TY - JOUR
T1 - Anti-Alzheimer's Drug, Donepezil, Markedly Improves Long-Term Survival After Chronic Heart Failure in Mice
AU - Handa, Takemi
AU - Katare, Rajesh G.
AU - Kakinuma, Yoshihiko
AU - Arikawa, Mikihiko
AU - Ando, Motonori
AU - Sasaguri, Shiro
AU - Yamasaki, Fumiyasu
AU - Sato, Takayuki
N1 - Funding Information:
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.
PY - 2009/11
Y1 - 2009/11
N2 - 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.
AB - 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.
KW - Acetylcholine
KW - heart failure
KW - survival
KW - vagus nerve
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U2 - 10.1016/j.cardfail.2009.05.008
DO - 10.1016/j.cardfail.2009.05.008
M3 - Article
C2 - 19879468
AN - SCOPUS:70350564898
SN - 1071-9164
VL - 15
SP - 805
EP - 811
JO - Journal of Cardiac Failure
JF - Journal of Cardiac Failure
IS - 9
ER -