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 (I(Ks)) and rapidly (I(Kr)) activating components of potassium current (I(K)). 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 (I(K1)), delayed rectifier potassium current (I(K)), ultrarapid delayed rectifier current (I(Kur)), and transient outward potassium current (I(to)) 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 microM 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 microM of azimilide for 10 minutes inhibited I(K) 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 I(Kur) was inhibited with 100 microM 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(to) in these cells was significantly inhibited with 100 microM 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 I(Ks) and I(Kur) 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.