Adding the Acetylcholinesterase Inhibitor, Donepezil, to Losartan Treatment Markedly Improves Long-Term Survival in Rats with Chronic Heart Failure

AIMS: Modulation of vagal tone using electrical vagal nerve stimulation or pharmacological acetylcholinesterase inhibition by donepezil exerts beneficial effects in an animal model of chronic heart failure (CHF). Considering different treatment mechanisms underlying renin-angiotensin system (RAS) suppression and parasympathetic activation, we hypothesized that parasympathetic activation together with RAS inhibition could attenuate CHF progression. To test this hypothesis, we investigated the therapeutic effects of a combination of donepezil and losartan in CHF rats with extensive myocardial infarction (MI). METHODS AND RESULTS: Rats (n = 85) that had survived extensive MI were implanted with a blood pressure transmitter and were randomly assigned to receive either a combination of donepezil and losartan (DLT group) or losartan alone (LT group). Compared with the LT group, the DLT group showed a significantly lower heart rate without hypotension. DLT therapy further improved 280-day overall survival relative to the LT group (31% vs. 8%, P = 0.022) by preventing cardiac dysfunction (LV dP/dtmax , 4064 ± 170 vs. 3430 ± 117 mmHg/s, P < 0.01; LV end-diastolic pressure, 17 ± 2 vs. 22 ± 2 mmHg, P < 0.05). DLT therapy was also associated with lower plasma BNP and catecholamine levels, lower cardiac angiotensin II concentrations, and higher capillary density in the peri-infarct region. CONCLUSIONS: Combined treatment with donepezil and losartan prevented the progression of cardiac dysfunction and improved the long-term survival of CHF rats with extensive MI, suggesting that this combination could be a novel pharmacotherapy for severe CHF.