Recovery of adenine nucleotide levels after global myocardial ischemia in dogs

Loss of myocardial adenosine triphosphate (ATP) during ischemia can result in decreased cardiac function. Postischemic ATP levels remain low, and the reason for this is poorly understood. Previous attempts to enhance ATP recovery after ischemia have been only partially successful. To determine the long-term dynamics of ATP recovery and evaluate the effect of providing ATP precursors, we devised a method of obtaining sequential ventricular biopsies in dogs after 20 minutes of normothermic global ischemia on cardiopulmonary bypass. Our kinetic data show adenine (A) is metabolically favored over adenosine to regenerate ATP levels when adequate ribose (R) is present to produce phosphoribosylpyrophosphate. Therefore A (20 mM) plus R (80 mM) or saline (NS) was infused (1.0 ml·min^-1) into the right atrium of dogs for 48 hours after ischemia. During A infusion myocardial tissue A was 0.19 ± 0.07 nmol·mg^-1, arterial A was 18.3 ± 1.3 μM, coronary sinus A was 11.0 ± 1.6 μM, and extraction of A by the myocardium was 38% ± 10%. We found that while the decrease in ATP levels during ischemia was at least 50% in both groups, the postischemic ATP recovery rate in A/R dogs was more than eightfold greater than de novo synthesis (2.8 ± 0.59 versus 0.34 ± 0.06 nmoles·mg^-1·day). ATP levels in NS dogs were only 54% ± 8% of preischemic values by 48 hours and required 9.9 ± 1.4 days for full recovery. Recovery in A/R dogs required 1.2 ± 0.2 days. Our results reveal that ATP recovery after a significant ischemic insult is slow, precursor availability is an important limiting factor in ATP recovery, and recovery time can be greatly shortened with precursor infusion even when started after the ischemic insult.