Cardiac sarcolemmal ion channels and transporters as possible targets for antiarrhythmic and positive inotropic drugs

Strategies of the past-perspectives of the future

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Abstract

In this article we overview the most important antiarrhythmic and positive inotropic mechanisms based on pharmacological modification of an ion channel or a transport protein in the surface membrane of cardiac myocytes. First we briefly characterize the ion currents mediated by these proteins in atrial and ventricular cells. Since the level of expression of ion channels is markedly altered in various types of chronic heart diseases, such as atrial fibrillation or heart failure, cardiac remodelling characteristic of these cases is also discussed. The paper gives evaluation of the currently applied most important antiarrhythmic strategies and some insight into the perspectives of the future by reviewing a few but promising mechanisms and drugs that are currently investigated. Positive inotropic agents and mechanisms are similarly treated, focusing primarily on proarrhythmic risks or potential antiarrhythmic effects of these compounds. Based on the backgrounds and aims above, modification of the followings factors is discussed in details: INa, ICa, IKr, IKs, IKl, Ito, IKur, IK,Ach, IK,ATP, If, gap-junction channel, Na+/K+ pump, Na+/Ca2 + exchanger, Na+/H+ exchanger, as well as the intracellular concentrations of sodium and calcium ions. In addition to the critical evaluation of each manipulation, the following general conclusions can be drawn. (1) Since large modifications in action potential parameters are usually disadvantageous at long time scale, combination of the various mechanisms, each represented at a moderate degree, appears to be better. (2) Regarding Class III. antiarrhythmic action, selective potassium channel blockers free of reverse rate-dependent properties should be preferred. (3) Partial inhibition of the Na+/Ca2+ exchanger may result-paradoxically in an antiarrhythmic action under specific conditions, in addition to its positive inotropic effect. We believe that investigation of new antiarrhythmic mechanisms, rather than new compounds of the old families, might be most beneficial in order to effectively treat life threatening cardiac arrhythmias in the future.

Original languageEnglish
Pages (from-to)2411-2427
Number of pages17
JournalCurrent Pharmaceutical Design
Volume10
Issue number20
DOIs
Publication statusPublished - 2004

Fingerprint

Ion Channels
Potassium Channel Blockers
Ions
Sodium-Hydrogen Antiporter
Gap Junctions
Cardiac Myocytes
Pharmaceutical Preparations
Atrial Fibrillation
Action Potentials
Cardiac Arrhythmias
Heart Diseases
Carrier Proteins
Chronic Disease
Heart Failure
Adenosine Triphosphate
Sodium
Pharmacology
Calcium
Membranes
Proteins

Keywords

  • Action potential
  • Antiarrhythmic drugs
  • Ca-current
  • Cardiac myocytes
  • Human cardiac cells
  • Ion channels
  • K-current
  • Positive inotropic drugs

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

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title = "Cardiac sarcolemmal ion channels and transporters as possible targets for antiarrhythmic and positive inotropic drugs: Strategies of the past-perspectives of the future",
abstract = "In this article we overview the most important antiarrhythmic and positive inotropic mechanisms based on pharmacological modification of an ion channel or a transport protein in the surface membrane of cardiac myocytes. First we briefly characterize the ion currents mediated by these proteins in atrial and ventricular cells. Since the level of expression of ion channels is markedly altered in various types of chronic heart diseases, such as atrial fibrillation or heart failure, cardiac remodelling characteristic of these cases is also discussed. The paper gives evaluation of the currently applied most important antiarrhythmic strategies and some insight into the perspectives of the future by reviewing a few but promising mechanisms and drugs that are currently investigated. Positive inotropic agents and mechanisms are similarly treated, focusing primarily on proarrhythmic risks or potential antiarrhythmic effects of these compounds. Based on the backgrounds and aims above, modification of the followings factors is discussed in details: INa, ICa, IKr, IKs, IKl, Ito, IKur, IK,Ach, IK,ATP, If, gap-junction channel, Na+/K+ pump, Na+/Ca2 + exchanger, Na+/H+ exchanger, as well as the intracellular concentrations of sodium and calcium ions. In addition to the critical evaluation of each manipulation, the following general conclusions can be drawn. (1) Since large modifications in action potential parameters are usually disadvantageous at long time scale, combination of the various mechanisms, each represented at a moderate degree, appears to be better. (2) Regarding Class III. antiarrhythmic action, selective potassium channel blockers free of reverse rate-dependent properties should be preferred. (3) Partial inhibition of the Na+/Ca2+ exchanger may result-paradoxically in an antiarrhythmic action under specific conditions, in addition to its positive inotropic effect. We believe that investigation of new antiarrhythmic mechanisms, rather than new compounds of the old families, might be most beneficial in order to effectively treat life threatening cardiac arrhythmias in the future.",
keywords = "Action potential, Antiarrhythmic drugs, Ca-current, Cardiac myocytes, Human cardiac cells, Ion channels, K-current, Positive inotropic drugs",
author = "A. Varr{\'o} and P. N{\'a}n{\'a}si and K. Acsai and L. Vir{\'a}g and J. Papp",
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T2 - Strategies of the past-perspectives of the future

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AU - Nánási, P.

AU - Acsai, K.

AU - Virág, L.

AU - Papp, J.

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AB - In this article we overview the most important antiarrhythmic and positive inotropic mechanisms based on pharmacological modification of an ion channel or a transport protein in the surface membrane of cardiac myocytes. First we briefly characterize the ion currents mediated by these proteins in atrial and ventricular cells. Since the level of expression of ion channels is markedly altered in various types of chronic heart diseases, such as atrial fibrillation or heart failure, cardiac remodelling characteristic of these cases is also discussed. The paper gives evaluation of the currently applied most important antiarrhythmic strategies and some insight into the perspectives of the future by reviewing a few but promising mechanisms and drugs that are currently investigated. Positive inotropic agents and mechanisms are similarly treated, focusing primarily on proarrhythmic risks or potential antiarrhythmic effects of these compounds. Based on the backgrounds and aims above, modification of the followings factors is discussed in details: INa, ICa, IKr, IKs, IKl, Ito, IKur, IK,Ach, IK,ATP, If, gap-junction channel, Na+/K+ pump, Na+/Ca2 + exchanger, Na+/H+ exchanger, as well as the intracellular concentrations of sodium and calcium ions. In addition to the critical evaluation of each manipulation, the following general conclusions can be drawn. (1) Since large modifications in action potential parameters are usually disadvantageous at long time scale, combination of the various mechanisms, each represented at a moderate degree, appears to be better. (2) Regarding Class III. antiarrhythmic action, selective potassium channel blockers free of reverse rate-dependent properties should be preferred. (3) Partial inhibition of the Na+/Ca2+ exchanger may result-paradoxically in an antiarrhythmic action under specific conditions, in addition to its positive inotropic effect. We believe that investigation of new antiarrhythmic mechanisms, rather than new compounds of the old families, might be most beneficial in order to effectively treat life threatening cardiac arrhythmias in the future.

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