title: Postischemic administration of succinate reverses the impairment of oxidative phosphorylation after cardiac ischemia and reperfusion injury.
abstract: BACKGROUND
  Ischemia and reperfusion (IR) can lead to impaired myocardial mechanical function and inhibition of key metabolic enzyme systems after IR. In this study, we sought to identify the postischemic lesion in oxidative phosphorylation and hypothesized that selective substrate repletion would restore mitochondrial metabolic function during reperfusion.
  
  
  RESULTS
  Isolated rat hearts were subjected to global ischemia (25 minutes; 37 degrees C) and reperfusion (40 minutes). Left ventricular developed pressure (LVDP) and the cytochrome a,a3 redox state (near infrared spectroscopy) were continuously monitored. Oxygen consumption was measured for the NADH (mitochondrial complex I) and FADH2 (complex II) pathways in both the resting and maximal ADP-stimulated states. Myocellular oxidative phosphorylation capacity was measured using an NADPH-linked assay specific for mitochondrial ATPase. The hearts were randomized to either succinate (200 micromol/L) or control for the first 5 minutes of reperfusion after ischemia. IR in the control group resulted in an impairment of NADH (complex I) oxidative phosphorylation capacity (1.4+/-0.4 versus control 3.9+/-0.6 nmol ATP/min/mg) and depressed LVDP (49+/-3% of baseline; P<.05). The oxidative phosphorylation capacity for the succinate-using FADH2 pathway remained intact (2.6+/-0.3 versus 2.4+/-0.4). Postischemic succinate administration enhanced LVDP recovery after IR (89+/-8% of baseline; P<.05). Diminished electron transport resulted in depletion of electrons from cytochrome a,a3 during ischemia and early reperfusion, which was reversed by providing succinate as substrate.
  
  
  CONCLUSIONS
  Cardiac ischemia and reperfusion results in a defect at mitochondrial complex I but not complex II. Cytochrome a,a3 undergoes anomalous oxidation during ischemia. Postischemic administration of succinate infusion restores the cytochrome a,a3 redox state balance and myocardial function after IR.
authors.affiliation: Colorado Emergency Medicine Research Center, Department of Surgery, University of Colorado Health Sciences Center, Denver 80262, USA. Charles.Cairns@UCHSC.edu
authors.forename: C B
authors.initials: CB
authors.lastname: Cairns
authors.forename: A A
authors.initials: AA
authors.lastname: Ferroggiaro
authors.forename: J M
authors.initials: JM
authors.lastname: Walther
authors.forename: A H
authors.initials: AH
authors.lastname: Harken
authors.forename: A
authors.initials: A
authors.lastname: Banerjee
mesh_terms: D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D017202:Myocardial Ischemia / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D051381:Rats; D017207:Rats, Sprague-Dawley; D019802:Succinic Acid / Q000494:pharmacology*
chemical_list: D000255:Adenosine Triphosphate; D019802:Succinic Acid