Time course and mechanism of endothelial dysfunction in isolated ischemic- and hypoxic-perfused rat hearts.
Isolated perfused rat hearts were subjected to global ischemia for 30 min followed by reperfusion for 2.5, 5, 10, or 20 min and then were tested for responsiveness to the endothelium-dependent vasodilator acetylcholine (ACh) and the endothelium-independent vasodilator nitroglycerin (NTG). ACh relaxation was impaired 2.5 min after reperfusion (32 +/- 3% of initial control, P less than 0.01) and remained comparably depressed at every time thereafter. No significant decrease in vasodilator response to NTG occurred at any time. Endothelial dysfunction was prevented by recombinant human superoxide dismutase (hSOD, 5 mg/heart) but not by the hydroxyl radical scavenger N-(2-mercaptopropionyl)-glycine (8 mg/heart). Comparable effects and a similar time course were observed in hypoxic hearts reoxygenated for periods up to 20 min. Chemiluminescence of perfusion effluent employed as an index of free radical production was measured at all postreperfusion times in ischemic hearts. Ischemia alone produced small increases in chemiluminescence. Reperfusion, however, produced significantly higher increases in chemiluminescence, with a large burst of activity at 0.25 min, which was blocked by hSOD. These findings suggest that endothelial dysfunction resulting in decreased release of endothelium-derived relaxing factor occurs very early after reperfusion or reoxygenation and may be due to the action of superoxide free radicals.
Tsao
P S
PS
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Lefer
A M
AM
D000818:Animals; D003327:Coronary Disease / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D015425:Myocardial Reperfusion; D010100:Oxygen / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D013482:Superoxide Dismutase / Q000494:pharmacology; D013997:Time Factors; D008625:Tiopronin / Q000494:pharmacology
D008625:Tiopronin; D013482:Superoxide Dismutase; D010100:Oxygen