MECHANISM OF THE EFFECT OF EXOGENOUS FRUCTOSE-1,6-BISPHOSPHATE ON MYOCARDIAL ENERGY-METABOLISM

The effects of fructose 1,6-bisphosphate (F-1,6-P2) on the isolated Langendorff-perfused heart were studied by monitoring flavoprotein fluorescence, oxygen consumption (MVo2), coronary flow (F(c)), systolic intraventricular pressure (P(sys)), diastolic intraventricular pressure, and contraction frequency. The cellular energy state and cytosolic pH were determined by means of P-31 nuclear magnetic resonance. Infusion of 5 mM F-1,6-P2 caused a rapid shift toward reduction in the flavoprotein redox state and initial 50% and 44% decreases in P(sys) and MVo2, respectively. After a partial recovery, these measures remained in 11% and 25% below the basal value. Concomitantly, after an initial transient increase of 13%, F(c) remained 17% lower than in the basal state. When the F-1,6-P2 concentration was subsequently increased to 10 mM, P(sys) and MVo2 dropped temporarily to 31% and 29% of the basal value and then remained at 50% and 53%, respectively. Simultaneously, a brief increase was observed in F(c), which then fell 34% below the basal value. Rapid reoxidation of the flavoproteins and increases in MVo2, P(sys). and F(c) occurred on discontinuation of the F-1,6-P2 infusion. P-31 nuclear magnetic resonance during infusions of both 5 and 10 mM F-1,6-P2 revealed a decrease in cytosolic inorganic phosphate and a tendency to increase creatine phosphate, suggesting elevation in the cellular energy state. No changes in intracellular pH occurred as estimated from the chemical shift of the nuclear magnetic resonance of inorganic phosphate. F-1,6-P2 (5 mM and 10 mM) lowered the free Ca2+ concentration in the Krebs-Henseleit bicarbonate buffer (by 32% and 47%, respectively). This probably explains the effects of F-1,6-P2 on mechanical work performance and cellular respiration. A direct metabolic effect also exists, however, because flavoprotein reduction by F-1,6-P2 could be observed in the K+-arrested heart, where its effects on MVo2 were minimal. This redox effect may not be caused by changes in free Ca2+ concentration because it could not be reproduced by infusion of EGTA.