Vanoxerine: cellular mechanism of a new antiarrhythmic

Area of Science:

• Cardiovascular Pharmacology
• Electrophysiology
• Drug Discovery

Background:

• An unmet need exists for safe and effective antiarrhythmic drugs, particularly for atrial fibrillation.
• Vanoxerine, a novel compound, shows promise due to its lack of adverse cardiac events in preliminary studies.
• Its potent blockade of the hERG (hK(v)11.1) potassium channel warrants further investigation into its effects on other cardiac ion channels.

Purpose of the Study:

• To investigate the effects of Vanoxerine on cardiac calcium (Ca) and sodium (Na) currents.
• To determine if Vanoxerine affects transmural dispersion of repolarization.
• To evaluate Vanoxerine's potential as a safe and effective antiarrhythmic agent.

Main Methods:

• Whole-cell patch clamp electrophysiology was employed using cloned ion channels and isolated ventricular myocytes.
• Intracellular action potentials were recorded from canine ventricular wedge preparations and Purkinje fibers using sharp microelectrodes.

Main Results:

• Vanoxerine demonstrated potent blockade of hERG (hK(v)11.1) channels.
• Submicromolar concentrations of Vanoxerine blocked cardiac Ca and Na currents in a frequency-dependent manner.
• Vanoxerine did not significantly alter transmural action potential waveforms, QT interval, or transmural dispersion of repolarization in canine ventricular wedges.

Conclusions:

• Vanoxerine is a potent blocker of cardiac hERG, Na, and Ca channels, with frequency-dependent effects.
• The drug preserves transmural dispersion of ventricular repolarization, a favorable characteristic for antiarrhythmic therapy.
• Vanoxerine's multichannel blockade and repolarization uniformity profile, distinct from amiodarone's toxicity, suggest its potential as a safe and effective antiarrhythmic drug.