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Related Experiment Videos

Azimilide causes reverse rate-dependent block while reducing both components of delayed-rectifier current in canine

G A Gintant1

  • 1Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan, USA.

Journal of Cardiovascular Pharmacology
|June 26, 1998
PubMed
Summary

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Therapeutic concentrations of azimilide comparably reduce canine ventricular rapidly activating delayed-rectifier current (IKr) and slowly activating delayed-rectifier current (IKs). This antiarrhythmic drug exhibits reverse rate-dependent effects on action potential duration.

Area of Science:

  • Cardiovascular Pharmacology
  • Electrophysiology
  • Cardiac Ion Channels

Background:

  • Class III antiarrhythmic drugs typically target the rapidly activating delayed-rectifier potassium current (IKr).
  • Azimilide (NE-10064) has shown complex effects on IKr and IKs, with reported enhancement at low concentrations and blockade at higher concentrations.
  • Understanding azimilide's precise electrophysiologic actions is crucial for its clinical application.

Purpose of the Study:

  • To investigate the effects of azimilide on IKr and IKs in canine ventricular myocytes.
  • To evaluate the impact of azimilide on action potential duration (APD) and its rate-dependent properties.
  • To clarify the concentration-dependent electrophysiologic profile of azimilide.

Main Methods:

  • Whole-cell patch-clamp techniques to measure IKr and IKs.

Related Experiment Videos

  • Microelectrode and perforated-patch techniques to record action potentials.
  • Assessment of azimilide's effects at nanomolar (50 nM) and micromolar (2 microM) concentrations.

    • Main Results:

    • A therapeutic concentration (2 microM) of azimilide equally reduced IKr and IKs by approximately 40% and tail currents by 38% and 33%, respectively.
    • Low concentration (50 nM) azimilide did not enhance IKs.
    • High concentration azimilide delayed repolarization and induced reverse rate-dependent effects on APD, particularly in myocytes with steep APD-rate relationships.

    Conclusions:

    • Therapeutic azimilide concentrations cause comparable blockade of canine ventricular IKr and IKs.
    • Azimilide exhibits reverse rate-dependent effects on action potential duration, influenced by the baseline APD-rate relationship.
    • These findings provide insight into the electrophysiologic mechanisms underlying azimilide's antiarrhythmic potential.