Abstract 5938: Donepezil Markedly Suppresses Ventricular Dysfunction and Improves Neurohumoral States on Top of Losartan in Rats With Extensive Myocardial Infarction
Introduction: We have demonstrated that acetylcholinesterase inhibition by donepezil improved long-term survival of rats with chronic heart failure (CHF). It has been verified that losartan has beneficial effects on ventricular remodeling through specific angiotensin II receptor blockade. To develop a new pharmacotherapy for CHF, we examined if donepezil is effective in suppressing ventricular remodeling and dysfunction on top of the known effects of losartan in rats with extensive myocardial infarction (MI).
Methods: A blood pressure transmitter was implanted in 30 rats survived after extensive MI, which would develop severe CHF in 8 weeks (Cardiac index, 78±14 ml/min/kg). These rats were randomly assigned to the combination of donepezil (5 mg/kg/day) and losartan (increased from 10 mg/kg/day to 30 mg/kg/day) treated (DLT), or losartan alone treated (LT) groups. At the end of 6-week treatment, we evaluated hemodynamic parameters, neurohumoral states, and the capillary density in the peri-infarct area.
Results: Besides obvious effects of losartan, donepezil rats were significantly more bradycardiac (315±14 vs. 341±21bpm, p<0.05), but not more hypotensive. DLT prevented ventricular dysfunction (LV dp/dt max, +18%; Cardiac index, +44%; LVEDP, −23%). Additionally, DLT further decreased BNP, norepinephrine (NE), and cardiac angiotensin (Ang) II. Increased capillary density by donepezil may have contributed to these hemodynamic and neurohumoral improvements(Table⇓).
Conclusions: Donepezil and losartan cooperatively suppressed the progression of ventricular dysfunction in rats with extensive myocardial infarction through promoting the angiogenic potency and inhibiting the renin-angiotensin system, suggesting donepezil as a new candidate of additional drugs to combat severe CHF.