Role of high-energy phosphate metabolism in hydrogen peroxide-induced cardiac dysfunction

This study was undertaken to clarify the role of high-energy phosphate meta bolism in hydrogen peroxide-induced cardiac dysfunction using phosphorus an d fluorine nuclear magnetic resonance spectroscopy. The exposure of a Lange ndorff-perfused heart to hydrogen peroxide (200-400 mu mol/L, 8 min) provok ed biphasic contractile dysfunction characterized by a transient depression of left ventricular developed pressure during the administration of hydrog en peroxide and a delayed elevation of left ventricular end-diastolic press ure after the washout of hydrogen peroxide. The initial phase of cardiac dy sfunction correlated well with the accumulation of sugar phosphates (r = 0. 89, p < 0.01). Furthermore, we demonstrated that glibenclamide, a potent in hibitor of the ATP-sensitive K+ channel, attenuated the initial depression of developed pressure. On the other hand, the delayed elevation of end-dias tolic pressure correlated well with the total ATP depletion (r = 0.96, p < 0.01). However, ATP loss was supposed to be a mere result from the increase d ATP consumption corresponding to a rise in intracellular free Ca2+ (from the control value of 315 +/- 23 nmol/L to 708 +/- 104 after the administrat ion of hydrogen peroxide, p < 0.01), which also paralleled the elevation of end-diastolic pressure. Thus glycolytic inhibition and intracellular Ca2overload are independently responsible for the biphasic contractile dysfunc tion induced by hydrogen peroxide.