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

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.

• Authors: Mihoko Hagiwara-Nagasawa, Ryuichi Kambayashi, Ai Goto, Yoshio Nunoi, Hiroko Izumi-Nakaseko, Yoshinori Takei, Akio Matsumoto, Atsushi Sugiyama
• Journal: Cardiovascular toxicology (Cardiovasc Toxicol) Vol. 21 Issue 3 Pg. 206-215 (03 2021) ISSN: 1559-0259 [Electronic] United States
• PMID: 33074476 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anesthetics, Inhalation
• Anti-Arrhythmia Agents
• Dopamine Uptake Inhibitors
• Piperazines
• vanoxerine
• Halothane

Topics

• Action Potentials (drug effects)
• Anesthesia, Inhalation
• Anesthetics, Inhalation
• Animals
• Anti-Arrhythmia Agents (toxicity)
• Atrial Fibrillation (drug therapy, metabolism, physiopathology)
• Dogs
• Dopamine Uptake Inhibitors (toxicity)
• Female
• Halothane
• Heart Conduction System (drug effects, metabolism, physiopathology)
• Heart Rate (drug effects)
• Piperazines (toxicity)
• Refractory Period, Electrophysiological (drug effects)
• Risk Assessment
• Time Factors
• Torsades de Pointes (chemically induced, metabolism, physiopathology)