Iron chelation in myocardial preservation after ischemia-reperfusion injury: the importance of pretreatment and toxicity.
Oxygen-derived free radicals have been implicated in myocardial ischemia-reperfusion injury. It has been proposed that deferoxamine, an iron chelator, improves myocardial preservation by reducing the iron-catalyzed production of the hydroxyl radical. The objectives of this study were to define the appropriate timing of iron chelation therapy and the dose-response properties of deferoxamine. Isolated working rat hearts were subjected to 25 minutes of normothermic global ischemia. Deferoxamine was given as pretreatment (n = 39; doses of 10 or 30 mg/kg), added to cardioplegic solution (n = 43; doses 0.46 to 1.90 mmol/L), or administered upon reperfusion (n = 52; doses 0.15 to 0.76 mmol/L) and compared with saline controls (n = 25). Deferoxamine pretreatment improved survival at each dose from a control value of 44% to 71% and 72% (p less than 0.05), respectively. A cardioplegia dose of 0.46 mmol/L improved survival from 48% to 75%. Higher doses reduced survival and implied a toxic effect. Reperfusion therapy did not alter survival. Regardless of time of administration, deferoxamine did not improve ventricular function or adenosine triphosphate levels. Deferoxamine given as pretreatment 1 hour before ischemia at doses of 30 mg/kg, and perhaps as low as 10 mg/kg, significantly improved survival. The addition of deferoxamine to cardioplegic solution was safe and may be protective at approximately 0.50 mmol/L; however, toxicity should be considered at concentrations greater than 0.76 mmol/L. These data support the postulate that iron catalysis is involved in the production of oxygen-derived free radicals during ischemia-reperfusion injury. We conclude that pretreatment before ischemia is an important component of iron chelation therapy in myocardial preservation.
DeBoer
D A
DA
Surgery Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
Clark
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RE
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015913:Chelation Therapy; D003676:Deferoxamine / Q000008:administration & dosage* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000503:physiopathology*; D006439:Hemodynamics; D007501:Iron; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D051381:Rats; D011919:Rats, Inbred Strains
D000255:Adenosine Triphosphate; D007501:Iron; D003676:Deferoxamine