Protective effect of melatonin against homocysteine-induced vasoconstriction of human umbilical artery.
Hyperhomocysteinemia is a major and independent risk factor for vascular disease. Oxidative stress is a possible mechanism for homocysteine (Hcy)-induced endothelial dysfunction. Herein, we evaluated the antioxidant property of melatonin (MLT) in relation to the vasoconstrictive effect of Hcy on the human umbilical artery. In an initial experiment in a cell-free system, a micromolar concentration of iron was found to catalyze oxygen-dependent oxidation of Hcy. MLT (10 or 100 microM) did not affect oxygen-dependent oxidation of Hcy. Next, smooth muscle contraction induced by prostaglandin F(2alpha) (10 microM) was measured in arterial strips. Hcy (10 to 500 microM) increased this vascular tension in a concentration-dependent manner (P < 0.0001). Addition of Fe(2+) (10 microM) significantly potentiated the Hcy effect. Removal of endothelium (P < 0.05), pretreatment with a nitric oxide (NO) synthesis inhibitor (l-N(G)-monomethylarginine, 200 microM, P < 0.001), or pretreatment with a hydroxyl radical ((*)OH) scavenger (mannitol, 10 mM, P < 0.001) significantly attenuated contraction potentiated by Hcy plus Fe(2+). At a much lower concentration than mannitol, MLT (1 to 100 microM) significantly reduced the contractile effect of Hcy and Fe(2+) in a concentration-dependent manner. Hcy plus Fe(2+) significantly impaired calcium ionophore A 23187-induced relaxation (P < 0.0001), while MLT restored this relaxation in a concentration-dependent manner. These findings suggest that Hcy potentiates vascular tension in human umbilical artery, possibly by suppressing bioavailable NO. MLT protects against the vasoconstrictive effect of Hcy, most likely by scavenging (*)OH arising from Hcy autooxidation.
Okatani
Y
Y
Department of Obstetrics and Gynecology, Kochi Medical School, Japan. okataniy@med.kochi-ms.ac.jp
Wakatsuki
A
A
Reiter
R J
RJ
D000704:Analysis of Variance; D000975:Antioxidants / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D002474:Cell-Free System; D015237:Dinoprost / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006710:Homocysteine / Q000378:metabolism*; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D007501:Iron / Q000494:pharmacology; D008550:Melatonin / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D013997:Time Factors; D014469:Umbilical Arteries / Q000187:drug effects* / Q000378:metabolism; D014661:Vasoconstriction; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000975:Antioxidants; D004791:Enzyme Inhibitors; D007476:Ionophores; D006710:Homocysteine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D000001:Calcimycin; D015237:Dinoprost; D007501:Iron; D008550:Melatonin; D010100:Oxygen