POSTISCHEMIC ADMINISTRATION OF SUCCINATE REVERSES THE IMPAIRMENT OF OXIDATIVE-PHOSPHORYLATION AFTER CARDIAC ISCHEMIA AND REPERFUSION INJURY

Background Ischemia and reperfusion (IR) can lead to impaired myocardi al 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 substrat e repletion would restore mitochondrial metabolic function during repe rfusion. Methods and Results Isolated rat hearts were subjected to glo bal ischemia (25 minutes; 37 degrees C) and reperfusion (40 minutes). Left ventricular developed pressure (LVDP) and the cytochrome a,a(3) r edox state (near infrared spectroscopy) were continuously monitored. O xygen consumption was measured for the NADH (mitochondrial complex I) and FADH(2) (complex II) pathways in both the resting and maximal ADP- stimulated slates. Myocellular oxidative phosphorylation capacity was measured using an NADPH-linked assay specific for mitochondrial ATPase . The hearts were randomized to either succinate (200 mu mol/L) or con trol 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 oxidativ e phosphorylation capacity for the succinate-using FADH(2) pathway rem ained intact (2.6+/-0.3 versus 2.4+/-0.4). Postischemic succinate admi nistration enhanced LVDP recovery after IR (89+/-8% of baseline; P<.05 ). Diminished electron transport resulted in depletion of electrons fr om cytochrome a,a(3) during ischemia and early reperfusion, which was reversed by providing succinate as substrate. Conclusions Cardiac isch emia and reperfusion results in a defect at mitochondrial complex I bu t not complex II. Cytochrome chrome a,a(3) undergoes anomalous oxidati on during ischemia. Postischemic administration of succinate infusion restores the cytochrome a,a(3) redox state balance and myocardial func tion after IR.