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Donepezil attenuates progression of cardiovascular remodeling and improves prognosis in spontaneously hypertensive rats with chronic myocardial infarction

Hypertension Research volume 47, pages 1298–1308 (2024)Cite this article

Abstract

The acetylcholinesterase inhibitor donepezil restores autonomic balance, reduces inflammation, and improves long-term survival in rats with chronic heart failure (CHF) following myocardial infarction (MI). As arterial hypertension is associated with a significant risk of cardiovascular death, we investigated the effectiveness of donepezil in treating CHF in spontaneously hypertensive rats (SHR). CHF was induced in SHR by inducing permanent MI. After 2 weeks, the surviving SHR were randomly assigned to sham-operated (SO), untreated (UT), or oral donepezil-treated (DT, 5 mg/kg/day) groups, and various vitals and parameters were monitored. After 7 weeks of treatment, heart rate and arterial hypertension reduced significantly in DT rats than in UT rats. Donepezil treatment improved 50-day survival (41% to 80%, P = 0.004); suppressed progression of cardiac hypertrophy, cardiac dysfunction (cardiac index: 133 ± 5 vs. 112 ± 5 ml/min/kg, P < 0.05; left ventricular end-diastolic pressure: 12 ± 3 vs. 22 ± 2 mmHg, P < 0.05; left ventricular +dp/dtmax: 5348 ± 338 vs. 4267 ± 114 mmHg/s, P < 0.05), systemic inflammation, and coronary artery remodeling (wall thickness: 26.3 ± 1.4 vs. 34.7 ± 0.7 μm, P < 0.01; media-to-lumen ratio: 3.70 ± 0.73 vs. 8.59 ± 0.84, P < 0.001); increased capillary density; and decreased plasma catecholamine, B-type natriuretic peptide, arginine vasopressin, and angiotensin II levels. Donepezil treatment attenuated cardiac and coronary artery remodeling, mitigated cardiac dysfunction, and significantly improved the prognosis of SHR with CHF.

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Data availability

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

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Funding

This study was partly supported by JSPS KAKENHI (grant numbers 26461099, 26430103, 20K20622, 22K08222), the research program of the Japan Agency for Medical Research and Development (22ama121050j0001), the Research Program of the Ministry of Internal Affairs and Communications (SCOPE: JP225006004), the Intramural Research Fund for Cardiovascular Diseases of the National Cerebral and Cardiovascular Center (21-2-7, 21-2-9), a research grant from JST (JPMJPF2018), and the research grant from NTT Research, Inc. The authors confirm that the funders did not influence the study design, contents of the article, or selection of this journal.

Author information

Authors and Affiliations

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

    Meihua Li, Can Zheng, Toru Kawada, Shohei Yokota, Hiroki Matsushita & Keita Saku

  2. New Business Development Group, Business Planning Department, Sanyo Chemical Industries, LTD, Kyoto, Japan

    Can Zheng

  3. Bio Digital Twin Center, National Cerebral and Cardiovascular Center, Osaka, 564–8565, Japan

    Kazunori Uemura & Keita Saku

Authors
  1. Meihua Li
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  2. Can Zheng
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Contributions

Meihua Li and Can Zheng designed and performed the experiments. Meihua Li performed the statistical analyses and drafted the first manuscript. Toru Kawada, Kazunori Uemura, Shohei Yokota, Hiroki Matsushita, and Keita Saku interpreted the results. Toru Kawada and Keita Saku edited and reviewed the manuscript. All authors commented on the previous versions of the manuscript and read and approved the final manuscript.

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Correspondence to Meihua Li.

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Ethics approval and consent to participate

Animal care protocols and all experiments were performed in strict accordance with the Guiding Principles for the Care and Use of Animals in the Field of Physiological Science, which was approved by the Physiological Society of Japan. All protocols were reviewed and approved by the Animal Subject Committee of the National Cerebral and Cardiovascular Center (#15004 and #16002).

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The authors declare no competing interests.

Research involving human participants and/or animals

This study did not involve human participants. The Animal Subject Committee of the National Cerebral and Cardiovascular Center has approved the animal experiments.

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Li, M., Zheng, C., Kawada, T. et al. Donepezil attenuates progression of cardiovascular remodeling and improves prognosis in spontaneously hypertensive rats with chronic myocardial infarction. Hypertens Res 47, 1298–1308 (2024). https://doi.org/10.1038/s41440-024-01629-3

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