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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.

No MeSH data available.


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The antiarrhythmic-induced changes in the single-channel lifetimes of gA−(13) channels versus the changes in the lifetimes of gA(15) channels. (A) Natural logarithm of relative changes in τ13 (ln(τ13/τ13cntrl)) versus the natural logarithm of relative changes in τ15 (ln(τ15/τ15cntrl)) observed for dronedarone (green), amiodarone (orange circle), propranolol (blue triangle), and pindolol (black square) plotted together with results from Lundbæk et al. (2010b) and Rusinova et al. (2011). The points cluster around a straight line with slope 1.2 ± 0.03 (error bars represent mean ± SE). (B) Distribution of the slopes for the lnτ13 versus lnτ15 relations for the individual compounds in A. The distribution is fit by Gaussian function with a mean ± SD (σ calculated from the fit) of 1.3 ± 0.2, σ = 0.3. Changes in the histogram bin size result in the median slope ranging between 1.2 and 1.3. Inset illustrates an individual linear fit to the (ln(τ13/τ13cntrl)) versus ln(τ15/τ15cntrl) in the presence of dronedarone (green symbols). Slopes of the linear fits, such as that in the inset, obtained for each compound were used to construct the distribution in B.
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fig4: The antiarrhythmic-induced changes in the single-channel lifetimes of gA−(13) channels versus the changes in the lifetimes of gA(15) channels. (A) Natural logarithm of relative changes in τ13 (ln(τ13/τ13cntrl)) versus the natural logarithm of relative changes in τ15 (ln(τ15/τ15cntrl)) observed for dronedarone (green), amiodarone (orange circle), propranolol (blue triangle), and pindolol (black square) plotted together with results from Lundbæk et al. (2010b) and Rusinova et al. (2011). The points cluster around a straight line with slope 1.2 ± 0.03 (error bars represent mean ± SE). (B) Distribution of the slopes for the lnτ13 versus lnτ15 relations for the individual compounds in A. The distribution is fit by Gaussian function with a mean ± SD (σ calculated from the fit) of 1.3 ± 0.2, σ = 0.3. Changes in the histogram bin size result in the median slope ranging between 1.2 and 1.3. Inset illustrates an individual linear fit to the (ln(τ13/τ13cntrl)) versus ln(τ15/τ15cntrl) in the presence of dronedarone (green symbols). Slopes of the linear fits, such as that in the inset, obtained for each compound were used to construct the distribution in B.

Mentions: Confirming previous studies (Lundbæk et al., 2010b; Rusinova et al., 2011), structurally diverse compounds produce remarkably similar relative increases in the lifetimes of the short gA−(13) channels relative to the long gA(15) channels. Fig. 4 A shows the linear relation between the natural logarithms of the changes in τ for the short gA−(13) channels ln[τ13/τ13cntrl] versus the changes for the long gA(15) channels ln[τ15/τ15cntrl], where we included earlier results from Rusinova et al. (2011) and Ingólfsson et al. (2014).


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

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

The antiarrhythmic-induced changes in the single-channel lifetimes of gA−(13) channels versus the changes in the lifetimes of gA(15) channels. (A) Natural logarithm of relative changes in τ13 (ln(τ13/τ13cntrl)) versus the natural logarithm of relative changes in τ15 (ln(τ15/τ15cntrl)) observed for dronedarone (green), amiodarone (orange circle), propranolol (blue triangle), and pindolol (black square) plotted together with results from Lundbæk et al. (2010b) and Rusinova et al. (2011). The points cluster around a straight line with slope 1.2 ± 0.03 (error bars represent mean ± SE). (B) Distribution of the slopes for the lnτ13 versus lnτ15 relations for the individual compounds in A. The distribution is fit by Gaussian function with a mean ± SD (σ calculated from the fit) of 1.3 ± 0.2, σ = 0.3. Changes in the histogram bin size result in the median slope ranging between 1.2 and 1.3. Inset illustrates an individual linear fit to the (ln(τ13/τ13cntrl)) versus ln(τ15/τ15cntrl) in the presence of dronedarone (green symbols). Slopes of the linear fits, such as that in the inset, obtained for each compound were used to construct the distribution in B.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig4: The antiarrhythmic-induced changes in the single-channel lifetimes of gA−(13) channels versus the changes in the lifetimes of gA(15) channels. (A) Natural logarithm of relative changes in τ13 (ln(τ13/τ13cntrl)) versus the natural logarithm of relative changes in τ15 (ln(τ15/τ15cntrl)) observed for dronedarone (green), amiodarone (orange circle), propranolol (blue triangle), and pindolol (black square) plotted together with results from Lundbæk et al. (2010b) and Rusinova et al. (2011). The points cluster around a straight line with slope 1.2 ± 0.03 (error bars represent mean ± SE). (B) Distribution of the slopes for the lnτ13 versus lnτ15 relations for the individual compounds in A. The distribution is fit by Gaussian function with a mean ± SD (σ calculated from the fit) of 1.3 ± 0.2, σ = 0.3. Changes in the histogram bin size result in the median slope ranging between 1.2 and 1.3. Inset illustrates an individual linear fit to the (ln(τ13/τ13cntrl)) versus ln(τ15/τ15cntrl) in the presence of dronedarone (green symbols). Slopes of the linear fits, such as that in the inset, obtained for each compound were used to construct the distribution in B.
Mentions: Confirming previous studies (Lundbæk et al., 2010b; Rusinova et al., 2011), structurally diverse compounds produce remarkably similar relative increases in the lifetimes of the short gA−(13) channels relative to the long gA(15) channels. Fig. 4 A shows the linear relation between the natural logarithms of the changes in τ for the short gA−(13) channels ln[τ13/τ13cntrl] versus the changes for the long gA(15) channels ln[τ15/τ15cntrl], where we included earlier results from Rusinova et al. (2011) and Ingólfsson et al. (2014).

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