title: Donepezil markedly improves long-term survival in rats with chronic heart failure after extensive myocardial infarction.
abstract: BACKGROUND
  Vagal activation by electrical stimulation has been shown to improve the long-term survival of rats with chronic heart failure (CHF) after extensive myocardial infarction (MI). Acetylcholinesterase inhibition increases synaptic acetylcholine, and can disproportionately increase vagal tone. To develop an alternative therapy for CHF using a clinically available drug, the present study investigated whether oral donepezil, an acetylcholinesterase inhitor, could reproduce the beneficial effects of electrical vagal stimulation in rats.
  
  
  RESULTS
  At 2 weeks after ligation of the proximal left coronary artery, resulting in extensive MI, surviving rats were randomly assigned to donepezil-treated and untreated groups. Donepezil treatment started 14 days after MI significantly decreased the heart rate (325 ± 6 vs. 355 ± 10 beats/min, P<0.05) and improved 140-day survival (29% to 54%, P=0.03) by preventing pump failure (cardiac index: +29%, P<0.001; left ventricular+dp/dtmax: +18%, P<0.01; left ventricular end-diastolic pressue: -26%, P<0.01) and cardiac remodeling (biventricular weight: 2.73 ± 0.04 vs. 3.06 ± 0.08 g/kg, P<0.001). In addition, donepezil treatment lowered the levels of plasma arginine vasopressin, brain natriuretic peptide, catecholamine, and tissue pro-inflammation markers.
  
  
  CONCLUSIONS
  Oral donepezil markedly improved the long-term survival of CHF rats by preventing pump failure and cardiac remodeling, indicating that donepezil may be a new alternative therapy for CHF.
authors.affiliation: Department of Cardiovascular Dynamics, National Cerebral and Cardiovascular Center.
authors.forename: Meihua
authors.initials: M
authors.lastname: Li
authors.forename: Can
authors.initials: C
authors.lastname: Zheng
authors.forename: Toru
authors.initials: T
authors.lastname: Kawada
authors.forename: Masashi
authors.initials: M
authors.lastname: Inagaki
authors.forename: Kazunori
authors.initials: K
authors.lastname: Uemura
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Shishido
authors.forename: Masaru
authors.initials: M
authors.lastname: Sugimachi
mesh_terms: D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002908:Chronic Disease; D000077265:Donepezil; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D007189:Indans / Q000494:pharmacology*; D008297:Male; D009203:Myocardial Infarction / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil