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Pyruvate modulates cardiac sarcoplasmic reticulum Ca²⁺ release in rats via mitochondria-dependent and -independent mechanisms

Aleksey V. Zima, Jens Kockskämper, Rafael Mejia-Alvarez and Lothar A. Blatter

The glycolytic product pyruvate has beneficial effects on cardiac contractile function. The postulated cellular mechanisms underlying the positive inotropic effect of pyruvate, however, are contradictory or have remained elusive. Therefore, we studied the effects of pyruvate on cardiac Ca²⁺ regulation, intracellular pH (pH_i) and flavoprotein oxidation using fluorescence confocal microscopy in intact and permeabilized rat ventricular myocytes and single channel recordings from rat cardiac ryanodine receptors (RyRs) incorporated into planar lipid bilayers. In intact cells extracellular pyruvate (10 mM) elevated diastolic [Ca²⁺]_i, which was due, at least in part, to a concomitant acidification of the cytosol. Furthermore, pyruvate increased the amplitude and slowed the kinetics of the electrically evoked [Ca²⁺]_i transient, and augmented sarcoplasmic reticulum (SR) Ca²⁺ content. Recording of flavoprotein (FAD) fluorescence indicated that pyruvate caused a reduction of mitochondrial redox potential, which is proportional to an increase of the rate of ATP synthesis. Inhibitors of mitochondrial monocarboxylate transport (-cyano-4-hydroxycinnamate, 0.5 mM), adenine nucleotide translocation (atractyloside, 0.3 mM) and the electron transport chain (cyanide, 4 mM) abolished or attenuated the pyruvate-mediated increase of the amplitude of the [Ca²⁺]_i transient, but did not change the effect of pyruvate on diastolic [Ca²⁺]_i. Results from experiments with permeabilized myocytes indicated a direct correlation between ATP/ADP ratio and SR Ca²⁺ content. Furthermore, pyruvate (4 mM) reduced the frequency of spontaneous Ca²⁺ sparks by ~50 %. Single RyR channel recordings revealed a ~60 % reduction of the open probability of the channel by pyruvate (1 mM), but no change in conductance. This effect of pyruvate on RyR channel activity was neither Ca²⁺ nor ATP dependent. Taken together, these findings suggest that, in cardiac tissue, pyruvate has a dual effect on SR Ca²⁺ release consisting of a direct inhibition of RyR channel activity and elevation of SR Ca²⁺ content. The latter effect was most probably mediated by an enhanced SR Ca²⁺ uptake due to an augmentation of mitochondria-dependent ATP synthesis.

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