Depending on its duration, temporary
myocardial ischemia leads to a disturbance of myocardial function before irreversible cellular
necrosis is developed. Mechanical, electrical, and metabolic disturbances were suggested to be possible mechanisms accounting for the altered mechanical performance in ischemic hearts. To further investigate the alteration of myocardial energy metabolism on the subcellular level, we determined, by means of nonaqueous fractionation, the cytosolic-mitochondrial distribution of high-energy
phosphates and other metabolites (
ATP,
ADP,
phosphocreatine,
creatine, and
inorganic phosphate) in ischemic (zero-flow) guinea pig hearts after isolated perfused working heart preparation. Additional experiments using 31P nuclear magnetic resonance spectroscopy were performed to determine pHi and [Mg2+]i changes during global
ischemia. The total
ATP content of myocardial tissue dropped only slowly to 76% of control
ATP at 10 minutes and to 51% at 30 minutes and reached almost zero at 60 minutes of
ischemia. However, striking differences were observed on the subcellular level: While cytosolic
phosphocreatine was almost completely consumed after 3 minutes of
ischemia (from 19.1 +/- 1.6 to 3.3 +/- 0.5 mmol/L),
ATP concentration in the cytosol decreased within 30 minutes from 8.4 +/- 0.6 to only 5.4 +/- 0.9 mmol/L. Mitochondrial
ATP was rapidly and linearly reduced to 60% after 5 minutes of
ischemia and was nearly unmeasurable after a further 20 minutes. Thus, in contrast to the breakdown of
phosphocreatine in cytosol, the only slight alteration of cytosolic
ATP reveals a reduction in cytosolic
ATP utilization. Moreover, the unaffected cytosolic-mitochondrial difference in the phosphorylation potential of
ATP demonstrates the intact function of the
ADP/ATP carrier during early
ischemia. These results might indicate a disturbance of the functional coupling between carrier and
phosphocreatine kinase (
phosphocreatine shuttle), which could be of importance for the early contractile failure in
myocardial ischemia.