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Ion Fluxes through K(Ca)2 (SK) and Ca(v)1 (L-type) Channels Contribute to Chronoselectivity of Adenosine A(1) Receptor-Mediated Actions in Spontaneously Beating Rat Atria
Impulse generation in supraventricular tissue is inhibited by adenosine and acetylcholine via the activation of A(1) and M(2) receptors coupled to inwardly rectifying GIRK/K(IR)3.1/3.4 channels, respectively. Unlike M(2) receptors, bradycardia produced by A(1) receptors activation predominates over...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780064/ https://www.ncbi.nlm.nih.gov/pubmed/27014060 http://dx.doi.org/10.3389/fphar.2016.00045 |
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author | Bragança, Bruno Oliveira-Monteiro, Nádia Ferreirinha, Fátima Lima, Pedro A. Faria, Miguel Fontes-Sousa, Ana P. Correia-de-Sá, Paulo |
author_facet | Bragança, Bruno Oliveira-Monteiro, Nádia Ferreirinha, Fátima Lima, Pedro A. Faria, Miguel Fontes-Sousa, Ana P. Correia-de-Sá, Paulo |
author_sort | Bragança, Bruno |
collection | PubMed |
description | Impulse generation in supraventricular tissue is inhibited by adenosine and acetylcholine via the activation of A(1) and M(2) receptors coupled to inwardly rectifying GIRK/K(IR)3.1/3.4 channels, respectively. Unlike M(2) receptors, bradycardia produced by A(1) receptors activation predominates over negative inotropy. Such difference suggests that other ion currents may contribute to adenosine chronoselectivity. In isolated spontaneously beating rat atria, blockade of K(Ca)2/SK channels with apamin and Ca(v)1 (L-type) channels with nifedipine or verapamil, sensitized atria to the negative inotropic action of the A(1) agonist, R-PIA, without affecting the nucleoside negative chronotropy. Patch-clamp experiments in the whole-cell configuration mode demonstrate that adenosine, via A(1) receptors, activates the inwardly-rectifying GIRK/K(IR)3.1/K(IR)3.4 current resulting in hyperpolarization of atrial cardiomyocytes, which may slow down heart rate. Conversely, the nucleoside inactivates a small conductance Ca(2+)-activated K(Ca)2/SK outward current, which eventually reduces the repolarizing force and thereby prolong action potentials duration and Ca(2+) influx into cardiomyocytes. Immunolocalization studies showed that differences in A(1) receptors distribution between the sinoatrial node and surrounding cardiomyocytes do not afford a rationale for adenosine chronoselectivity. Immunolabelling of K(IR)3.1, K(Ca)2.2, K(Ca)2.3, and Ca(v)1 was also observed throughout the right atrium. Functional data indicate that while both A(1) and M(2) receptors favor the opening of GIRK/K(IR)3.1/3.4 channels modulating atrial chronotropy, A(1) receptors may additionally restrain K(Ca)2/SK activation thereby compensating atrial inotropic depression by increasing the time available for Ca(2+) influx through Ca(v)1 (L-type) channels. |
format | Online Article Text |
id | pubmed-4780064 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-47800642016-03-24 Ion Fluxes through K(Ca)2 (SK) and Ca(v)1 (L-type) Channels Contribute to Chronoselectivity of Adenosine A(1) Receptor-Mediated Actions in Spontaneously Beating Rat Atria Bragança, Bruno Oliveira-Monteiro, Nádia Ferreirinha, Fátima Lima, Pedro A. Faria, Miguel Fontes-Sousa, Ana P. Correia-de-Sá, Paulo Front Pharmacol Pharmacology Impulse generation in supraventricular tissue is inhibited by adenosine and acetylcholine via the activation of A(1) and M(2) receptors coupled to inwardly rectifying GIRK/K(IR)3.1/3.4 channels, respectively. Unlike