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.
Adeagbo
Ayotunde S O
AS
Department of Physiology and Biophysics, Health Sciences Center, A-1214, University of Louisville, Louisville, KY 40292, USA. asadea01@louisville.edu
Joshua
Irving G
IG
Falkner
Cameron
C
Matheson
Paul J
PJ
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D001685:Biological Factors / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects; D002120:Calcium Channel Agonists / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003900:Desoxycorticosterone; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D013113:Spin Labels; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D000975:Antioxidants; D001562:Benzimidazoles; D001685:Biological Factors; D002120:Calcium Channel Agonists; D003497:Cyclic N-Oxides; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D005609:Free Radicals; D007093:Imidazoles; D017673:Sodium Chloride, Dietary; D013113:Spin Labels; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; C075750:8-epi-prostaglandin F2alpha; D003900:Desoxycorticosterone; D015237:Dinoprost; D019001:Nitric Oxide Synthase; C102635:1-ethyl-2-benzimidazolinone; D000109:Acetylcholine; C014282:cirazoline; C001803:tempol; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin