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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 increase gA single-channel activity and decrease the bilayer deformation energy (). (A) gA single-channel traces without (top row) and with (bottom row) the antiarrhythmics at the indicated concentrations; red and blue dashed lines indicate the average gA−(13) and gA(15) single-channel current amplitudes. (B) Changes in  which were estimated from the ratio of the time-averaged number of gA channels in the presence (τdrug · fdrug) and absence (τ · f) of the antiarrhythmic (compare Eq. 4). Blue symbols denote results for gA(15) channels, and red symbols denote results for gA−(13) channels. Error bars represent mean ± SD, if n ≥ 3; mean ± range/2, if n = 2.
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fig3: Antiarrhythmics increase gA single-channel activity and decrease the bilayer deformation energy (). (A) gA single-channel traces without (top row) and with (bottom row) the antiarrhythmics at the indicated concentrations; red and blue dashed lines indicate the average gA−(13) and gA(15) single-channel current amplitudes. (B) Changes in which were estimated from the ratio of the time-averaged number of gA channels in the presence (τdrug · fdrug) and absence (τ · f) of the antiarrhythmic (compare Eq. 4). Blue symbols denote results for gA(15) channels, and red symbols denote results for gA−(13) channels. Error bars represent mean ± SD, if n ≥ 3; mean ± range/2, if n = 2.

Mentions: All the antiarrhythmics increased τ and f (Figs. 3 A and S1, and Table 2). The initial experiments with amiodarone showed a time-dependent increase in channel activity (Fig. S4), which we surmised might be caused by the iodine in amiodarone. We therefore did experiments in which we added Na2S2O3, which reduces I2 to I− (Finkelstein and Cass, 1968), together with the amiodarone. Na2S2O3 did indeed abolish the time-dependent increase in channel activity (lifetime), but the effect of amiodarone could not be mimicked by adding I2 (Fig. S4, legend). In any case, all the experiments with amiodarone were done in the presence of 50 µM Na2S2O3. Dronedarone and amiodarone produced larger changes in τ and f for the shorter gA−(13) channels, as compared with the longer gA(15) channels; within experimental error, propranolol and pindolol produced similar changes in τ and f for both channels (Table 2 and Fig. S1).


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

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

Antiarrhythmics increase gA single-channel activity and decrease the bilayer deformation energy (). (A) gA single-channel traces without (top row) and with (bottom row) the antiarrhythmics at the indicated concentrations; red and blue dashed lines indicate the average gA−(13) and gA(15) single-channel current amplitudes. (B) Changes in  which were estimated from the ratio of the time-averaged number of gA channels in the presence (τdrug · fdrug) and absence (τ · f) of the antiarrhythmic (compare Eq. 4). Blue symbols denote results for gA(15) channels, and red symbols denote results for gA−(13) channels. Error bars represent mean ± SD, if n ≥ 3; mean ± range/2, if n = 2.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig3: Antiarrhythmics increase gA single-channel activity and decrease the bilayer deformation energy (). (A) gA single-channel traces without (top row) and with (bottom row) the antiarrhythmics at the indicated concentrations; red and blue dashed lines indicate the average gA−(13) and gA(15) single-channel current amplitudes. (B) Changes in which were estimated from the ratio of the time-averaged number of gA channels in the presence (τdrug · fdrug) and absence (τ · f) of the antiarrhythmic (compare Eq. 4). Blue symbols denote results for gA(15) channels, and red symbols denote results for gA−(13) channels. Error bars represent mean ± SD, if n ≥ 3; mean ± range/2, if n = 2.
Mentions: All the antiarrhythmics increased τ and f (Figs. 3 A and S1, and Table 2). The initial experiments with amiodarone showed a time-dependent increase in channel activity (Fig. S4), which we surmised might be caused by the iodine in amiodarone. We therefore did experiments in which we added Na2S2O3, which reduces I2 to I− (Finkelstein and Cass, 1968), together with the amiodarone. Na2S2O3 did indeed abolish the time-dependent increase in channel activity (lifetime), but the effect of amiodarone could not be mimicked by adding I2 (Fig. S4, legend). In any case, all the experiments with amiodarone were done in the presence of 50 µM Na2S2O3. Dronedarone and amiodarone produced larger changes in τ and f for the shorter gA−(13) channels, as compared with the longer gA(15) channels; within experimental error, propranolol and pindolol produced similar changes in τ and f for both channels (Table 2 and Fig. S1).

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