A general mechanism for drug promiscuity: Studies with amiodarone and other antiarrhythmics Academic Article uri icon

Overview

MeSH Major

  • Amiodarone
  • Anti-Arrhythmia Agents

abstract

  • Amiodarone is a widely prescribed antiarrhythmic drug used to treat the most prevalent type of arrhythmia, atrial fibrillation (AF). At therapeutic concentrations, amiodarone alters the function of many diverse membrane proteins, which results in complex therapeutic and toxicity profiles. Other antiarrhythmics, such as dronedarone, similarly alter the function of multiple membrane proteins, suggesting that a multipronged mechanism may be beneficial for treating AF, but raising questions about how these antiarrhythmics regulate a diverse range of membrane proteins at similar concentrations. One possible mechanism is that these molecules regulate membrane protein function by altering the common environment provided by the host lipid bilayer. We took advantage of the gramicidin (gA) channels' sensitivity to changes in bilayer properties to determine whether commonly used antiarrhythmics--amiodarone, dronedarone, propranolol, and pindolol, whose pharmacological modes of action range from multi-target to specific--perturb lipid bilayer properties at therapeutic concentrations. Using a gA-based fluorescence assay, we found that amiodarone and dronedarone are potent bilayer modifiers at therapeutic concentrations; propranolol alters bilayer properties only at supratherapeutic concentration, and pindolol has little effect. Using single-channel electrophysiology, we found that amiodarone and dronedarone, but not propranolol or pindolol, increase bilayer elasticity. The overlap between therapeutic and bilayer-altering concentrations, which is observed also using plasma membrane-like lipid mixtures, underscores the need to explore the role of the bilayer in therapeutic as well as toxic effects of antiarrhythmic agents.

publication date

  • December 2015

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4664825

Digital Object Identifier (DOI)

  • 10.1085/jgp.201511470

PubMed ID

  • 26573624

Additional Document Info

start page

  • 463

end page

  • 75

volume

  • 146

number

  • 6