title: Vitamin K1 (phylloquinone) induces vascular endothelial dysfunction: role of oxidative stress.
abstract: We aimed to investigate the mechanisms underlying the vascular effects induced by phylloquinone (Vitamin K1; VK1). Vascular reactivity experiments, using standard muscle bath procedures, showed that VK1 (5 and 50 microM) enhances the contractile response of endothelium-intact, but not denuded, rat carotid rings to phenylephrine. Similarly, maximal contraction induced by phenylephrine was enhanced in the presence of the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). The combination of L-NAME and VK1 did not produce any further additional effect. Pre-incubation of intact-rings with VK1 reduced both acetylcholine- and bradykinin-induced relaxation. VK1 induced an increment in tension on carotid rings submaximally pre-contracted with phenylephrine. VK1-induced increment in tension was completely abolished by endothelial removal or incubation of intact rings with L-NAME and L-NNA. Conversely, 7-nitroindazole, 1400 W, or indomethacin did not affect VK1-induced contraction. Moreover, VK1 reduced L-arginine-induced relaxation in endothelium-intact rings. Lucigenin-amplified chemiluminescence assays showed that VK1 induced an increase in the level of superoxide anions in endothelium-intact but not denuded rings. Measurement of nitrite and nitrate generation showed that VK1 did not alter nitrate formation but strongly inhibited the generation of nitrite. Finally, the superoxide anions scavenger tiron prevented the endothelial vasomotor dysfunction caused by VK1 on phenyleprine-induced contraction and acetylcholine or bradykinin-induced relaxation. In conclusion, our data show that VK1 disrupts the vasomotor function of rat carotid. Our results suggest that VK1-induced oxidative stress through production of superoxide anion is interfering with the NO pathway, which in turn is responsible for the altered vascular reactivity induced by VK1.
authors.affiliation: Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Tirapelli
authors.forename: Claudia R
authors.initials: CR
authors.lastname: De Andrade
authors.forename: Marcel
authors.initials: M
authors.lastname: Lieberman
authors.forename: Francisco R
authors.initials: FR
authors.lastname: Laurindo
authors.forename: Heraldo P
authors.initials: HP
authors.lastname: De Souza
authors.forename: Ana M
authors.initials: AM
authors.lastname: de Oliveira
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D010837:Vitamin K 1 / Q000494:pharmacology*; D014815:Vitamins / Q000494:pharmacology*
chemical_list: D014815:Vitamins; D010837:Vitamin K 1