title: Protection by Cyclosporin A of ischemia/reperfusion-induced damage in isolated rat hearts.
abstract: Reperfusion following a period of ischemia can salvage the myocardium only if the ischemic episode has not exceeded a certain time limit; beyond this point damage becomes irreversible. A key feature of the transition from reversible to irreversible injury is mitochondrial dysfunction which may involve the opening of a non-specific pore in the mitochondrial inner membrane. Pore opening can be induced in vitro by exposure of isolated mitochondria to high [Ca2+] and Pi. Such pore formation is sensitized by adenine nucleotide depletion and oxidative stress and can be blocked by the immunosuppressant cyclosporin A. Here we show that in isolated perfused rat hearts subjected to 30 min ischemia and 15 min reperfusion, 0.2 microM cyclosporin A restored the ATP/ADP ratio and AMP content (decreased and increased respectively during ischemia) to pre-ischemic values. In separate experiments functional recovery was assessed by monitoring the restoration of left ventricular developed pressure (LVP) during reperfusion after 30, 40 or 45 min ischemia. LVP was substantially improved in the presence of 0.2 microM cyclosporin A but did not return to pre-ischemic levels. The cyclosporin analogues G and H were less effective than cyclosporin A in protecting the heart during reperfusion. This is consistent with their reduced ability to protect isolated mitochondria from damage caused by Ca2+ overload. Surprisingly, reperfusion of hearts with 1 microM cyclosporin A reversed the protective effect seen at 0.2 microM.
authors.affiliation: Department of Biochemistry, School of Medical Sciences, University of Bristol, UK.
authors.forename: E J
authors.initials: EJ
authors.lastname: Griffiths
authors.forename: A P
authors.initials: AP
authors.lastname: Halestrap
mesh_terms: D000227:Adenine Nucleotides / Q000378:metabolism; D000591:Amino Acid Isomerases / Q000037:antagonists & inhibitors*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D016572:Cyclosporine / Q000494:pharmacology* / Q000627:therapeutic use; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects*; D007425:Intracellular Membranes / Q000187:drug effects / Q000648:ultrastructure; D008929:Mitochondria, Heart / Q000187:drug effects; D017202:Myocardial Ischemia / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D019696:Peptidylprolyl Isomerase; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D000227:Adenine Nucleotides; D002352:Carrier Proteins; D016572:Cyclosporine; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase; D002118:Calcium; D016559:Tacrolimus