Donepezil as a novel therapy for suppressing the progression of cardiovascular remodeling in obesity-induced hypertensive rats with reperfused myocardial infarction. (25th November 2020)

• Record Type: Journal Article
• Authors: Li, M; Zheng, C; Kawada, T; Inagaki, M; Uemura, K; Sugimachi, M
• Is Part Of: European heart journal. Volume 41:(2020)Supplement 2
• Publication Date: 2020-11-25
• Subjects: Acute Heart Failure: Pharmacotherapy; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/ehjci/ehaa946.1227
• Languages: English
• ISSNs: 0195-668X

Abstract

Abstract: Introduction: Acetylcholinesterase inhibition by donepezil has been shown to improve long-term survival in permanent myocardial infarction (MI)-induced chronic heart failure rats. This study examined whether donepezil is applicable to the treatment of obesity-induced hypertension with reperfused MI (RMI). Methods: Four-week-old SD rats were fed a high-fat diet (57% kcal as fat) for 15 weeks. We implanted a blood pressure (BP) telemetry into the animals (8-week-old) for monitoring artery pressure. After a 1-week recovery, RMI was created by occluding the left coronary artery (30min) followed by reperfusion. Surviving animals were randomly assigned to untreated (UT, n=16) or donepezil treated (DT, n=16, 3 mg/kg/day) group. After a 10-week treatment, the effects of donepezil were evaluated by hemodynamics, blood biomarkers, immunohistochemistry, and morphology. Results: The high-fat diet caused obesity and hypertension (9-week-old: systolic BP = 134±4 mmHg; diastolic BP = 92±2 mmHg) in the normal rats. Compared with UT, DT significantly decreased the heart rate (296±5 vs. 318±8 bpm, P<0.05). DT significantly prevented the progression of cardiac remodeling and dysfunction [cardiac index: 91±4 vs. 73±9 ml/min/kg, P<0.01; left ventricular (LV) end-diastolic pressure: 11±1 vs. 20±2 mmHg, P<0.01; LV dp/dt max: 5347±206 vs. 3637±433 mmHg/sec, P<0.01], through increasing capillary density (+120%/field, P<0.001), reducing cardiac fibrosis (−50%, P<0.01) and myocardial infarcted area (17±2 vs. 24±2%, P<0.05), suppressing cardiac hypertrophy (2.35±0.04 vs. 2.70±0.14 g/kg, P<0.01) and coronary artery remodeling (wall thickness: 30±1 vs. 37±2 mm, P<0.01; media-to-lumen ratio: 2.3±0.2 vs. 6.2±1.6, P<0.001). Additionally, DT not only decreased plasma levels of insulin, norepinephrine, BNP, angiotensin II, but also improved the systemic inflammation. Conclusions: Donepezil treatment significantly suppressed the progression of cardiovascular remodeling and dysfunction following RMI in obesity-induced hypertensive rats, suggesting that donepezil may be used as a potential candidate for post-RMI therapy in obesity-induced hypertensive patients. Funding Acknowledgement: Type of funding source: None