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Impact of Peripheral α7-Nicotinic Acetylcholine Receptors on Cardioprotective Effects of Donepezil in Chronic Heart Failure Rats

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Abstract

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 α7-nicotinic acetylcholine receptor (α7-nAChR) reportedly plays an important role in the cholinergic anti-inflammatory pathway. The purpose of this study was to examine whether blockade of α7-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 α7-nAChR antagonist methyllycaconitine (α7PDT), and brain infusion of saline (SBDT) or the α7-nAChR antagonist (α7BDT).

Results

After the 4-week treatment, the role of α7-nAChR was evaluated using hemodynamic parameters, neurohumoral states, and histological and morphological assessment. Between the peripheral infusion groups, α7PDT (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, α7BDT (vs. SBDT) showed no changes in either cardiac remodeling or hemodynamics.

Conclusion

Peripheral blockade of α7-nAChR significantly attenuated the cardioprotective effects of donepezil in CHF rats, whereas central blockade did not. This suggests that peripheral activation of α7-nAChR plays an important role in cholinergic pharmacotherapy for CHF.

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Availability of Data and Material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This study was partly supported by JSPS KAKENHI (Grant Number: 17K09544, 18K08091).

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Authors and Affiliations

  1. Department of Cardiovascular Dynamics, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka, 564-8565, Japan

    Meihua Li, Can Zheng, Toru Kawada, Masashi Inagaki, Kazunori Uemura & Masaru Sugimachi

  2. Department of Cardiac Physiology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan

    Tsuyoshi Akiyama

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  1. Meihua Li
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  2. Can Zheng
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Contributions

ML and CZ designed the study. ML and CZ performed the measurements and statistical analyses and drafted the manuscript. TK, MI, KU, TA, and MS joined in interpreting the data. ML and CZ wrote and edited, while TK and MS reviewed the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Meihua Li.

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The authors declare that they have no conflict of interest.

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The care of animals and all animal experiments were performed in strict accordance with the guiding principles of the Physiological Society of Japan and the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publications No 85-23, revised 1996). All protocols were reviewed and approved by the Animal Subject Committee in the National Cerebral and Cardiovascular Center.

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Li, M., Zheng, C., Kawada, T. et al. Impact of Peripheral α7-Nicotinic Acetylcholine Receptors on Cardioprotective Effects of Donepezil in Chronic Heart Failure Rats. Cardiovasc Drugs Ther 35, 877–888 (2021). https://doi.org/10.1007/s10557-020-07062-1

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