title: Studies of hypoxemic/reoxygenation injury: without aortic clamping. IV. Role of the iron-catalyzed pathway: deferoxamine.
abstract: This study tests the hypothesis that an iron chelator, deferoxamine, can reduce oxygen-mediated myocardial injury and avoid myocardial dysfunction after cardiopulmonary bypass by its action on the iron-catalyzed Haber-Weiss pathway. Twenty-one immature 2- to 3-week-old piglets were placed on cardiopulmonary bypass for 120 minutes, and five piglets served as biochemical controls without cardiopulmonary bypass. Five piglets underwent cardiopulmonary bypass without hypoxemia (cardiopulmonary bypass control). Sixteen others became hypoxemic while undergoing cardiopulmonary bypass for 60 minutes by lowering oxygen tension to about 25 mm Hg, followed by reoxygenation at oxygen tension about 400 mm Hg for 60 minutes. Oxygen delivery was maintained during hypoxemia by increasing cardiopulmonary bypass flow and hematocrit level. In seven piglets deferoxamine (50 mg/kg total dose) was given both intravenously just before reoxygenation and by a bolus injection (5 mg/kg) into the cardiopulmonary bypass circuit; nine others were not treated (no therapy). Myocardial function after cardiopulmonary bypass was evaluated form end-systolic elastance (conductance catheter) and Starling curve analysis. Myocardial conjugated diene production and creatine kinase leakage were assessed as biochemical markers of injury, and antioxidant reserve capacity was determined by measuring malondialdehyde in postcardiopulmonary bypass myocardium incubated in the oxidant, t-butylhydroperoxide. Cardiopulmonary bypass without hypoxemia caused no oxidant or functional damage. Conversely, reoxygenation (no therapy) raised myocardial conjugated diene levels and creatine kinase production (conjugated diene: 3.5 +/- 0.7 absorbance 233 nm/min/100 g, creatine kinase: 8.5 +/- 1.5 U/min/100 g; p < 0.05 versus cardiopulmonary bypass control), reduced antioxidant reserve capacity (malondialdehyde: 1115 +/- 60 nmol/g protein at 4 mmol/L t-butylhydroperoxide; p < 0.05 versus control), and produced severe post-bypass dysfunction (end-systolic elastance recovered only 39% +/- 7%, p < 0.05 versus cardiopulmonary bypass control). Deferoxamine avoided conjugated diene production and creatine kinase release and retained normal antioxidant reserve, and functional recovery was complete (95% +/- 11%, p < 0.05 versus no treatment). These findings show that iron-catalyzed oxidants may contribute to a reoxygenation injury and imply that deferoxamine may be used to surgical advantage.
mesh_terms: D000466:Alkadienes / Q000378:metabolism; D000818:Animals; D002315:Cardiopulmonary Bypass / Q000009:adverse effects* / Q000379:methods; D003402:Creatine Kinase / Q000096:biosynthesis; D003676:Deferoxamine / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D000860:Hypoxia / Q000150:complications / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D017262:Siderophores / Q000494:pharmacology*; D013552:Swine
chemical_list: D000466:Alkadienes; D017262:Siderophores; D007501:Iron; D003402:Creatine Kinase; D003676:Deferoxamine