Substrate-dependent proton load and recovery of stunned hearts during pyruvate dehydrogenase stimulation

Stimulation of pyruvate dehydrogenase (PDH) improves functional recovery of postischemic hearts. This study examined the potential for a mechanism med iated by substrate-dependent proton production and intracellular pH. After 20 min of ischemia, isolated rabbit hearts were reperfused with or without 5 mM dichloroacetate (DCA) in the presence of either 5 mM glucose, 5 mM glu cose + 2.5 mM lactate, or 5 mM glucose + 2.5 mM pyruvate. DCA inhibits PDH kinase, increasing the proportion of dephosphorylated, active PDH. Unlike p yruvate or glucose alone, lactate + glucose did not support the effects of DCA on the recovery of rate-pressure product (RPP) (without DCA, RPP = 14,0 00 +/- 1,200, n = 6; with DCA, RPP = 13,700 +/- 1,800, n = 9). Intracellula r pH, from P-31 nuclear magnetic resonance spectra, returned to normal with in 2.1 min of reperfusion with all substrates except for lactate 1 glucose 1 DCA or lactate 1 DCA, which delayed pH recovery for up to 12 min (at 2.1 min pH = 6.00 +/- 0.08, lactate + glucose + DCA; pH = 6.27 +/- 0.34, for la ctate + DCA). Hearts were also reperfused after 10 min of ischemia with 0.5 mM palmitate + 5 mM DCA and either 2.5 mM pyruvate or 2.5 mM lactate. Agai n, intracellular pH recovery was delayed in the presence of lactate. PDH ac tivation in the presence of lactate also decreased coupling of oxidative me tabolism to mechanical work. These findings have implications for therapeut ic use of stimulated carbohydrate oxidation in stunned hearts.