Effect of the cholinesterase inhibitor donepezil on cardiac remodeling and autonomic balance in rats with heart failure.

In an earlier study we demonstrated the beneficial effect of direct vagal electrical stimulation on cardiac remodeling and survival. In the study reported here, we attempted to reproduce the effect of vagal enhancement through the administration of an acetylcholinesterase inhibitor, donepezil. A rat model of heart failure following extensive healed myocardial infarction was used. Compared to their nontreated counterparts, rats given donepezil (5 mg/kg/day) in their drinking water had a smaller biventricular weight (3.40 +/- 0.13 vs. 3.02 +/- 0.21 g/kg body weight, P < 0.05), and maximal rate of rise (3256 +/- 955 vs. 3822 +/- 389 mmHg/s, P < 0.05) and the end-diastolic value (30.1 +/- 5.6 vs. 23.2 +/- 5.7 mmHg, P < 0.05) of left ventricular pressure were improved. Neurohumoral factors were suppressed in donepezil-treated rats (norepinephrine 1885 +/- 1423 vs. 316 +/- 248 pg/ml, P < 0.01; brain natriuretic peptide 457 +/- 68 vs. 362 +/- 80 ng/ml, P < 0.05), and the high-frequency component of heart rate variability showed a nocturnal increase. These findings indicated that donepezil reproduced the anti-remodeling effect of electrical vagal stimulation. Further studies are warranted to evaluate the clinical usefulness of donepezil in heart failure.