Anti-Alzheimer's Drug, Donepezil, Markedly Improves Long-Term Survival After Chronic Heart Failure in Mice
Received 22 December 2008; received in revised form 17 April 2009; accepted 7 May 2009. published online 29 June 2009.
Abstract
Background
We previously reported that chronic vagal nerve stimulation markedly improved long-term survival after chronic heart failure (CHF) in rats through cardioprotective effects of acetylcholine, independent of the heart rate–slowing mechanism. However, such an approach is invasive and its safety is unknown in clinical settings. To develop an alternative therapy with a clinically available drug, we examined the chronic effect of oral donepezil, an acetylcholinesterase inhibitor against Alzheimer's disease, on cardiac remodeling and survival with a murine model of volume-overloaded CHF.
Methods and Results
Four weeks after surgery of aortocaval shunt, CHF mice were randomized into untreated and donepezil-treated groups. Donepezil was orally given at a dosage of 5 mg·kg−1·day−1. After 4 weeks of treatment, we evaluated in situ left ventricular (LV) pressure, ex vivo LV pressure-volume relationships, and LV expression of brain natriuretic peptides (BNP). We also observed survival for 50 days. When compared with the untreated group, the donepezil-treated group had significantly low LV end-diastolic pressure, high LV contractility, and low LV expression of BNP. Donepezil significantly reduced the heart weight and markedly improved the survival rate during the 50-day treatment period (54% versus 81%, P < .05).
Conclusions
Oral donepezil improves survival of CHF mice through prevention of pumping failure and cardiac remodeling.
1Department of Cardiovascular Control, Kochi Medical School, Nankoku, Japan
2Department of Cardiovascular Surgery, Kochi Medical School, Nankoku, Japan
3Department of Clinical Laboratory, Kochi Medical School, Nankoku, Japan
Correspondence to: Takemi Handa, Department of Cardiovascular Control, Kochi Medical School, Nankoku, Kochi 783-8505, Japan. Tel: (+81) 88-880-2309; Fax: (+81) 88-880-2310.
Supported by a grant-in-aid for scientific research (19659355) from the Ministry of Education, Science, Sports, and Culture of Japan, and by a Health and Labor Sciences research grant (H15-KOKORO-019, H16-NANO-005) from the Ministry of Health, Labor, and Welfare of Japan.
ABSTRACT