Several studies have shown that maintenance of glycolysis limits the metabolic and functional consequences of low-flow
ischemia. Because diabetic animals are known to have impaired glycolytic metabolism coupled with increased flux through the
aldose reductase (AR) pathway, we hypothesized that inhibition of AR would enhance glycolysis and thereby improve metabolic and functional recovery during low-flow
ischemia. Hearts (n = 12) from nondiabetic control and diabetic rats were isolated and retrograde perfused using 11 mM
glucose with or without the AR inhibitor
zopolrestat (1 microM). Hearts were subjected to 30 min of low-flow
ischemia (10% of baseline flow) and 30 min of reperfusion. 31P NMR spectroscopy was used to monitor time-dependent changes in
phosphocreatine (PCr),
ATP, and intracellular pH. Changes in the cytosolic redox ratio of
NADH to NAD+ were obtained by measuring the ratio of tissue
lactate to
pyruvate. Effluent
lactate concentrations and oxygen consumption were determined from the perfusate. AR inhibition improved functional recovery in both control and diabetic hearts, coupled with a lower cytosolic redox state and greater effluent
lactate concentrations during
ischemia.
ATP levels during
ischemia were significantly higher in AR-inhibited hearts, as was recovery of PCr. In diabetic hearts, AR inhibition also limited
acidosis during
ischemia and normalized pH recovery on reperfusion. These data demonstrate that AR inhibition maintains higher levels of high-energy
phosphates and improves functional recovery upon reperfusion in hearts subjected to low-flow
ischemia, consistent with an increase in glycolysis. Accordingly, this approach of inhibiting AR offers a novel method for protecting ischemic myocardium.