Oxygen free radical-mediated selective endothelial dysfunction in isolated coronary artery.
To understand the direct involvement of free radicals causing reduction in endothelium-dependent relaxation of isolated canine coronary ring preparations, this study was undertaken to examine the effect of free radicals generated from dihydroxy fumarate (DHF) plus Fe(3+)-ADP or from H2O2 plus FeSO4. The vasodilators (acetylcholine, bradykinin, A23187, and nitroglycerin) were given after DHF/Fe(3+)-ADP or H2O2/FeSO4 was removed from the organ chamber. The earlier DHF/Fe(3+)-ADP exposure produced an attenuation of the relaxation of the rings induced by acetylcholine, bradykinin, or A23187 but not of the relaxation induced by nitroglycerin. The observed effect of previous DHF/Fe(3+)-ADP exposure was significantly protected in the vessels isolated from the dogs treated with alpha-tocopherol. In the experiments for assessing the effect of various scavengers, 1O2 scavenger histidine or iron chelator deferoxamine effectively protected the attenuation induced by DHF/Fe(3+)-ADP exposure of the relaxation elicited by acetylcholine; superoxide dismutase (SOD), catalase, or dimethyl sulfoxide (DMSO) had no effect on this system. Furthermore, the relaxation elicited by acetylcholine, but not nitroglycerin, was significantly attenuated by the earlier exposure to .OH generated by Fenton's reagent (H2O2+FeSO4); the attenuation was significantly protected by DMSO. These results are consistent with the view that .OH, 1O2, and/or iron-dependent reactive species selectively damage endothelium-dependent relaxation as opposed to endothelium-independent relaxation in endothelium-intact coronary ring preparations. It is also postulated that lipid peroxidation may be responsible for this effect.
Todoki
K
K
Department of Pharmacology, Kanagawa Dental College, Japan.
Okabe
E
E
Kiyose
T
T
Sekishita
T
T
Ito
H
H
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D003497:Cyclic N-Oxides; D004285:Dogs; D004578:Electron Spin Resonance Spectroscopy; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D005609:Free Radicals; D005650:Fumarates / Q000494:pharmacology; D066298:In Vitro Techniques; D007501:Iron / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D005996:Nitroglycerin / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism*; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D003497:Cyclic N-Oxides; D005609:Free Radicals; D005650:Fumarates; D013113:Spin Labels; D014665:Vasodilator Agents; D013481:Superoxides; C005998:dihydroxyfumarate; D000001:Calcimycin; C017245:5,5-dimethyl-1-pyrroline-1-oxide; D007501:Iron; D005996:Nitroglycerin; D000109:Acetylcholine; D010100:Oxygen; D001920:Bradykinin