Tempol, an antioxidant, restores endothelium-derived hyperpolarizing factor-mediated vasodilation during hypertension.

Acetylcholine releases a non-prostanoid endothelium-derived hyperpolarizing factor (EDHF) and nitric oxide from physiological salt solution perfused rat mesenteric arteries. This study reports an impairment in EDHF-mediated vasodilation in deoxycorticosterone acetate (DOCA)-salt hypertensive versus control normotensive rats. Nitric oxide-mediated vasodilation to acetylcholine was not altered in the animals. We hypothesize that free radical species generated as by-products of arachidonic acid metabolism contribute to impaired EDHF-mediated dilation in DOCA-salt hypertension. With or without reduced nicotinamide adenine dinucleotide phosphate (NADPH) as co-factor, arterial microsomes generate free radical species upon incubation with arachidonic acid. The production of free radicals was significantly higher in DOCA-salt versus control rat microsomes, and was totally eliminated by addition of cyclooxygenase-2 inhibitors NS-398 or celecoxib at 30 microM. Treatment of DOCA-salt rats with tempol (an antioxidant; 15 mg/kg, i.p., 21 days) alleviates hypertension; improves acetylcholine-induced EDHF-mediated vasodilation in DOCA-salt rats, and decreases arachidonic acid-driven microsomal free radical production. Serum level of 8-isoprostanes is elevated in DOCA-salt hypertension versus control or sham-salt rats, and the increase was reversed by tempol treatment. These results show that EDHF-mediated dilation of rat mesenteric arteries is impaired in DOCA-salt induced hypertension. Our data also suggest that cyclooxygenase-2 mediates free radical production, and that free radicals modulate the EDHF-mediated vascular response in DOCA-salt induced hypertension.