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Cardiohemodynamic and Arrhythmogenic Effects of the Anti-Atrial Fibrillatory Compound Vanoxerine in Halothane-Anesthetized Dogs

Cardiovascular Toxicology volume 21, pages 206–215 (2021)Cite this article

Abstract

While vanoxerine (GBR-12909) is a synaptosomal dopamine uptake inhibitor, it also suppresses IKr, INa and ICa,L in vitro. Based on these profiles on ionic currents, vanoxerine has been developed as a candidate compound for treating atrial fibrillation. To investigate electropharmacological profiles, vanoxerine dihydrochloride was intravenously administered at 0.03 and 0.3 mg/kg to halothane-anesthetized dogs (n = 4), possibly providing subtherapeutic and therapeutic concentrations, respectively. The low dose increased the heart rate and cardiac output, whereas it prolonged the ventricular refractoriness. The high dose decreased the heart rate but increased the total peripheral vascular resistance, whereas it delayed the ventricular repolarization and increased the atrial refractoriness in addition to further enhancing the ventricular refractoriness. The extent of increase in the refractoriness in the atrium was 0.8 times of that in the ventricle. The high dose also prolonged the early and late repolarization periods of the ventricle as well as the terminal repolarization period. Meanwhile, no significant change was detected in the mean blood pressure, ventricular contraction, preload to the left ventricle, or the intra-atrial, intra-ventricular or atrioventricular conductions. The high dose can be considered to inhibit IKr, but it may not suppress INa or ICa in the in situ heart, partly explaining its poor atrial selectivity for increasing refractoriness. The prolongation of early repolarization period may reflect enhancement of net inward current, providing potential risk for intracellular Ca2+ overload. Thus, vanoxerine may provide both trigger and substrate toward torsade de pointes, which would make the drug less promising as an anti-atrial fibrillatory drug.

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Acknowledgements

The authors thank Mrs. Yuri Ichikawa for her technical assistance during preparation of the manuscript.

Funding

This study was supported in part by research grants from Japan Society for the Promotion of Science (JSPS KAKENHI grant number 19K16505).

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Author notes

  1. Mihoko Hagiwara-Nagasawa and Ryuichi Kambayashi have equally contributed this work.

Affiliations

  1. Faculty of Medicine, Department of Pharmacology, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan

    Mihoko Hagiwara-Nagasawa, Ryuichi Kambayashi, Ai Goto, Yoshio Nunoi, Hiroko Izumi-Nakaseko & Atsushi Sugiyama

  2. Faculty of Medicine, Department of Translational Research & Cellular Therapeutics, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan

    Yoshinori Takei & Atsushi Sugiyama

  3. Faculty of Medicine, Department of Aging Pharmacology, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan

    Akio Matsumoto & Atsushi Sugiyama

Authors
  1. Mihoko Hagiwara-Nagasawa
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  2. Ryuichi Kambayashi
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  3. Ai Goto
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  4. Yoshio Nunoi
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  5. Hiroko Izumi-Nakaseko
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  6. Yoshinori Takei
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  7. Akio Matsumoto
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  8. Atsushi Sugiyama
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Corresponding author

Correspondence to Atsushi Sugiyama.

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The authors declare no conflicts of interest.

Ethical Approval

All experiments were approved by the Toho University Animal Care and User Committee (Approval Number: 18-51-395 and 19-52-395) and performed according to the Guideline for the Care and Use of Laboratory Animals of Toho University.

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Hagiwara-Nagasawa, M., Kambayashi, R., Goto, A. et al. Cardiohemodynamic and Arrhythmogenic Effects of the Anti-Atrial Fibrillatory Compound Vanoxerine in Halothane-Anesthetized Dogs. Cardiovasc Toxicol 21, 206–215 (2021). https://doi.org/10.1007/s12012-020-09612-3

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  • DOI: https://doi.org/10.1007/s12012-020-09612-3

Keywords

  • Atrial fibrillation
  • I kr
  • Torsade de pointes
  • Vanoxerine