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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.


Related in: MedlinePlus

Dronedarone alters gA(15) channel function in bilayers formed from ternary DC18:1PC/bSM/Chol 1:1:1 mixtures. (A) Relative changes in τ. (B) Relative changes in f. (C) The decrease in  Error bars represent mean ± range/2 (n = 2).
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fig6: Dronedarone alters gA(15) channel function in bilayers formed from ternary DC18:1PC/bSM/Chol 1:1:1 mixtures. (A) Relative changes in τ. (B) Relative changes in f. (C) The decrease in Error bars represent mean ± range/2 (n = 2).

Mentions: Dronedarone produced similar changes in the reference DC18:1PC bilayers and in bilayers formed from DC18:1PC/bSM/Chol 1:1:1 (Fig. 6), as a mimic of the extracellular leaflet of the plasma membrane (Feigenson, 2007). Dronedarone increased both τ and f for gA(15) channels over a similar concentration range as in DC18:1PC membranes, but to a greater extent (Table 2 and Figs. S1 and 6, A and B): at 3 µM dronedarone, ΔΔGbilayer was doubled from 5.2 kJ/mole in DC18:1PC to 10.5 kJ/mole in DC18:1PC/bSM/Chol (compare Figs. 3 B and 6 C). The increased effect on ΔΔGbilayer most likely reflects that the liquid-ordered domains in the ternary mixture are stiffer than the DC18:1PC bilayers, which would lead to larger absolute changes in the amphiphile-induced changes in bilayer elasticity (Bruno et al., 2013). In any case, these results show that there are no qualitative differences in the antiarrhythmics’ effects on single-component and multicomponent bilayers.


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

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

Dronedarone alters gA(15) channel function in bilayers formed from ternary DC18:1PC/bSM/Chol 1:1:1 mixtures. (A) Relative changes in τ. (B) Relative changes in f. (C) The decrease in  Error bars represent mean ± range/2 (n = 2).
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig6: Dronedarone alters gA(15) channel function in bilayers formed from ternary DC18:1PC/bSM/Chol 1:1:1 mixtures. (A) Relative changes in τ. (B) Relative changes in f. (C) The decrease in Error bars represent mean ± range/2 (n = 2).
Mentions: Dronedarone produced similar changes in the reference DC18:1PC bilayers and in bilayers formed from DC18:1PC/bSM/Chol 1:1:1 (Fig. 6), as a mimic of the extracellular leaflet of the plasma membrane (Feigenson, 2007). Dronedarone increased both τ and f for gA(15) channels over a similar concentration range as in DC18:1PC membranes, but to a greater extent (Table 2 and Figs. S1 and 6, A and B): at 3 µM dronedarone, ΔΔGbilayer was doubled from 5.2 kJ/mole in DC18:1PC to 10.5 kJ/mole in DC18:1PC/bSM/Chol (compare Figs. 3 B and 6 C). The increased effect on ΔΔGbilayer most likely reflects that the liquid-ordered domains in the ternary mixture are stiffer than the DC18:1PC bilayers, which would lead to larger absolute changes in the amphiphile-induced changes in bilayer elasticity (Bruno et al., 2013). In any case, these results show that there are no qualitative differences in the antiarrhythmics’ effects on single-component and multicomponent bilayers.

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