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Markov Models of Use-Dependence and Reverse Use-Dependence during the Mouse Cardiac Action Potential
The fast component of the cardiac transient outward current, I(Ktof), is blocked by a number of drugs. The major molecular bases of I(Ktof) are Kv4.2/Kv4.3 voltage-gated potassium channels. Drugs with similar potencies but different blocking mechanisms have differing effects on action potential dura...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412869/ https://www.ncbi.nlm.nih.gov/pubmed/22879935 http://dx.doi.org/10.1371/journal.pone.0042295 |
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author | Zhou, Qinlian Bett, Glenna C. L. Rasmusson, Randall L. |
author_facet | Zhou, Qinlian Bett, Glenna C. L. Rasmusson, Randall L. |
author_sort | Zhou, Qinlian |
collection | PubMed |
description | The fast component of the cardiac transient outward current, I(Ktof), is blocked by a number of drugs. The major molecular bases of I(Ktof) are Kv4.2/Kv4.3 voltage-gated potassium channels. Drugs with similar potencies but different blocking mechanisms have differing effects on action potential duration (APD). We used in silico analysis to determine the effect of I(Ktof)-blocking drugs with different blocking mechanisms on mouse ventricular myocytes. We used our existing mouse model of the action potential, and developed 4 new Markov formulations for I(Ktof), I(Ktos), I(Kur), I(Ks). We compared effects of theoretical I(Ktof)-specific channel blockers: (1) a closed state, and (2) an open channel blocker. At concentrations lower or close to IC(50), the drug which bound to the open state always had a much greater effect on APD than the drug which bound to the closed state. At concentrations much higher than IC(50), both mechanisms had similar effects at very low pacing rates. However, an open state binding drug had a greater effect on APD at faster pacing rates, particularly around 10 Hz. In summary, our data indicate that drug effects on APD are strongly dependent not only on IC(50), but also on the drug binding state. |
format | Online Article Text |
id | pubmed-3412869 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-34128692012-08-09 Markov Models of Use-Dependence and Reverse Use-Dependence during the Mouse Cardiac Action Potential Zhou, Qinlian Bett, Glenna C. L. Rasmusson, Randall L. PLoS One Research Article The fast component of the cardiac transient outward current, I(Ktof), is blocked by a number of drugs. The major molecular bases of I(Ktof) are Kv4.2/Kv4.3 voltage-gated potassium channels. Drugs with similar potencies but different blocking mechanisms have differing effects on action potential duration (APD). We used in silico analysis to determine the effect of I(Ktof)-blocking drugs with different blocking mechanisms on mouse ventricular myocytes. We used our existing mouse model of the action potential, and developed 4 new Markov formulations for I(Ktof), I(Ktos), I(Kur), I(Ks). We compared effects of theoretical I(Ktof)-specific channel blockers: (1) a closed state, and (2) an open channel blocker. At concentrations lower or close to IC(50), the drug which bound to the open state always had a much greater effect on APD than the drug which bound to the closed state. At concentrations much higher than IC(50), both mechanisms had similar effects at very low pacing rates. However, an open state binding drug had a greater effect on APD at faster pacing rates, particularly around 10 Hz. In summary, our data indicate that drug effects on APD are strongly dependent not only on IC(50), but also on the drug binding state. Public Library of Science 2012-08-06 /pmc/articles/PMC3412869/ /pubmed/22879935 http://dx.doi.org/10.1371/journal.pone.0042295 Text en © 2012 Zhou 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 Zhou, Qinlian Bett, Glenna C. L. Rasmusson, Randall L. Markov Models of Use-Dependence and Reverse Use-Dependence during the Mouse Cardiac Action Potential |
title | Markov Models of Use-Dependence and Reverse Use-Dependence during the Mouse Cardiac Action Potential |
title_full | Markov Models of Use-Dependence and Reverse Use-Dependence during the Mouse Cardiac Action Potential |
title_fullStr | Markov Models of Use-Dependence and Reverse Use-Dependence during the Mouse Cardiac Action Potential |
title_full_unstemmed | Markov Models of Use-Dependence and Reverse Use-Dependence during the Mouse Cardiac Action Potential |
title_short | Markov Models of Use-Dependence and Reverse Use-Dependence during the Mouse Cardiac Action Potential |
title_sort | markov models of use-dependence and reverse use-dependence during the mouse cardiac action potential |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412869/ https://www.ncbi.nlm.nih.gov/pubmed/22879935 http://dx.doi.org/10.1371/journal.pone.0042295 |
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