Depletion of
adenosine triphosphate precursors, such as myocardial
adenosine, during global
ischemia results in poor postischemic
adenosine triphosphate repletion and functional recovery. Neonatal hearts may be more resistant to this deleterious effect of
ischemia, because they are characterized by low
5'-nucleotidase activity, which may result in higher sustained endogenous myocardial
adenosine triphosphate precursor levels during
ischemia. Adult hearts, however, have high levels of
5'-nucleotidase activity leading to depleted precursors during
ischemia and poor postischemic functional recovery. Augmenting myocardial
adenosine exogenously during
ischemia in adult hearts has a beneficial effect on recovery. The present study tested if preservation of
nucleotide precursors, better
adenosine triphosphate repletion, and enhanced postischemic myocardial recovery in adult hearts could be achieved with a "neonatal" strategy. Therefore
5'-nucleotidase inhibitors were administered to isolated, perfused adult rabbit hearts subjected to 120 minutes of
ischemia (at 34 degrees C) to determine if this improved functional recovery. Hearts received
St. Thomas' Hospital cardioplegic solution (control hearts) or
cardioplegic solution containing
5'-nucleotidase inhibitors:
pentoxifylline,
thioinosine, [s-(p-nitrophenyl)-4-
thioinosine], or
thioinosine's
dimethyl sulfoxide vehicle alone. After
ischemia and reperfusion, recovery of systolic function, diastolic function, and myocardial oxygen consumption was significantly better with
5'-nucleotidase inhibition. No changes in coronary flow were noted. We speculate and are pursuing the theory that the mechanism of
5'-nucleotidase inhibition's favorable action is due to preventing the catabolism, transport, and loss of
nucleotide precursors during
ischemia, maintaining
adenosine triphosphate precursor availability.