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The Positive Inotropic Effect of Pyruvate Involves an Increase in Myofilament Calcium Sensitivity

Pyruvate is a metabolic fuel that is a potent inotropic agent. Despite its unique inotropic and antioxidant properties, the molecular mechanism of its inotropic mechanism is still largely unknown. To examine the inotropic effect of pyruvate in parallel with intracellular calcium handling under near...

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Autores principales: Torres, Carlos A. A., Varian, Kenneth D., Canan, Cynthia H., Davis, Jonathan P., Janssen, Paul M. L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655183/
https://www.ncbi.nlm.nih.gov/pubmed/23691074
http://dx.doi.org/10.1371/journal.pone.0063608
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author Torres, Carlos A. A.
Varian, Kenneth D.
Canan, Cynthia H.
Davis, Jonathan P.
Janssen, Paul M. L.
author_facet Torres, Carlos A. A.
Varian, Kenneth D.
Canan, Cynthia H.
Davis, Jonathan P.
Janssen, Paul M. L.
author_sort Torres, Carlos A. A.
collection PubMed
description Pyruvate is a metabolic fuel that is a potent inotropic agent. Despite its unique inotropic and antioxidant properties, the molecular mechanism of its inotropic mechanism is still largely unknown. To examine the inotropic effect of pyruvate in parallel with intracellular calcium handling under near physiological conditions, we measured pH, myofilament calcium sensitivity, developed force, and calcium transients in ultra thin rabbit heart trabeculae at 37 °C loaded iontophoretically with the calcium indicator bis-fura-2. By contrasting conditions of control versus sarcoplasmic reticulum block (with either cyclopiazonic acid and ryanodine or with thapsigargin) we were able to characterize and isolate the effects of pyruvate on sarcoplasmic reticulum calcium handling and developed force. A potassium contracture technique was subsequently utilized to assess the force-calcium relationship and thus the myofilament calcium sensitivity. Pyruvate consistently increased developed force whether or not the sarcoplasmic reticulum was blocked (16.8±3.5 to 24.5±5.1 vs. 6.9±2.6 to 12.5±4.4 mN/mm(2), non-blocked vs. blocked sarcoplasmic reticulum respectively, p<0.001, n = 9). Furthermore, the sensitizing effect of pyruvate on the myofilaments was demonstrated by potassium contractures (EC50 at baseline versus 20 minutes of pyruvate infusion (peak force development) was 701±94 vs. 445±65 nM, p<0.01, n = 6). This study is the first to demonstrate that a leftward shift in myofilament calcium sensitivity is an important mediator of the inotropic effect of pyruvate. This finding can have important implications for future development of therapeutic strategies in the management of heart failure.
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spelling pubmed-36551832013-05-20 The Positive Inotropic Effect of Pyruvate Involves an Increase in Myofilament Calcium Sensitivity Torres, Carlos A. A. Varian, Kenneth D. Canan, Cynthia H. Davis, Jonathan P. Janssen, Paul M. L. PLoS One Research Article Pyruvate is a metabolic fuel that is a potent inotropic agent. Despite its unique inotropic and antioxidant properties, the molecular mechanism of its inotropic mechanism is still largely unknown. To examine the inotropic effect of pyruvate in parallel with intracellular calcium handling under near physiological conditions, we measured pH, myofilament calcium sensitivity, developed force, and calcium transients in ultra thin rabbit heart trabeculae at 37 °C loaded iontophoretically with the calcium indicator bis-fura-2. By contrasting conditions of control versus sarcoplasmic reticulum block (with either cyclopiazonic acid and ryanodine or with thapsigargin) we were able to characterize and isolate the effects of pyruvate on sarcoplasmic reticulum calcium handling and developed force. A potassium contracture technique was subsequently utilized to assess the force-calcium relationship and thus the myofilament calcium sensitivity. Pyruvate consistently increased developed force whether or not the sarcoplasmic reticulum was blocked (16.8±3.5 to 24.5±5.1 vs. 6.9±2.6 to 12.5±4.4 mN/mm(2), non-blocked vs. blocked sarcoplasmic reticulum respectively, p<0.001, n = 9). Furthermore, the sensitizing effect of pyruvate on the myofilaments was demonstrated by potassium contractures (EC50 at baseline versus 20 minutes of pyruvate infusion (peak force development) was 701±94 vs. 445±65 nM, p<0.01, n = 6). This study is the first to demonstrate that a leftward shift in myofilament calcium sensitivity is an important mediator of the inotropic effect of pyruvate. This finding can have important implications for future development of therapeutic strategies in the management of heart failure. Public Library of Science 2013-05-15 /pmc/articles/PMC3655183/ /pubmed/23691074 http://dx.doi.org/10.1371/journal.pone.0063608 Text en © 2013 Torres et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Torres, Carlos A. A.
Varian, Kenneth D.
Canan, Cynthia H.
Davis, Jonathan P.
Janssen, Paul M. L.
The Positive Inotropic Effect of Pyruvate Involves an Increase in Myofilament Calcium Sensitivity
title The Positive Inotropic Effect of Pyruvate Involves an Increase in Myofilament Calcium Sensitivity
title_full The Positive Inotropic Effect of Pyruvate Involves an Increase in Myofilament Calcium Sensitivity
title_fullStr The Positive Inotropic Effect of Pyruvate Involves an Increase in Myofilament Calcium Sensitivity
title_full_unstemmed The Positive Inotropic Effect of Pyruvate Involves an Increase in Myofilament Calcium Sensitivity
title_short The Positive Inotropic Effect of Pyruvate Involves an Increase in Myofilament Calcium Sensitivity
title_sort positive inotropic effect of pyruvate involves an increase in myofilament calcium sensitivity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655183/
https://www.ncbi.nlm.nih.gov/pubmed/23691074
http://dx.doi.org/10.1371/journal.pone.0063608
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