M(2) receptors, bradycardia produced by A(1) receptors activation predominates over negative inotropy. Such difference suggests that other ion currents may contribute to adenosine chronoselectivity. In isolated spontaneously beating rat atria, blockade of K(Ca)2/SK channels with apamin and Ca(v)1 (L-type) channels with nifedipine or verapamil, sensitized atria to the negative inotropic action of the A(1) agonist, R-PIA, without affecting the nucleoside negative chronotropy. Patch-clamp experiments in the whole-cell configuration mode demonstrate that adenosine, via A(1) receptors, activates the inwardly-rectifying GIRK/K(IR)3.1/K(IR)3.4 current resulting in hyperpolarization of atrial cardiomyocytes, which may slow down heart rate. Conversely, the nucleoside inactivates a small conductance Ca(2+)-activated K(Ca)2/SK outward current, which eventually reduces the repolarizing force and thereby prolong action potentials duration and Ca(2+) influx into cardiomyocytes. Immunolocalization studies showed that differences in A(1) receptors distribution between the sinoatrial node and surrounding cardiomyocytes do not afford a rationale for adenosine chronoselectivity. Immunolabelling of K(IR)3.1, K(Ca)2.2, K(Ca)2.3, and Ca(v)1 was also observed throughout the right atrium. Functional data indicate that while both A(1) and M(2) receptors favor the opening of GIRK/K(IR)3.1/3.4 channels modulating atrial chronotropy, A(1) receptors may additionally restrain K(Ca)2/SK activation thereby compensating atrial inotropic depression by increasing the time available for Ca(2+) influx through Ca(v)1 (L-type) channels. Frontiers Media S.A. 2016-03-07 /pmc/articles/PMC4780064/ /pubmed/27014060 http://dx.doi.org/10.3389/fphar.2016.00045 Text en Copyright © 2016 Bragança, Oliveira-Monteiro, Ferreirinha, Lima, Faria, Fontes-Sousa and Correia-de-Sá. 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) or licensor 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 | Pharmacology Bragança, Bruno Oliveira-Monteiro, Nádia Ferreirinha, Fátima Lima, Pedro A. Faria, Miguel Fontes-Sousa, Ana P. Correia-de-Sá, Paulo Ion Fluxes through K(Ca)2 (SK) and Ca(v)1 (L-type) Channels Contribute to Chronoselectivity of Adenosine A(1) Receptor-Mediated Actions in Spontaneously Beating Rat Atria |
title | Ion Fluxes through K(Ca)2 (SK) and Ca(v)1 (L-type) Channels Contribute to Chronoselectivity of Adenosine A(1) Receptor-Mediated Actions in Spontaneously Beating Rat Atria |
title_full | Ion Fluxes through K(Ca)2 (SK) and Ca(v)1 (L-type) Channels Contribute to Chronoselectivity of Adenosine A(1) Receptor-Mediated Actions in Spontaneously Beating Rat Atria |
title_fullStr | Ion Fluxes through K(Ca)2 (SK) and Ca(v)1 (L-type) Channels Contribute to Chronoselectivity of Adenosine A(1) Receptor-Mediated Actions in Spontaneously Beating Rat Atria |
title_full_unstemmed | Ion Fluxes through K(Ca)2 (SK) and Ca(v)1 (L-type) Channels Contribute to Chronoselectivity of Adenosine A(1) Receptor-Mediated Actions in Spontaneously Beating Rat Atria |
title_short | Ion Fluxes through K(Ca)2 (SK) and Ca(v)1 (L-type) Channels Contribute to Chronoselectivity of Adenosine A(1) Receptor-Mediated Actions in Spontaneously Beating Rat Atria |
title_sort | ion fluxes through k(ca)2 (sk) and ca(v)1 (l-type) channels contribute to chronoselectivity of adenosine a(1) receptor-mediated actions in spontaneously beating rat atria |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780064/ https://www.ncbi.nlm.nih.gov/pubmed/27014060 http://dx.doi.org/10.3389/fphar.2016.00045 |
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