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A New Class III Antiarrhythmic Drug Niferidil Prolongs Action Potentials in Guinea Pig Atrial Myocardium via Inhibition of Rapid Delayed Rectifier

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Abstract

Purpose

A new class III antiarrhythmic drug niferidil (RG-2) has been introduced as a highly effective therapy for cases of persistent atrial fibrillation, but ionic mechanisms of its action are poorly understood. In the present study, the effects of niferidil on action potential (AP) waveform and potassium currents responsible for AP repolarization were investigated in guinea pig atrial myocardium.

Methods

APs were recorded with sharp glass microelectrodes in multicellular atrial preparations. Whole-cell patch-clamp technique was used to measure K+ currents in isolated myocytes.

Results

In multicellular atrial preparations, 10−8 M niferidil effectively prolonged APs by 15.2 ± 2.8% at 90% repolarization level. However, even the highest tested concentrations, 10−6 M and 10−5 M failed to prolong APs more than 32.5% of control duration. The estimated concentration of niferedil for half-maximal AP prolongation was 1.13 × 10−8 M. Among the potassium currents responsible for AP repolarization phase, I K1 was found to be almost insensitive to niferidil. However, another inward rectifier, I KACh, was effectively suppressed by micromolar concentrations of niferidil with IC50 = 9.2 × 10−6 M. I KATP was much less sensitive to the drug with IC50 = 2.26 × 10−4 M. The slow component of delayed rectifier, I Ks, also demonstrated low sensitivity to niferidil—the highest used concentration, 10−4 M, decreased peak I Ks density to 46.2 ± 5.5% of control. Unlike I Ks, the rapid component of delayed rectifier, I Kr, appeared to be extremely sensitive to niferidil. The IC50 was 1.26 × 10−9 M. I Kr measured in ventricular myocytes was found to be less sensitive to niferidil with IC50 = 3.82 × 10−8 M.

Conclusions

Niferidil prolongs APs in guinea pig atrial myocardium via inhibition of I Kr.

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Funding

The study was funded by the Russian Science Foundation (grant number 14-15-00268).

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Authors and Affiliations

  1. Lomonosov Moscow State University, Moscow, Russia

    Denis V. Abramochkin & Vladislav S. Kuzmin

  2. Pirogov Russian National Research Medical University, Moscow, Russia

    Denis V. Abramochkin & Vladislav S. Kuzmin

  3. Department of Human and Animal Physiology, Moscow State University, Leninskije Gory, 1, 12, Moscow, Russia

    Denis V. Abramochkin

  4. Institute of Experimental Cardiology, Moscow, Russia

    Vladislav S. Kuzmin & Leonid V. Rosenshtraukh

Authors
  1. Denis V. Abramochkin
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  2. Vladislav S. Kuzmin
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  3. Leonid V. Rosenshtraukh
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Corresponding author

Correspondence to Denis V. Abramochkin.

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The authors declare that they have no conflict of interest.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

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Abramochkin, D.V., Kuzmin, V.S. & Rosenshtraukh, L.V. A New Class III Antiarrhythmic Drug Niferidil Prolongs Action Potentials in Guinea Pig Atrial Myocardium via Inhibition of Rapid Delayed Rectifier. Cardiovasc Drugs Ther 31, 525–533 (2017). https://doi.org/10.1007/s10557-017-6762-x

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  • DOI: https://doi.org/10.1007/s10557-017-6762-x

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