Low doses of superoxide dismutase and a stable prostacyclin analogue protect in myocardial ischemia and reperfusion.
The effects of low dose human superoxide dismutase and low dose taprostene, a stable analogue of prostacyclin, were investigated separately and together in a model of myocardial ischemia (1.5 h) with reperfusion (4.5 h) in open chest, anesthetized cats. Taprostene (60 ng/kg per min), human superoxide dismutase (0.25 mg/kg per h), both agents together, or their vehicle, were infused intravenously in cats starting 0.5 h after occlusion of the left anterior descending coronary artery. Neither low dose taprostene nor low dose human superoxide dismutase exerted any endothelial or myocardial protection in this model. However, the two agents together showed a significant endothelial and myocardial protection in cats with myocardial ischemia and reperfusion. Compared with cats that were untreated or received only taprostene or human superoxide dismutase, cats receiving both agents exhibited a lower plasma creatine kinase activity at every time point observed after reperfusion, a reduced area of cardiac necrosis (7 +/- 2% vs. 21 +/- 5% area at risk, p less than 0.001), lower myeloperoxidase activity in the ischemic region (p less than 0.01) and a significant preservation of vasorelaxant responses of left anterior descending coronary rings to endothelium-dependent vasodilators, acetylcholine (p less than 0.001) and A-23187 (p less than 0.001). Taprostene appears to act additively with human superoxide dismutase to inhibit neutrophil adherence and activation and to inactivate superoxide radicals, and thus reduce cellular injury 4.5 h after reperfusion of the ischemic heart. Use of this agent may allow low doses of superoxide dismutase to be used more effectively in early myocardial ischemia.
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Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylavania 19107-6799.
Johnson
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Lefer
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D000818:Animals; D002317:Cardiovascular Agents / Q000008:administration & dosage*; D002415:Cats; D003327:Coronary Disease / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D011464:Epoprostenol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D011465:Prostaglandins, Synthetic / Q000008:administration & dosage*; D013482:Superoxide Dismutase / Q000008:administration & dosage*
D002317:Cardiovascular Agents; D011465:Prostaglandins, Synthetic; C039188:taprostene; D011464:Epoprostenol; D013482:Superoxide Dismutase