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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

Survivor single-channel lifetime histograms for gA(15) in DC18:1PC and DC18:1PC/bSM/Chol bilayers with single-exponential fits. There is no evidence for the existence of more than one population of channels in either membrane.
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fig5: Survivor single-channel lifetime histograms for gA(15) in DC18:1PC and DC18:1PC/bSM/Chol bilayers with single-exponential fits. There is no evidence for the existence of more than one population of channels in either membrane.

Mentions: Experiments in DC18:1PC bilayers yield unambiguous information that can be used to calculate changes in the bilayer deformation energy caused by reversible partitioning (Artigas et al., 2006; Andersen et al., 2007; Lundbæk et al., 2010a; Rusinova et al., 2011) of drugs without the complications of domain reorganization and heterogeneous phospholipid mixing that may confound the quantification of effects on more complex bilayers. The bilayers of cell membranes, however, have complex lipid compositions (Wenk, 2005; van Meer et al., 2008). To explore whether the antiarrhythmics alter bilayer properties in bilayers with heterogenous lipid composition, where their effects could be dampened or obscured (or, maybe, enhanced) by lipid redistribution and changes in domain organization (e.g., Heerklotz, 2002; Heerklotz et al., 2003), we did experiments using DC18:1PC/bSM/Chol (1:1:1) mixtures, where there is coexistence of liquid-ordered and liquid-disordered domains (Veatch and Keller, 2005; Baumgart et al., 2007; Petruzielo et al., 2013). If gA forms conducting dimers in both the liquid-ordered and liquid-disordered domains that have different properties (i.e., stiffness), we would expect this to differentially alter gA single-channel properties, which would be observed as two populations of channels with different average lifetimes (τ). We observe only a single, kinetically homogeneous channel population, however (Fig. 5). The parsimonious interpretation of these results is that in the stiffer liquid-ordered domains is so much larger than in the liquid-disordered domains (e.g., Lundbæk et al., 2003) that we observe gA channel activity only in the liquid-disordered domains—and that the antiarrhythmics do not soften the liquid-ordered domains sufficiently to allow for channel formation.


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

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

Survivor single-channel lifetime histograms for gA(15) in DC18:1PC and DC18:1PC/bSM/Chol bilayers with single-exponential fits. There is no evidence for the existence of more than one population of channels in either membrane.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig5: Survivor single-channel lifetime histograms for gA(15) in DC18:1PC and DC18:1PC/bSM/Chol bilayers with single-exponential fits. There is no evidence for the existence of more than one population of channels in either membrane.
Mentions: Experiments in DC18:1PC bilayers yield unambiguous information that can be used to calculate changes in the bilayer deformation energy caused by reversible partitioning (Artigas et al., 2006; Andersen et al., 2007; Lundbæk et al., 2010a; Rusinova et al., 2011) of drugs without the complications of domain reorganization and heterogeneous phospholipid mixing that may confound the quantification of effects on more complex bilayers. The bilayers of cell membranes, however, have complex lipid compositions (Wenk, 2005; van Meer et al., 2008). To explore whether the antiarrhythmics alter bilayer properties in bilayers with heterogenous lipid composition, where their effects could be dampened or obscured (or, maybe, enhanced) by lipid redistribution and changes in domain organization (e.g., Heerklotz, 2002; Heerklotz et al., 2003), we did experiments using DC18:1PC/bSM/Chol (1:1:1) mixtures, where there is coexistence of liquid-ordered and liquid-disordered domains (Veatch and Keller, 2005; Baumgart et al., 2007; Petruzielo et al., 2013). If gA forms conducting dimers in both the liquid-ordered and liquid-disordered domains that have different properties (i.e., stiffness), we would expect this to differentially alter gA single-channel properties, which would be observed as two populations of channels with different average lifetimes (τ). We observe only a single, kinetically homogeneous channel population, however (Fig. 5). The parsimonious interpretation of these results is that in the stiffer liquid-ordered domains is so much larger than in the liquid-disordered domains (e.g., Lundbæk et al., 2003) that we observe gA channel activity only in the liquid-disordered domains—and that the antiarrhythmics do not soften the liquid-ordered domains sufficiently to allow for channel formation.

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