (4%) diet, or 3) a high cholesterol, vitamin E- and selenium-deficient diet. A subgroup of animals in each group were administered doxazosin (3.5 mg/100 g/day) for 16 weeks. In the aortas, vascular relaxations induced by acetylcholine were significantly decreased (P < .05) in high cholesterol/antioxidant-deficient rats compared with normal and high cholesterol animals. Doxazosin treatment prevented the impairment in endothelium-dependent vascular relaxation in the high cholesterol/antioxidant-deficient group. Vasorelaxation in response to the exogenous nitric oxide donor diethylamine nanoate, which was significantly impaired (P < .05) in aortas from high cholesterol/antioxidant-deficient animals compared with normal and high cholesterol animals, was normalized in aortas from high cholesterol/ antioxidant-deficient animals that had received doxazosin. The antioxidant effect of doxazosin may have therapeutic implications in diseases associated with endothelial dysfunction linked to products of lipid oxidation.
Raij
L
L
Renal Section 111J, Veterans Affairs Medical Center, Minneapolis, MN 55417, USA.
Hayakawa
H
H
Coffee
K
K
Guerra
J
J
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D017292:Doxazosin / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000503:physiopathology; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D012643:Selenium / Q000172:deficiency*; D014811:Vitamin E Deficiency / Q000503:physiopathology*
D000317:Adrenergic alpha-Antagonists; D000975:Antioxidants; D012643:Selenium; D017292:Doxazosin