Analysis of electropharmacological and proarrhythmic effects of donepezil using the halothane-anesthetized intact dogs and the conscious chronic atrioventricular block ones

• Published in: Naunyn-Schmiedeberg's archives of pharmacology Vol. 394; no. 4; pp. 581 - 589
• Main Authors: Hagiwara-Nagasawa, Mihoko, Kambayashi, Ryuichi, Goto, Ai, Nunoi, Yoshio, Izumi-Nakaseko, Hiroko, Chiba, Koki, Wada, Takeshi, Takei, Yoshinori, Matsumoto, Akio, Sugiyama, Atsushi
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-04-2021; Springer Nature B.V
• Subjects: Acetylcholinesterase; Alzheimer's disease; Biomedical and Life Sciences; Biomedicine; Blood pressure; Calcium; Cardiac arrhythmia; Central nervous system; Donepezil; Dosage; Halothane; Heart; Neurodegenerative diseases; Neurosciences; Original Article; Pharmacology/Toxicology; Tachycardia; Torsades de pointes; Ventricle; Sympathicotonia; Ventricular tachycardia; Chronic atrioventricular block dogs; Torsade de pointes; Donepezil; Halothane-anesthetized dogs
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-020-01997-w

Donepezil, an inhibitor for acetylcholinesterase used for patients with Alzheimer’s disease, has been shown to inhibit
I
Kr
, 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
I
Kr
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 Ca
2+
overload, triggering the ventricular arrhythmias, but might indirectly attenuate its
I
Kr
inhibitory action, preventing excessive repolarization delay.