title: A novel antioxidant, EPC-K1, stimulates endothelial nitric oxide production and scavenges hydroxyl radicals.
abstract: EPC-K1, a hydroxyl radical scavenger synthesized by phosphate linkage of vitamin E and vitamin C, prevents myocardial reperfusion injury in vivo; however, the direct effects of EPC-K1 on coronary arteries are unknown. These experiments were undertaken to define possible mechanisms through which EPC-K1 imparts its protective action on the coronary vasculature. EPC-K1 (10(-5) to 10(-1) mg/ml) induced concentration-dependent relaxation in contracted canine coronary artery segments with endothelium, but no change in tension of arterial segments without endothelium (p<0.05, ANOVA). Endothelium-dependent relaxation to EPC-K1 was inhibited by N(G)-monomethyl-(L)-arginine ((L)-NMMA) (10(-5) mol/L). Inhibition of relaxation by (L)-NMMA was reversed by the addition of (L)-arginine (10(-4) mol/L), but not by (D)-arginine (10 (-4) mol/L). Subsequent exposure of canine coronary artery segments with intact endothelium to hydroxyl radicals for 30 min (generated by FeSO(4) [0.56 mmol/L] + H(2)O(2) [0.56 mmol/L]) impaired endothelium-dependent relaxation. However, pretreating the vascular segments with EPC-K1 (10(-4) mg/ml) prevented hydroxyl radical-mediated endothelial cell injury and maintained endothelium-dependent relaxation. These experiments indicate that EPC-K1 stimulates the release of endothelium-derived nitric oxide, an endogenous vasodilator and inhibitor of platelet and leukocyte activation and adhesion, from the coronary artery endothelium. Additionally, EPC-K1 scavenges hydroxyl radicals that mediate endothelial cell injury. These 2 independent and important actions are possible mechanisms by which EPC-K1 prevents reperfusion injury in the ischemic heart.
authors.affiliation: Department of Cardiothoracic Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Takayama
authors.forename: Chad E
authors.initials: CE
authors.lastname: Hamner
authors.forename: James A
authors.initials: JA
authors.lastname: Caccitolo
authors.forename: Kunikazu
authors.initials: K
authors.lastname: Hisamochi
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Pearson
authors.forename: Hartzell V
authors.initials: HV
authors.lastname: Schaff
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001120:Arginine / Q000494:pharmacology; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D015237:Dinoprost / Q000494:pharmacology; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology*; D017665:Hydroxyl Radical / Q000378:metabolism*; D008297:Male; D023421:Models, Animal; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D014664:Vasodilation / Q000187:drug effects; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D016166:Free Radical Scavengers; D014810:Vitamin E; D019323:omega-N-Methylarginine; D017665:Hydroxyl Radical; C066638:potassium ascorbyl tocopheryl phosphate; D001120:Arginine; D015237:Dinoprost; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D001205:Ascorbic Acid