Menadione induces endothelial dysfunction mediated by oxidative stress and arylation.
Our previous studies showed that menadione causes endothelial dysfunction which results in decreased relaxation and increased contraction of blood vessels. This investigation examined the role of two possible mechanisms (oxidative stress and arylation) in menadione-induced endothelial dysfunction. Menadione increased superoxide anion generation in aortic rings in a dose-dependent manner. Superoxide dismutase (SOD), reversed the inhibitory effects of menadione on vascular relaxation. The relaxation induced by the NO donor, sodium nitroprusside, was inhibited by menadione pretreatment in a dose-dependent manner. Endothelial nitric oxide synthase activity (eNOS) was suppressed by menadione. Menadione resulted in a dose-dependent reduction of cGMP levels accumulated by acetylcholine. This reduction of cGMP levels was blocked by SOD treatment, suggesting that superoxide anion generated by menadione could play a role in the inhibition of the nitric oxide pathway. Evidence supporting a possible role for arylation in impaired vascular relaxation was suggested by the observation that benzoquinone, which does not induce oxidative stress in aortic rings, inhibited acetylcholine-induced vascular relaxation to the same extent as menadione. Collectively, these results suggest that menadione can cause endothelial dysfunction in blood vessels by the inhibition of the nitric oxide pathway via superoxide anion generation and that arylation activity may also be another important mechanism.
Lee
J Y
JY
College of Pharmacy, Seoul National University, Shinrim-dong San 56-1, 151-742, Seoul, South Korea.
Bae
O N
ON
Chung
S M
SM
Lee
M Y
MY
Chung
J H
JH
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D016166:Free Radical Scavengers / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D020030:Nitric Oxide Donors / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009599:Nitroprusside / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D011809:Quinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology; D024483:Vitamin K 3 / Q000494:pharmacology*
D000933:Antifibrinolytic Agents; D016166:Free Radical Scavengers; D020030:Nitric Oxide Donors; D011809:Quinones; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D013481:Superoxides; D009599:Nitroprusside; D024483:Vitamin K 3; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D013482:Superoxide Dismutase; D006152:Cyclic GMP; D000109:Acetylcholine