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A general mechanism for drug promiscuity: Studies with amiodarone and other antiarrhythmics.

Rusinova R, Koeppe RE, Andersen OS - J. Gen. Physiol. (2015)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology and Biophysics and Department of Anesthesiology, Weill Cornell Medical College, New York, NY 10065 Department of Physiology and Biophysics and Department of Anesthesiology, Weill Cornell Medical College, New York, NY 10065 rar2021@med.cornell.edu.

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Antiarrhythmics alter lipid bilayer properties. (A, left) Fluorescence quench traces showing Tl+ quenching of ANTS fluorescence in DC22:1PC LUVs without gA (−gA; the top two traces) and with gA (+gA; the bottom five traces) in the absence of drug (black, control) or with dronedarone (green), amiodarone (orange), propranolol (cyan), and pindolol (purple). Amiodarone, dronedarone, and propranolol increase the fluorescence signal up to 12% depending on the concentration, but the flux rate measurements were not affected. The results for each drug represent five to eight repeats (dots) and their averages (solid lines). (Right) Single repeats (dots) with stretched exponential fit (solid line). (B) Normalized quench rates determined from the stretched exponential fits at varying antiarrhythmic concentrations. Error bars represent mean ± SD (n = 3 – 5).
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fig2: Antiarrhythmics alter lipid bilayer properties. (A, left) Fluorescence quench traces showing Tl+ quenching of ANTS fluorescence in DC22:1PC LUVs without gA (−gA; the top two traces) and with gA (+gA; the bottom five traces) in the absence of drug (black, control) or with dronedarone (green), amiodarone (orange), propranolol (cyan), and pindolol (purple). Amiodarone, dronedarone, and propranolol increase the fluorescence signal up to 12% depending on the concentration, but the flux rate measurements were not affected. The results for each drug represent five to eight repeats (dots) and their averages (solid lines). (Right) Single repeats (dots) with stretched exponential fit (solid line). (B) Normalized quench rates determined from the stretched exponential fits at varying antiarrhythmic concentrations. Error bars represent mean ± SD (n = 3 – 5).

Mentions: The GBFA takes advantage of gA channels’ permeability to Tl+, a quencher of the water-soluble fluorophore ANTS, where the rate of influx is a function of the time-averaged number of gA channels in the LUV membrane (Ingólfsson and Andersen, 2010). In the absence of gA (top horizontal traces in Fig. 2 A), the drugs have no effect on the rate of fluorescence quenching, meaning that the compounds did not compromise lipid bilayer stability at the concentrations tested. In the presence of the drugs, the gA-dependent fluorescence quench rate increases (bottom traces in Fig. 2 A), demonstrating that the antiarrhythmics increase the rate of Tl+ influx into the LUVs. This increase is caused by a shift in the gA monomer↔dimer equilibrium toward the conducting dimer state as antiarrhythmics decrease and thereby the free energy of dimerization (Andersen et al., 2007):(5)[D][M]2=KM→D=exp{ΔGproteinM→D+ΔGbilayerM→DkBT}.The relative potency of each antiarrhythmic was quantified by plotting the change in quench rate (normalized to the rate in the absence of drug) as a function of drug concentration (Fig. 2 B).


A general mechanism for drug promiscuity: Studies with amiodarone and other antiarrhythmics.

Rusinova R, Koeppe RE, Andersen OS - J. Gen. Physiol. (2015)

Antiarrhythmics alter lipid bilayer properties. (A, left) Fluorescence quench traces showing Tl+ quenching of ANTS fluorescence in DC22:1PC LUVs without gA (−gA; the top two traces) and with gA (+gA; the bottom five traces) in the absence of drug (black, control) or with dronedarone (green), amiodarone (orange), propranolol (cyan), and pindolol (purple). Amiodarone, dronedarone, and propranolol increase the fluorescence signal up to 12% depending on the concentration, but the flux rate measurements were not affected. The results for each drug represent five to eight repeats (dots) and their averages (solid lines). (Right) Single repeats (dots) with stretched exponential fit (solid line). (B) Normalized quench rates determined from the stretched exponential fits at varying antiarrhythmic concentrations. Error bars represent mean ± SD (n = 3 – 5).
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4664825&req=5

fig2: Antiarrhythmics alter lipid bilayer properties. (A, left) Fluorescence quench traces showing Tl+ quenching of ANTS fluorescence in DC22:1PC LUVs without gA (−gA; the top two traces) and with gA (+gA; the bottom five traces) in the absence of drug (black, control) or with dronedarone (green), amiodarone (orange), propranolol (cyan), and pindolol (purple). Amiodarone, dronedarone, and propranolol increase the fluorescence signal up to 12% depending on the concentration, but the flux rate measurements were not affected. The results for each drug represent five to eight repeats (dots) and their averages (solid lines). (Right) Single repeats (dots) with stretched exponential fit (solid line). (B) Normalized quench rates determined from the stretched exponential fits at varying antiarrhythmic concentrations. Error bars represent mean ± SD (n = 3 – 5).
Mentions: The GBFA takes advantage of gA channels’ permeability to Tl+, a quencher of the water-soluble fluorophore ANTS, where the rate of influx is a function of the time-averaged number of gA channels in the LUV membrane (Ingólfsson and Andersen, 2010). In the absence of gA (top horizontal traces in Fig. 2 A), the drugs have no effect on the rate of fluorescence quenching, meaning that the compounds did not compromise lipid bilayer stability at the concentrations tested. In the presence of the drugs, the gA-dependent fluorescence quench rate increases (bottom traces in Fig. 2 A), demonstrating that the antiarrhythmics increase the rate of Tl+ influx into the LUVs. This increase is caused by a shift in the gA monomer↔dimer equilibrium toward the conducting dimer state as antiarrhythmics decrease and thereby the free energy of dimerization (Andersen et al., 2007):(5)[D][M]2=KM→D=exp{ΔGproteinM→D+ΔGbilayerM→DkBT}.The relative potency of each antiarrhythmic was quantified by plotting the change in quench rate (normalized to the rate in the absence of drug) as a function of drug concentration (Fig. 2 B).

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology and Biophysics and Department of Anesthesiology, Weill Cornell Medical College, New York, NY 10065 Department of Physiology and Biophysics and Department of Anesthesiology, Weill Cornell Medical College, New York, NY 10065 rar2021@med.cornell.edu.

No MeSH data available.


Related in: MedlinePlus