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Distinct Patterns of Constitutive Phosphodiesterase Activity in Mouse Sinoatrial Node and Atrial Myocardium
Phosphodiesterases (PDEs) are critical regulators of cyclic nucleotides in the heart. In ventricular myocytes, the L-type Ca(2+) current (I(Ca,L)) is a major target of regulation by PDEs, particularly members of the PDE2, PDE3 and PDE4 families. Conversely, much less is known about the roles of PDE2...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471891/ https://www.ncbi.nlm.nih.gov/pubmed/23077656 http://dx.doi.org/10.1371/journal.pone.0047652 |
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author | Hua, Rui Adamczyk, Andrew Robbins, Courtney Ray, Gibanananda Rose, Robert A. |
author_facet | Hua, Rui Adamczyk, Andrew Robbins, Courtney Ray, Gibanananda Rose, Robert A. |
author_sort | Hua, Rui |
collection | PubMed |
description | Phosphodiesterases (PDEs) are critical regulators of cyclic nucleotides in the heart. In ventricular myocytes, the L-type Ca(2+) current (I(Ca,L)) is a major target of regulation by PDEs, particularly members of the PDE2, PDE3 and PDE4 families. Conversely, much less is known about the roles of PDE2, PDE3 and PDE4 in the regulation of action potential (AP) properties and I(Ca,L) in the sinoatrial node (SAN) and the atrial myocardium, especially in mice. Thus, the purpose of our study was to measure the effects of global PDE inhibition with Isobutyl-1-methylxanthine (IBMX) and selective inhibitors of PDE2, PDE3 and PDE4 on AP properties in isolated mouse SAN and right atrial myocytes. We also measured the effects of these inhibitors on I(Ca,L) in SAN and atrial myocytes in comparison to ventricular myocytes. Our data demonstrate that IBMX markedly increases spontaneous AP frequency in SAN myocytes and AP duration in atrial myocytes. Spontaneous AP firing in SAN myocytes was also increased by the PDE2 inhibitor erythro-9-[2-hydroxy-3-nonyl] adenine (EHNA), the PDE3 inhibitor milrinone (Mil) and the PDE4 inhibitor rolipram (Rol). In contrast, atrial AP duration was increased by EHNA and Rol, but not by Mil. IBMX also potently, and similarly, increased I(Ca,L) in SAN, atrial and ventricular myocytes; however, important differences emerged in terms of which inhibitors could modulate I(Ca,L) in each myocyte type. Consistent with our AP measurements, EHNA, Mil and Rol each increased I(Ca,L) in SAN myocytes. Also, EHNA and Rol, but not Mil, increased atrial I(Ca,L). In complete contrast, no selective PDE inhibitors increased I(Ca,L) in ventricular myocytes when given alone. Thus, our data show that the effects of selective PDE2, PDE3 and PDE4 inhibitors are distinct in the different regions of the myocardium indicating important differences in how each PDE family constitutively regulates ion channel function in the SAN, atrial and ventricular myocardium. |
format | Online Article Text |
id | pubmed-3471891 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-34718912012-10-17 Distinct Patterns of Constitutive Phosphodiesterase Activity in Mouse Sinoatrial Node and Atrial Myocardium Hua, Rui Adamczyk, Andrew Robbins, Courtney Ray, Gibanananda Rose, Robert A. PLoS One Research Article Phosphodiesterases (PDEs) are critical regulators of cyclic nucleotides in the heart. In ventricular myocytes, the L-type Ca(2+) current (I(Ca,L)) is a major target of regulation by PDEs, particularly members of the PDE2, PDE3 and PDE4 families. Conversely, much less is known about the roles of PDE2, PDE3 and PDE4 in the regulation of action potential (AP) properties and I(Ca,L) in the sinoatrial node (SAN) and the atrial myocardium, especially in mice. Thus, the purpose of our study was to measure the effects of global PDE inhibition with Isobutyl-1-methylxanthine (IBMX) and selective inhibitors of PDE2, PDE3 and PDE4 on AP properties in isolated mouse SAN and right atrial myocytes. We also measured the effects of these inhibitors on I(Ca,L) in SAN and atrial myocytes in comparison to ventricular myocytes. Our data demonstrate that IBMX markedly increases spontaneous AP frequency in SAN myocytes and AP duration in atrial myocytes. Spontaneous AP firing in SAN myocytes was also increased by the PDE2 inhibitor erythro-9-[2-hydroxy-3-nonyl] adenine (EHNA), the PDE3 inhibitor milrinone (Mil) and the PDE4 inhibitor rolipram (Rol). In contrast, atrial AP duration was increased by EHNA and Rol, but not by Mil. IBMX also potently, and similarly, increased I(Ca,L) in SAN, atrial and ventricular myocytes; however, important differences emerged in terms of which inhibitors could modulate I(Ca,L) in each myocyte type. Consistent with our AP measurements, EHNA, Mil and Rol each increased I(Ca,L) in SAN myocytes. Also, EHNA and Rol, but not Mil, increased atrial I(Ca,L). In complete contrast, no selective PDE inhibitors increased I(Ca,L) in ventricular myocytes when given alone. Thus, our data show that the effects of selective PDE2, PDE3 and PDE4 inhibitors are distinct in the different regions of the myocardium indicating important differences in how each PDE family constitutively regulates ion channel function in the SAN, atrial and ventricular myocardium. Public Library of Science 2012-10-15 /pmc/articles/PMC3471891/ /pubmed/23077656 http://dx.doi.org/10.1371/journal.pone.0047652 Text en © 2012 Hua 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 Hua, Rui Adamczyk, Andrew Robbins, Courtney Ray, Gibanananda Rose, Robert A. Distinct Patterns of Constitutive Phosphodiesterase Activity in Mouse Sinoatrial Node and Atrial Myocardium |
title | Distinct Patterns of Constitutive Phosphodiesterase Activity in Mouse Sinoatrial Node and Atrial Myocardium |
title_full | Distinct Patterns of Constitutive Phosphodiesterase Activity in Mouse Sinoatrial Node and Atrial Myocardium |
title_fullStr | Distinct Patterns of Constitutive Phosphodiesterase Activity in Mouse Sinoatrial Node and Atrial Myocardium |
title_full_unstemmed | Distinct Patterns of Constitutive Phosphodiesterase Activity in Mouse Sinoatrial Node and Atrial Myocardium |
title_short | Distinct Patterns of Constitutive Phosphodiesterase Activity in Mouse Sinoatrial Node and Atrial Myocardium |
title_sort | distinct patterns of constitutive phosphodiesterase activity in mouse sinoatrial node and atrial myocardium |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471891/ https://www.ncbi.nlm.nih.gov/pubmed/23077656 http://dx.doi.org/10.1371/journal.pone.0047652 |
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