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Pyruvate Modulates Cardiac Sarcoplasmic Reticulum Ca 2+ Release in Rats Via Mitochondria‐Dependent and ‐Independent Mechanisms
Author(s) -
Zima Aleksey V.,
Kockskämper Jens,
MejiaAlvarez Rafael,
Blatter Lothar A.
Publication year - 2003
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2003.040345
Subject(s) - ryanodine receptor , chemistry , pyruvate decarboxylation , biophysics , ruthenium red , mitochondrion , pyruvate dehydrogenase complex , myocyte , endoplasmic reticulum , pyruvate dehydrogenase kinase , uniporter , cytosol , biochemistry , calcium , endocrinology , citric acid cycle , biology , metabolism , enzyme , organic chemistry
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 Ca 2+ 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 m m ) elevated diastolic [Ca 2+ ] 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 [Ca 2+ ] i transient, and augmented sarcoplasmic reticulum (SR) Ca 2+ 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 (α‐cyano‐4‐hydroxycinnamate, 0.5 m m ), adenine nucleotide translocation (atractyloside, 0.3 m m ) and the electron transport chain (cyanide, 4 m m ) abolished or attenuated the pyruvate‐mediated increase of the amplitude of the [Ca 2+ ] i transient, but did not change the effect of pyruvate on diastolic [Ca 2+ ] i . Results from experiments with permeabilized myocytes indicated a direct correlation between ATP/ADP ratio and SR Ca 2+ content. Furthermore, pyruvate (4 m m ) reduced the frequency of spontaneous Ca 2+ sparks by ≈50 %. Single RyR channel recordings revealed a ≈60 % reduction of the open probability of the channel by pyruvate (1 m m ), but no change in conductance. This effect of pyruvate on RyR channel activity was neither Ca 2+ nor ATP dependent. Taken together, these findings suggest that, in cardiac tissue, pyruvate has a dual effect on SR Ca 2+ release consisting of a direct inhibition of RyR channel activity and elevation of SR Ca 2+ content. The latter effect was most probably mediated by an enhanced SR Ca 2+ uptake due to an augmentation of mitochondria‐dependent ATP synthesis.