Aim: Proarrhythmic potential of donepezil was analyzed. Methods: Exp.1: We infused 0.1 and 1 mg/kg, i.v. of donepezil hydrochloride to the chronic atrioventricular block dogs (n=4). Exp.2: We infused 0.01, 0.1 and 1 mg/kg, i.v. of the drug to the halothane-anesthetized dogs (n=4). Results: Exp.1: Low dose did not alter the variables. High dose increased ventricular rate, and induced non-sustained VT in 2 animals at 14-16 min, but TdP was not observed. Exp.2: Low dose did not affect the variables. Middle dose prolonged HV and QRS without altering the other variables. High dose increased heart rate, mean blood pressure, cardiac output, ventricular contraction, but decreased the preload to left ventricle and total peripheral resistance. The dose delayed the repolarization for 5-10 min, prolonged JTpeakc for 5-30 min, Tpeak-Tend at 5 min, HV for 5-15 min and refractory period at 5 min, but shortened AH at 15 and 30 min. Conclusion: The high dose would have increased adrenergic tone, indirectly stimulating Ca2+ channel, which may explain its effects on JTpeakc and AH, whereas it may also directly inhibit Na+ and K+ channels, increasing ventricular refractoriness. Thus, temporal discordance between direct and indirect actions may well explain proarrhythmic profile of donepezil.

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