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Azimilide Inhibits Multiple Cardiac Potassium Currents in Human Atrial Myocytes

Azimilide Inhibits Multiple Cardiac Potassium Currents in Human Atrial Myocytes Background: Studies in animal cell preparations suggest that azimilide may produce a more desirable rate-dependent profile of class III action as a result of its effects on both the slowly (IKS) and rapidly (I cr) activating components of potassium current (IK). However, relatively little is known about the effects of azimilide on K+ currents in human atrial cells. The present study investigated the effect of azimilide on the inward rectifier potassium current (IKI), delayed rectifier potassium current (IK), ultrarapid delayed rectifier current (IKJ,), and transient outward potassium current (Ito) in isolated single human atrial myocytes.Methods: The tight-seal, whole-cell voltage clamp technique was used to investigate the acute effects of azimilide on K+ currents in single human atrial myocytes. The cells were isolated enzymatically from atrial tissues that were obtained from patients undergoing open heart surgeries, with the approval of the local Institutional Review Board.Results: The average cell capacitance of the human atrial myocytes was 77.5 ± 2.8 pF (Mean ± standard error of mean, total 28 cells from 17 patients). We found that 100,uM of azimilide in the extracellular solution significantly inhibited the inward rectifier potassium current (12.3 ± 3.1 vs 6.7 ± 2.0 pA/pF, n = 12, P < 0.05) at the testing potential of -100 mV. Superfusion with 100,uM of azimilide for 10 minutes inhibited IK by 51.7 ± 5.1% (from 3.4 ± 0.5 to 1.6 ± 0.2 pA/pF, n = 9, P < 0.01) at the clamping membrane potential of +40 mV. Human atrial cell IK, was inhibited with 100 jM of azimilide by 38.6 ± 4.4% (from 3.9 ± 0.5 to 2.3 ± 0.2 pA/pF, n = 9, P < 0.01, test potential = 40 mV). We also found that the average peak current amplitude of I,. in these cells was significantly inhibited with 100,uM of azimilide by 60.3 ± 5.9% (from 10.3 ± 1.5 to 3.6 ± 0.3 pA/pF, n = 6, P < 0.01, test potential = 50 mV).Conclusion: The present study provides direct evidence that azimilide inhibits multiple cellular transmembrane K+ currents in freshly isolated human atrial myocytes. Inhibition of these K+ currents by azimilide, especially of IKS and IKu, is likely to be the electrophysiologic basis for the prolongation of the action potential duration in the human atria which mediates its known antifibrillatory effects in atrial fibrillation and flutter. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Cardiovascular Pharmacology and Therapeutics SAGE

Azimilide Inhibits Multiple Cardiac Potassium Currents in Human Atrial Myocytes

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References (18)

Publisher
SAGE
Copyright
Copyright © by SAGE Publications
ISSN
1074-2484
eISSN
1940-4034
DOI
10.1177/107424840200700409
pmid
12490972
Publisher site
See Article on Publisher Site

Abstract

Background: Studies in animal cell preparations suggest that azimilide may produce a more desirable rate-dependent profile of class III action as a result of its effects on both the slowly (IKS) and rapidly (I cr) activating components of potassium current (IK). However, relatively little is known about the effects of azimilide on K+ currents in human atrial cells. The present study investigated the effect of azimilide on the inward rectifier potassium current (IKI), delayed rectifier potassium current (IK), ultrarapid delayed rectifier current (IKJ,), and transient outward potassium current (Ito) in isolated single human atrial myocytes.Methods: The tight-seal, whole-cell voltage clamp technique was used to investigate the acute effects of azimilide on K+ currents in single human atrial myocytes. The cells were isolated enzymatically from atrial tissues that were obtained from patients undergoing open heart surgeries, with the approval of the local Institutional Review Board.Results: The average cell capacitance of the human atrial myocytes was 77.5 ± 2.8 pF (Mean ± standard error of mean, total 28 cells from 17 patients). We found that 100,uM of azimilide in the extracellular solution significantly inhibited the inward rectifier potassium current (12.3 ± 3.1 vs 6.7 ± 2.0 pA/pF, n = 12, P < 0.05) at the testing potential of -100 mV. Superfusion with 100,uM of azimilide for 10 minutes inhibited IK by 51.7 ± 5.1% (from 3.4 ± 0.5 to 1.6 ± 0.2 pA/pF, n = 9, P < 0.01) at the clamping membrane potential of +40 mV. Human atrial cell IK, was inhibited with 100 jM of azimilide by 38.6 ± 4.4% (from 3.9 ± 0.5 to 2.3 ± 0.2 pA/pF, n = 9, P < 0.01, test potential = 40 mV). We also found that the average peak current amplitude of I,. in these cells was significantly inhibited with 100,uM of azimilide by 60.3 ± 5.9% (from 10.3 ± 1.5 to 3.6 ± 0.3 pA/pF, n = 6, P < 0.01, test potential = 50 mV).Conclusion: The present study provides direct evidence that azimilide inhibits multiple cellular transmembrane K+ currents in freshly isolated human atrial myocytes. Inhibition of these K+ currents by azimilide, especially of IKS and IKu, is likely to be the electrophysiologic basis for the prolongation of the action potential duration in the human atria which mediates its known antifibrillatory effects in atrial fibrillation and flutter.

Journal

Journal of Cardiovascular Pharmacology and Therapeutics – SAGE

Published: Dec 1, 2002

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