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Transmural Autonomic Regulation of Cardiac Contractility at the Intact Heart Level

The relationship between cardiac excitability and contractility depends on when Ca(2+) influx occurs during the ventricular action potential (AP). In mammals, it is accepted that Ca(2+) influx through the L-type Ca(2+) channels occurs during AP phase 2. However, in murine models, experimental eviden...

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Autores principales: Aguilar-Sanchez, Yuriana, Rodriguez de Yurre, Ainhoa, Argenziano, Mariana, Escobar, Ariel L., Ramos-Franco, Josefina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616252/
https://www.ncbi.nlm.nih.gov/pubmed/31333477
http://dx.doi.org/10.3389/fphys.2019.00773
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author Aguilar-Sanchez, Yuriana
Rodriguez de Yurre, Ainhoa
Argenziano, Mariana
Escobar, Ariel L.
Ramos-Franco, Josefina
author_facet Aguilar-Sanchez, Yuriana
Rodriguez de Yurre, Ainhoa
Argenziano, Mariana
Escobar, Ariel L.
Ramos-Franco, Josefina
author_sort Aguilar-Sanchez, Yuriana
collection PubMed
description The relationship between cardiac excitability and contractility depends on when Ca(2+) influx occurs during the ventricular action potential (AP). In mammals, it is accepted that Ca(2+) influx through the L-type Ca(2+) channels occurs during AP phase 2. However, in murine models, experimental evidence shows Ca(2+) influx takes place during phase 1. Interestingly, Ca(2+) influx that activates contraction is highly regulated by the autonomic nervous system. Indeed, autonomic regulation exerts multiple effects on Ca(2+) handling and cardiac electrophysiology. In this paper, we explore autonomic regulation in endocardial and epicardial layers of intact beating mice hearts to evaluate their role on cardiac excitability and contractility. We hypothesize that in mouse cardiac ventricles the influx of Ca(2+) that triggers excitation–contraction coupling (ECC) does not occur during phase 2. Using pulsed local field fluorescence microscopy and loose patch photolysis, we show sympathetic stimulation by isoproterenol increased the amplitude of Ca(2+) transients in both layers. This increase in contractility was driven by an increase in amplitude and duration of the L-type Ca(2+) current during phase 1. Interestingly, the β-adrenergic increase of Ca(2+) influx slowed the repolarization of phase 1, suggesting a competition between Ca(2+) and K(+) currents during this phase. In addition, cAMP activated L-type Ca(2+) currents before SR Ca(2+) release activated the Na(+)-Ca(2+) exchanger currents, indicating Ca(v)1.2 channels are the initial target of PKA phosphorylation. In contrast, parasympathetic stimulation by carbachol did not have a substantial effect on amplitude and kinetics of endocardial and epicardial Ca(2+) transients. However, carbachol transiently decreased the duration of the AP late phase 2 repolarization. The carbachol-induced shortening of phase 2 did not have a considerable effect on ventricular pressure and systolic Ca(2+) dynamics. Interestingly, blockade of muscarinic receptors by atropine prolonged the duration of phase 2 indicating that, in isolated hearts, there is an intrinsic release of acetylcholine. In addition, the acceleration of repolarization induced by carbachol was blocked by the acetylcholine-mediated K(+) current inhibition. Our results reveal the transmural ramifications of autonomic regulation in intact mice hearts and support our hypothesis that Ca(2+) influx that triggers ECC occurs in AP phase 1 and not in phase 2.
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spelling pubmed-66162522019-07-22 Transmural Autonomic Regulation of Cardiac Contractility at the Intact Heart Level Aguilar-Sanchez, Yuriana Rodriguez de Yurre, Ainhoa Argenziano, Mariana Escobar, Ariel L. Ramos-Franco, Josefina Front Physiol Physiology The relationship between cardiac excitability and contractility depends on when Ca(2+) influx occurs during the ventricular action potential (AP). In mammals, it is accepted that Ca(2+) influx through the L-type Ca(2+) channels occurs during AP phase 2. However, in murine models, experimental evidence shows Ca(2+) influx takes place during phase 1. Interestingly, Ca(2+) influx that activates contraction is highly regulated by the autonomic nervous system. Indeed, autonomic regulation exerts multiple effects on Ca(2+) handling and cardiac electrophysiology. In this paper, we explore autonomic regulation in endocardial and epicardial layers of intact beating mice hearts to evaluate their role on cardiac excitability and contractility. We hypothesize that in mouse cardiac ventricles the influx of Ca(2+) that triggers excitation–contraction coupling (ECC) does not occur during phase 2. Using pulsed local field fluorescence microscopy and loose patch photolysis, we show sympathetic stimulation by isoproterenol increased the amplitude of Ca(2+) transients in both layers. This increase in contractility was driven by an increase in amplitude and duration of the L-type Ca(2+) current during phase 1. Interestingly, the β-adrenergic increase of Ca(2+) influx slowed the repolarization of phase 1, suggesting a competition between Ca(2+) and K(+) currents during this phase. In addition, cAMP activated L-type Ca(2+) currents before SR Ca(2+) release activated the Na(+)-Ca(2+) exchanger currents, indicating Ca(v)1.2 channels are the initial target of PKA phosphorylation. In contrast, parasympathetic stimulation by carbachol did not have a substantial effect on amplitude and kinetics of endocardial and epicardial Ca(2+) transients. However, carbachol transiently decreased the duration of the AP late phase 2 repolarization. The carbachol-induced shortening of phase 2 did not have a considerable effect on ventricular pressure and systolic Ca(2+) dynamics. Interestingly, blockade of muscarinic receptors by atropine prolonged the duration of phase 2 indicating that, in isolated hearts, there is an intrinsic release of acetylcholine. In addition, the acceleration of repolarization induced by carbachol was blocked by the acetylcholine-mediated K(+) current inhibition. Our results reveal the transmural ramifications of autonomic regulation in intact mice hearts and support our hypothesis that Ca(2+) influx that triggers ECC occurs in AP phase 1 and not in phase 2. Frontiers Media S.A. 2019-07-03 /pmc/articles/PMC6616252/ /pubmed/31333477 http://dx.doi.org/10.3389/fphys.2019.00773 Text en Copyright © 2019 Aguilar-Sanchez, Rodriguez de Yurre, Argenziano, Escobar and Ramos-Franco. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Aguilar-Sanchez, Yuriana
Rodriguez de Yurre, Ainhoa
Argenziano, Mariana
Escobar, Ariel L.
Ramos-Franco, Josefina
Transmural Autonomic Regulation of Cardiac Contractility at the Intact Heart Level
title Transmural Autonomic Regulation of Cardiac Contractility at the Intact Heart Level
title_full Transmural Autonomic Regulation of Cardiac Contractility at the Intact Heart Level
title_fullStr Transmural Autonomic Regulation of Cardiac Contractility at the Intact Heart Level
title_full_unstemmed Transmural Autonomic Regulation of Cardiac Contractility at the Intact Heart Level
title_short Transmural Autonomic Regulation of Cardiac Contractility at the Intact Heart Level
title_sort transmural autonomic regulation of cardiac contractility at the intact heart level
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616252/
https://www.ncbi.nlm.nih.gov/pubmed/31333477
http://dx.doi.org/10.3389/fphys.2019.00773
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