Li_2021_Cardiovasc.Drugs.Ther_35_877

PURPOSE: Pharmacological modulation of parasympathetic activity with donepezil, an acetylcholinesterase inhibitor, improves the long-term survival of rats with chronic heart failure (CHF) after myocardial infarction (MI). However, its mechanism is not well understood. The alpha7-nicotinic acetylcholine receptor (alpha7-nAChR) reportedly plays an important role in the cholinergic anti-inflammatory pathway. The purpose of this study was to examine whether blockade of alpha7-nAChR, either centrally or peripherally, affects cardioprotection by donepezil during CHF. METHODS: One-week post-MI, the surviving rats were implanted with an electrocardiogram or blood pressure transmitter to monitor hemodynamics continuously. Seven days after implantation, the MI rats (n=74) were administered donepezil in drinking water or were untreated (UT). Donepezil-treated MI rats were randomly assigned to the following four groups: peripheral infusion of saline (SPDT) or an alpha7-nAChR antagonist methyllycaconitine (alpha7PDT), and brain infusion of saline (SBDT) or the alpha7-nAChR antagonist (alpha7BDT). RESULTS: After the 4-week treatment, the role of alpha7-nAChR was evaluated using hemodynamic parameters, neurohumoral states, and histological and morphological assessment. Between the peripheral infusion groups, alpha7PDT (vs. SPDT) showed significantly increased heart weight and cardiac fibrosis, deteriorated hemodynamics, increased plasma neurohumoral and cytokine levels, and significantly decreased microvessel density (as assessed by anti-von Willebrand factor-positive cells). In contrast, between the brain infusion groups, alpha7BDT (vs. SBDT) showed no changes in either cardiac remodeling or hemodynamics. CONCLUSION: Peripheral blockade of alpha7-nAChR significantly attenuated the cardioprotective effects of donepezil in CHF rats, whereas central blockade did not. This suggests that peripheral activation of alpha7-nAChR plays an important role in cholinergic pharmacotherapy for CHF.