Cardiohemodynamic and Arrhythmogenic Effects of the Anti-Atrial Fibrillatory Compound Vanoxerine in Halothane-Anesthetiz
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Cardiohemodynamic and Arrhythmogenic Effects of the Anti‑Atrial Fibrillatory Compound Vanoxerine in Halothane‑Anesthetized Dogs Mihoko Hagiwara‑Nagasawa1 · Ryuichi Kambayashi1 · Ai Goto1 · Yoshio Nunoi1 · Hiroko Izumi‑Nakaseko1 · Yoshinori Takei2 · Akio Matsumoto3 · Atsushi Sugiyama1,2,3 Received: 2 May 2020 / Accepted: 10 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
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 C a2+ 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. Keywords Atrial fibrillation · Ikr · Torsade de pointes · Vanoxerine
Introduction
Handling Editor: Dakshesh Patel. Mihoko Hagiwara-Nagasawa and Ryuichi Kambayashi have equally contributed this work. * Atsushi Sugiyama [email protected]‑u.ac.jp 1
Faculty of Medicine, Department of Pharmacology, Toho University, 5‑21‑16 Omori‑nishi, Ota‑ku, Tokyo 143‑8540, Japan
2
Faculty of Medicine, Department of Translational Research & Cellular Therapeutics, Toho University, 5‑21‑16 Omori‑nishi, Ota‑ku, Tokyo 143‑8540, Japan
3
Faculty of Medicine, Department of Aging Pharmacology, Toho University, 5‑21‑16 Omori‑nishi, Ota‑ku, Tokyo 143‑8540, Japan
Vanoxerine (GBR-12909) is a potent synaptosomal dopamine uptake inhibitor with K i value of 1-9 nmol/L [1, 2]. Also, vanoxerine was reported to suppress IKr, ICa,L and INa with IC50 valu
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