Donepezil, Therapeutic Acetylcholinesterase Inhibitor, Prevents the Progression of Ventricular Dysfunction by Promoting Myocardial Glucose Utilization in Rat Model of Chronic Heart Failure Following Myocardial Infarction

Mikihiko Arikawa, Yoshihiko Kakinuma, Tatsuya Noguchi and Takayuki Sato

Background: Donepezil, an acetylcholinesterase inhibitor, is reported to prevent cardiac pumping dysfunction in rats with chronic heart failure (CHF). Because energy substrate switching is a potential therapeutic target for the pharmacological treatment of CHF, we investigated the effect of donepezil on cardiac energy metabolism.

Methods and Results: After induction of myocardial infarction (MI), rats were assigned to untreated and donepezil-treated (DPZ) groups. At the chronic phase of MI, resting heart rate was comparable between the untreated and DPZ groups. Nevertheless, left ventricular contractility evaluated in Langendorff-perfused hearts was significantly improved by donepezil treatment. At the same time point, the expression level of cardiac glucose transporter (GLUT) was significantly higher in the DPZ group than in the untreated group. In vitro studies showed that cultured cardiomyocytes treated with donepezil expressed high levels of GLUT and also exhibited accelerated cellular glucose uptake. Moreover, the beating rate of DPZ cardiomyocytes was approximately 2-fold higher than that of untreated control cells. Fasentin, a glucose transporter inhibitor, nullified the effects of donepezil, indicating that donepezil increases cellular activity by promoting glucose utilization in cardiomyocytes.

Conclusion: The present study suggests that donepezil exhibits cardioprotective action by chronically modulating glucose metabolism in the failing heart.