Vesnarinone prolongs action potential duration without reverse frequency dependence in rabbit ventricular muscle by...

Area of Science:

• Cardiology
• Pharmacology
• Electrophysiology

Background:

• Methanesulfonanilide derivatives inhibit the rapidly activating component of the delayed rectifier potassium current (I(Kr)).
• These inhibitors prolong action potential duration (APD) with reverse frequency dependence, limiting clinical use due to proarrhythmia.
• Vesnarinone, a cardiotonic agent, exhibits complex properties including I(K) reduction.

Purpose of the Study:

• To investigate the mechanism of I(K) block by vesnarinone.
• To compare vesnarinone's I(K) block kinetics with E-4031.
• To evaluate vesnarinone's effect on APD and frequency dependence in cardiac muscle.

Main Methods:

• Voltage-clamp experiments on rabbit ventricular myocytes.
• Assessing I(K) block development and recovery kinetics.
• Measuring APD in rabbit papillary muscles at various stimulation frequencies.

Main Results:

• Vesnarinone (3 µmol/L) showed monoexponential I(K) block development (361 ms) and recovery (1.87 s).
• E-4031 (0.3 µmol/L) exhibited instantaneous I(K) block with no recovery.
• Vesnarinone's I(K) block increased with frequency, prolonging APD at higher rates (>0.2 Hz), unlike E-4031.

Conclusions:

• Vesnarinone may prolong human cardiac repolarization without reverse frequency dependence.
• The I(K) channel, targeted by vesnarinone, is present in both rabbit and human hearts.
• Vesnarinone represents a potential model for an ideal Class III antiarrhythmic drug with reduced proarrhythmia risk.