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

• Published in: European journal of pharmacology Vol. 481; no. 1; pp. 91 - 100
• Main Authors: Adeagbo, Ayotunde S.O., Joshua, Irving G., Falkner, Cameron, Matheson, Paul J.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 14-11-2003; Elsevier
• Subjects: Acetylcholine - pharmacology; Animals; Antioxidants - pharmacology; Benzimidazoles - pharmacology; Biological and medical sciences; Biological Factors - physiology; Blood Pressure - drug effects; Calcium Channel Agonists - pharmacology; Cyclic N-Oxides - pharmacology; Cyclooxygenase Inhibitors - pharmacology; Desoxycorticosterone; Dinoprost - analogs & derivatives; Dinoprost - blood; DOCA-salt hypertension; Dose-Response Relationship, Drug; Endothelium-derived hyperpolarizing factor; Enzyme Inhibitors - pharmacology; Free radical species; Free Radicals - metabolism; Hypertension - chemically induced; Hypertension - physiopathology; Imidazoles - pharmacology; In Vitro Techniques; Indomethacin - pharmacology; Male; Medical sciences; Mesenteric Arteries - drug effects; Mesenteric Arteries - physiology; Mesenteric Arteries - physiopathology; Mesenteric vascular bed; Microsomes - drug effects; Microsomes - metabolism; NG-Nitroarginine Methyl Ester - pharmacology; Nitric Oxide Synthase - antagonists & inhibitors; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Sodium Chloride, Dietary - administration & dosage; Spin Labels; Tempol; Vasoconstrictor Agents - pharmacology; Vasodilation - drug effects; Vasodilator Agents - pharmacology; DOCA-salt hypertension; Tempol; Free radical species; Mesenteric vascular bed; Endothelium-derived hyperpolarizing factor; Hypertension; Vasomotricity; Endothelium-derived hyperpolarizing factor; DOCA-salt hypertension; Cardiovascular disease; species; Mesenteric vascular bed; Antioxidant; Vasodilation; Endothelium
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2003.09.005

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 μM. 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.