EFFECT OF DOXAZOSIN ON ENDOTHELIAL DYSFUNCTION IN HYPERCHOLESTEROLEMIC ANTIOXIDANT-DEFICIENT RATS/

Hypertension, hypercholesterolemia, atherosclerosis, and coronary hear t disease are associated with abnormal endothelium-dependent, nitric o xide-mediated vasorelaxation. In rats, hypercholesterolemia in combina tion with deficiencies of vitamin E and selenium results in increased endogenous lipid oxidation and endothelial dysfunction. Two hydroxymet abolites of doxazosin, an alpha(1)-adrenergic blocking antihypertensiv e agent, inhibit human lipid oxidation in vitro in a dose-dependent fa shion. The present studies were performed to determine the effect of i n vivo treatment with doxazosin on endothelial dysfunction in hypercho lesterolemic/antioxidant-deficient rats. Dahl rats were fed 1) a stand ard diet, 2) a high cholesterol (4%) diet, or 3) a high cholesterol, v itamin E-and selenium-deficient diet. A subgroup of animals in each gr oup were administered doxazosin (3.5 mg/100 g/day) for 16 weeks. In th e aortas, vascular relaxations induced by acetylcholine were significa ntly decreased (P < .05) in high cholesterol/antioxidant-deficient rat s compared with normal and high cholesterol animals. Doxazosin treatme nt prevented the impairment in endothelium-dependent vascular relaxati on 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 choles terol/antioxidant-deficient animals compared with normal and high chol esterol animals, was normalized in aortas from high cholesterol/antiox idant-deficient animals that had received doxazosin. The antioxidant e ffect of doxazosin may have therapeutic implications in diseases assoc iated with endothelial dysfunction linked to products of lipid oxidati on. (C) 1997 American Journal of Hypertension, Ltd.