Analysis of electropharmacological and proarrhythmic effects of donepezil using the halothane-anesthetized intact dogs a
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ORIGINAL ARTICLE
Analysis of electropharmacological and proarrhythmic effects of donepezil using the halothane-anesthetized intact dogs and the conscious chronic atrioventricular block ones Mihoko Hagiwara-Nagasawa 1 & Ryuichi Kambayashi 1 & Ai Goto 1 & Yoshio Nunoi 1 & Hiroko Izumi-Nakaseko 1 & Koki Chiba 1 & Takeshi Wada 1 & Yoshinori Takei 2 & Akio Matsumoto 3 & Atsushi Sugiyama 1,2,3 Received: 18 September 2020 / Accepted: 8 October 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Donepezil, an inhibitor for acetylcholinesterase used for patients with Alzheimer’s disease, has been shown to inhibit IKr, occasionally inducing torsade de pointes. In order to analyze the causal relationship between donepezil treatment and onset of lethal arrhythmias, we initially assessed electropharmacological effects of donepezil hydrochloride of 0.01, 0.1, and 1 mg/kg, i.v. over 10 min using the halothane-anesthetized intact dogs (n = 4), possibly providing subtherapeutic to supratherapeutic plasma concentrations. Although the low or middle dose did not exert any effect, the high dose transiently increased the ventricular refractoriness along with modest prolongation of the late repolarization period, indicating potential IKr inhibitory action in vivo. Moreover, the high dose induced the positive chronotropic, inotropic, and dromotropic actions along with the pressor effect and prolongation of early repolarization period, suggesting sympathicotonic condition in the central nervous system. Next, we examined proarrhythmic effects of donepezil hydrochloride of 0.1 and 1 mg/kg, i.v. over 10 min using the conscious chronic atrioventricular block dogs (n = 4). Although the low dose hardly affected the cardiovascular variables, the high dose increased the atrial and ventricular rate without significantly altering the repolarization period, possibly reflecting sympathicotonic condition. Importantly, the high dose induced non-sustained ventricular tachycardia in half of the animals. Thus, donepezil by itself did not induce torsade de pointes in vivo, which suggests that donepezil-induced sympathicotonic condition may induce Ca2+ overload, triggering the ventricular arrhythmias, but might indirectly attenuate its IKr inhibitory action, preventing excessive repolarization delay. Keywords Chronic atrioventricular block dogs . Donepezil . Halothane-anesthetized dogs . Sympathicotonia . Torsade de pointes . Ventricular tachycardia
Introduction Mihoko Hagiwara-Nagasawa and Ryuichi Kambayashi contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00210-020-01997-w) contains supplementary material, which is available to authorized users. * Atsushi Sugiyama [email protected] 1
Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan
2
Department of Translational Research & Cellular Therapeutics, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo
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