Enhancement of mitochondrial oxidative phosphorylation capability by hypoperfusion in isolated perfused rat heart

Abstract

To define alterations in myocardial mitochondrial function due to hypoperfusion, oxidative phosphorylation was simultaneously studied in 17 control (stable perfusion pressure) rat hearts and 17 hypoperfused isolated rat hearts. Hypoperfusion for 30 minutes was achieved by a reduction in coronary perfusion pressure from 77.8 ± 1.2 mm Hg (mean ± SEM) to 20.2 ± 1.8 mm Hg in the experimental group (control perfusion pressure after 30 minutes 75.6 ± 1.2). Hypoperfusion caused a reduction in left ventricular developed pressure to 20.5 ± 1.5 mm Hg (versus control 74.8 ± 3.3, p < 0.0001), a reduction of coronary flow rate to 4.9 ± 0.3 ml/min (versus control 19.4 ± 1.2, p < 0.0001), and a drop in myocardial oxygen consumption to 0.06 ± 0.005 ml O2/min (versus control 0.17 ± 0.01, p < 0.0001). Myocardial lactate production was increased by hypoperfusion (3.0 ± 0.6 μmol/min) compared with controls (0.7 ± 0.5, p < 0.02), but myocardial creatine kinase release was similar in the hypoperfused and control groups. Hypoperfusion was associated with an augmentation of state 3 mitochondrial respiration with glutamate and malate as respiratory substrates (448.8 ± 14.0 ng atoms O/min/mg mitochondrial protein versus controls 290.7 ± 13.4, p < 0.001). When rates were normalized for mitochondrial malate dehydrogenase (MDHm), state 3 respiration was still increased in hypoperfused hearts (24.1 ± 2.1 ng atoms O/min/IU MDHm) compared with controls (15.5 ± 1.6, p < 0.02). The rates of dinitrophenol-uncoupled electron transport were similar to the rates of state 3 respiration in both the hypoperfused and control groups. No alterations in mitochondrial function were found with succinate as substrate. Therefore, moderate levels of hypoperfusion enhanced mitochondrial oxidative phosphorylation when glutamate and malate were the respiratory substrates, consistent with an augmentation of the activity of electron transfer complex I and/or the rates of mitochondrial glutamate/malate uptake. This enhancement may be an adaptive mechanism to maximize ATP synthesis during or following myocardial oxygen supply/demand imbalance.