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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...

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Autores principales: Zhou, Qinlian, Bett, Glenna C. L., Rasmusson, Randall L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
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.
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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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