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Vanoxerine: Cellular Mechanism of a New Antiarrhythmic

Authors


  • The research described in this report was supported in part by NIH grant R44 HL067503 and ChanTest Corporation.

  • Antonio E. Lacerda and Yuri A. Kuryshev are employed at ChanTest Corporation, which holds a use patent on vanoxerine. Dr. Brown is coinventor listed on the patent and majority owner of ChanTest. Dr. Waldo reports participation in research grants supported by CV Therapeutics and Sequel Pharmaceuticals; compensation for participation in a speaker's bureau relevant to this topic from GlaxoSmithKline; honoraria from Sanofi-Aventis and participation on the advisory board for dronedarone.

Address for correspondence: Antonio E. Lacerda, Ph.D., ChanTest Corporation, 14656 Neo Parkway, Cleveland, OH 44128. Fax: 216-332-1706; E-mail: alacerda@chantest.com

Abstract

Cellular Electrophysiology of Vanoxerine. Introduction: There remains an unmet need for safe and effective antiarrhythmic drugs, especially for the treatment of atrial fibrillation. Vanoxerine is a drug that is free of adverse cardiac events in normal volunteers, yet is a potent blocker of the hERG (hKv11.1) cardiac potassium channel. Consequently,we hypothesized that vanoxerine might also be a potent blocker of cardiac calcium (Ca) and sodium (Na) currents, and would not affect transmural dispersion of repolarization.

Methods: The whole cell patch clamp technique was used to measure currents from cloned ion channels overexpressed in stable cell lines and single ventricular myocytes. We measured intracellular action potentials from canine ventricular wedges and Purkinje fibers using sharp microelectrode technique.

Results: We found that vanoxerine was a potent hKv11.1 blocker, and at submicromolar concentrations, it blocked Ca and Na currents in a strongly frequency-dependent manner. In the canine ventricular wedge preparation vanoxerine did not significantly affect transmural action potential waveforms, QT interval or transmural dispersion of repolarization.

Conclusions: Vanoxerine (1) is a potent blocker of cardiac hERG, Na and Ca channels; (2) block is strongly frequency-dependent especially for Na and Ca channels; and (3) transmural dispersion of ventricular repolarization is unaffected. The multichannel block and repolarization uniformity resemble the effects of amiodarone, the exemplar atrial fibrillation drug. Vanoxerine is a completely different chemical and has none of amiodarone's toxic effects. Vanoxerine has characteristics of a potentially effective and safe antiarrhythmic. (J Cardiovasc Electrophysiol, Vol. 21, pp. 301–310, March 2010)

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