INTERMITTENT ISCHEMIA PRODUCES A CUMULATIVE DEPLETION OF MITOCHONDRIAL ADENINE-NUCLEOTIDES IN THE ISOLATED PERFUSED RAT-HEART

The purpose of the present study was to determine if repetitive myocardial ischemia would result in the cumulative loss of mitochondrial adenine nucleotides. Isolated perfused rat hearts were subjected to continuous or intermittent ischemia. A single 5-minute period of continuous ischemia did not result in a significant decrease in the mitochondrial adenine nucleotide pool; A single 10-minute period of ischemia resulted in a decrease of approximately 17%. Next, the adenine nucleotide content of mitochondria from preischemic and 30-minute continuous ischemic hearts was compared with two groups of hearts undergoing intermittent ischemia (both groups receiving a total of 30 minutes of ischemia). One groups received three 10-minute episodes of ischemia interrupted by 5-minute periods of reperfusion (3 x 10-minute intermittent ischemia); the other intermittent ischemic group received six 5-minute episodes of ischemia interrupted by 5-minute periods of perfusion (6 x 5-minute intermittent ischemia). The mitochondrial adenine nucleotide content (expressed as nanomoles per nanomole cytochrome a) for the preischemic and 30-minute continuous ischemic hearts was 14.7 ± 0.6 and 8.0 ± 0.4, respectively. The mitochondrial adenine nucleotide content of the 3 x 10-minute intermittent ischemia group (8.5 ± 0.5) was not significantly different from the 30-minute continuous ischemic group. The mitochondrial adenine nucleotide content of the 6 x 5-minute intermittent ischemia group (11.0 ± 0.6) was significantly larger than that of the 30-minute continuous and the 3 x 10-minute intermittent ischemia groups (p < 0.05). Postischemic reperfusion for up to 1 hour did not result in levels of mitochondrial adenine nucleotides significantly above those observed at the end of ischemia. Moreover, isolated rat heart mitochondria were unable to accumulate adenine nucleotides when incubated in 2 mM ATP; conversely, the adenine nucleotide content of isolated liver mitochondria increased approximately fivefold within 60 minutes when incubated under the same conditions. The study suggests that short, repetitive episodes of ischemia result in the cumulative loss of mitochondrial adenine nucleotides. The results also indicate that heart mitochondria may not have a mechanism to replenish the lost pool of adenine nucleotides, indicating that short episodes of ischemia interrupted by long periods of perfusion could also result in the cumulative loss of mitochondrial adenine nucleotides.