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

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.
• 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.