Adding the acetylcholinesterase inhibitor, donepezil, to losartan treatment markedly improves long‐term survival in rats with chronic heart failure

Abstract

AimsModulation 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 resultsRats (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/dt max , 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.

The effects of acetylcholinesterase inhibitors on the heart in acute myocardial infarction and heart failure: From cells to patient reports

“…129,130 However, the mortality rate of heart failure patients remains high. 39 In that study, donepezil was added to losartan (ARB) and this combination decreased neurohumoral activation and adverse cardiac remodelling, improved cardiac function and increased survival in rats with heart failure compared to losartan alone. 39 In that study, donepezil was added to losartan (ARB) and this combination decreased neurohumoral activation and adverse cardiac remodelling, improved cardiac function and increased survival in rats with heart failure compared to losartan alone.…”

“…131 Novel therapeutic strategies involved in both RAS suppression and parasympathetic activation were demonstrated by Li and coworkers. 39 In addition, several reports demonstrated that exercise training to modulate vagal activity could provide greater efficacy when added to treatment with an AChE inhibitor as shown in experimental studies of heart failure. These findings suggested that AChE inhibitors may provide effects synergistic with conventional treatment in cases of heart failure to improve the outcome.…”

“…21 However, further clinical studies are needed to warrant its clinical use. [26][27][28][29][30][31][32][33][34][35][36][37][38][39] Despite its potential clinical benefits for CVDs patients, the role of AChE inhibitors in AMI and heart failure remediation remains unclear. 22,23 Use of AChE inhibitors is a non-invasive intervention which increases the parasympathetic activity.…”

Midodrine and Pyridostigmine; Novelties in Heart Failure Therapy

“…17 None of the studies involving pro-cholinergic agents in the treatment of heart failure have reached clinical application yet. [18][19][20][21][22] Pyridostigmine is a reversible acetylcholine esterase inhibitor, it augments the effect of the parasympathetic system. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] It is currently used in the treatment of myasthenia gravis.…”

Donepezil, a potential therapeutic agent for heart failure

“…We read with great interest the study by Li et al who demonstrated that the addition of donepezil prevented the deterioration of heart dysfunction and improved the longterm survival in rats with chronic heart failure (CHF) beyond that seen with losartan alone. 1 This suggested that combination treatment with losartan plus donepezil might be a potential therapeutic strategy for CHF.…”