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: Hiroo Takayama, Chad E Hamner, James A Caccitolo, Kunikazu Hisamochi, Paul J Pearson, Hartzell V Schaff
• Journal: Circulation journal : official journal of the Japanese Circulation Society (Circ J) Vol. 67 Issue 12 Pg. 1046-52 (Dec 2003) ISSN: 1346-9843 [Print] Japan
• PMID: 14639022 (Publication Type: Journal Article)

Chemical References

• Antioxidants
• Free Radical Scavengers
• Vitamin E
• omega-N-Methylarginine
• Hydroxyl Radical
• potassium ascorbyl tocopheryl phosphate
• Arginine
• Dinoprost
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type III
• Ascorbic Acid

Topics

• Animals
• Antioxidants (pharmacology)
• Arginine (pharmacology)
• Ascorbic Acid (analogs & derivatives, pharmacology)
• Coronary Vessels (drug effects, enzymology, physiology)
• Dinoprost (pharmacology)
• Dogs
• Endothelium, Vascular (drug effects, enzymology, physiology)
• Female
• Free Radical Scavengers (pharmacology)
• Hydroxyl Radical (metabolism)
• Male
• Models, Animal
• Nitric Oxide Synthase (metabolism)
• Nitric Oxide Synthase Type III
• Vasodilation (drug effects)
• Vitamin E (analogs & derivatives, pharmacology)
• omega-N-Methylarginine (pharmacology)