A Novel Antioxidant, EPC-K1, Stimulates Endothelial Nitric Oxide Production and Scavenges Hydroxyl Radicals

Hiroo Takayama, Chad E. Hamner, James A. Caccitolo, Kunikazu Hisamochi, Paul J. Pearson, Hartzell V. Schaff

Research output: Contribution to journalArticle

11 Scopus citations

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 NG-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 FeSO4 [0.56 mmol/L]+ H 2O2 [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.

Original languageEnglish (US)
Pages (from-to)1046-1052
Number of pages7
JournalCirculation Journal
Volume67
Issue number12
DOIs
StatePublished - Dec 1 2003

Keywords

  • Endothelium
  • Free radicals
  • Ischemia
  • Nitric oxide
  • Reperfusion

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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