Postischemic administration of succinate reverses the impairment of oxidative phosphorylation after cardiac ischemia and reperfusion injury

Charles B. Cairns, Anthony Ferroggiaro, James M. Walther, Alden H. Harken, Anirban Banerjee

Research output: Contribution to journalArticle

27 Citations (Scopus)

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. Methods and Results: Isolated rat hearts were subjected to global ischemia (25 minutes; 37°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 μmol/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; P2 pathway remained intact (2.6±0.3 versus 2.4±0.4). Postischemic succinate administration enhanced LVDP recovery after IR (89±8% of baseline; P3 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.

Original languageEnglish (US)
JournalCirculation
Volume96
Issue number9 SUPPL.
StatePublished - Nov 4 1997
Externally publishedYes

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Oxidative Phosphorylation
Succinic Acid
Reperfusion Injury
Reperfusion
Ischemia
Ventricular Pressure
Electron Transport Complex IV
NAD
Oxidation-Reduction
Near-Infrared Spectroscopy
NADP
Oxygen Consumption
Adenosine Diphosphate
Adenosine Triphosphatases
Adenosine Triphosphate
Control Groups

Keywords

  • Ischemia
  • Metabolism
  • Myocardial contraction
  • Oxygen
  • Succinate

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Postischemic administration of succinate reverses the impairment of oxidative phosphorylation after cardiac ischemia and reperfusion injury. / Cairns, Charles B.; Ferroggiaro, Anthony; Walther, James M.; Harken, Alden H.; Banerjee, Anirban.

In: Circulation, Vol. 96, No. 9 SUPPL., 04.11.1997.

Research output: Contribution to journalArticle

Cairns, Charles B. ; Ferroggiaro, Anthony ; Walther, James M. ; Harken, Alden H. ; Banerjee, Anirban. / Postischemic administration of succinate reverses the impairment of oxidative phosphorylation after cardiac ischemia and reperfusion injury. In: Circulation. 1997 ; Vol. 96, No. 9 SUPPL.
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AU - Banerjee, Anirban

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N2 - 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. Methods and Results: Isolated rat hearts were subjected to global ischemia (25 minutes; 37°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 μmol/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; P2 pathway remained intact (2.6±0.3 versus 2.4±0.4). Postischemic succinate administration enhanced LVDP recovery after IR (89±8% of baseline; P3 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.

AB - 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. Methods and Results: Isolated rat hearts were subjected to global ischemia (25 minutes; 37°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 μmol/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; P2 pathway remained intact (2.6±0.3 versus 2.4±0.4). Postischemic succinate administration enhanced LVDP recovery after IR (89±8% of baseline; P3 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.

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