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Intracerebroventricular infusion of donepezil prevents cardiac remodeling and improves the prognosis of chronic heart failure rats.

ABSTRACT: Oral administration of donepezil, a centrally acting acetylcholinesterase inhibitor, improves the survival of rats with chronic heart failure (CHF). The mechanisms of cardioprotective effects of donepezil, however, remain totally unknown. To elucidate potential mechanisms, we examined whether central microinfusion of donepezil would exert cardioprotection. Intracerebroventricular microinfusion pumps with cerebroventricular cannula were implanted in rats with myocardial infarction. The rats were randomly divided into central saline treatment (CST) and central donepezil treatment (CDT) groups. We evaluated cardiac remodeling and function after a 6-week treatment and examined the 160-day survival rate. Compared to the CST, the CDT markedly improved the 160-day survival rate (68% vs. 32%, P?=?0.002) through the prevention of cardiac remodeling and the lowering of plasma catecholamine, brain natriuretic peptide, and angiotensin II. These results suggest that the central mechanism plays an important role in the cardioprotective effects of donepezil.

SUBMITTER: Li M

PROVIDER: S-EPMC7026239 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Intracerebroventricular infusion of donepezil prevents cardiac remodeling and improves the prognosis of chronic heart failure rats.

Li Meihua M Zheng Can C Kawada Toru T Inagaki Masashi M Uemura Kazunori K Sugimachi Masaru M

The journal of physiological sciences : JPS 20200217 1

Oral administration of donepezil, a centrally acting acetylcholinesterase inhibitor, improves the survival of rats with chronic heart failure (CHF). The mechanisms of cardioprotective effects of donepezil, however, remain totally unknown. To elucidate potential mechanisms, we examined whether central microinfusion of donepezil would exert cardioprotection. Intracerebroventricular microinfusion pumps with cerebroventricular cannula were implanted in rats with myocardial infarction. The rats were ...[more]

PMID: 32066375

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Project description:Acute heart failure (AHF) is characterized by inadequate cardiac output (CO), congestive symptoms, poor peripheral perfusion and end-organ dysfunction. Treatment often includes a combination of diuretics, oxygen, positive pressure ventilation, inotropes and vasodilators or vasopressors. Lactate is a marker of illness severity but is also an important metabolic substrate for the myocardium at rest and during stress. We tested the effects of half-molar sodium lactate infusion on cardiac performance in AHF.We conducted a prospective, randomised, controlled, open-label, pilot clinical trial in 40 patients fulfilling two of the following three criteria for AHF: (1) left ventricular ejection fraction <40%, (2) acute pulmonary oedema or respiratory failure of predominantly cardiac origin requiring mechanical ventilation and (3) currently receiving vasopressor and/or inotropic support. Patients in the intervention group received a 3 ml/kg bolus of half-molar sodium lactate over the course of 15 minutes followed by 1 ml/kg/h continuous infusion for 24 hours. The control group received only a 3 ml/kg bolus of Hartmann's solution without continuous infusion. The primary outcome was CO assessed by transthoracic echocardiography 24 hours after randomisation. Secondary outcomes included a measure of right ventricular systolic function (tricuspid annular plane systolic excursion (TAPSE)), acid-base balance, electrolyte and organ function parameters, along with length of stay and mortality.The infusion of half-molar sodium lactate increased (mean?±?SD) CO from 4.05?±?1.37 L/min to 5.49?±?1.9 L/min (P?<?0.01) and TAPSE from 14.7?±?5.5 mm to 18.3?±?7 mm (P?=?0.02). Plasma sodium and pH increased (136?±?4 to 146?±?6 and 7.40?±?0.06 to 7.53?±?0.03, respectively; both P?<?0.01), but potassium, chloride and phosphate levels decreased. There were no significant differences in the need for vasoactive therapy, respiratory support, renal or liver function tests, duration of ICU and hospital stay or 28- and 90-day mortality.Infusion of half-molar sodium lactate improved cardiac performance and led to metabolic alkalosis in AHF patients without any detrimental effects on organ function.Clinicaltrials.gov NCT01981655. Registered 13 August 2013.

Dataset Information

Intracerebroventricular infusion of donepezil prevents cardiac remodeling and improves the prognosis of chronic heart failure rats.

Publications

Intracerebroventricular infusion of donepezil prevents cardiac remodeling and improves the prognosis of chronic heart failure rats.

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