Early donepezil monotherapy or combination with metoprolol significantly prevents subsequent chronic heart failure in rats with reperfused myocardial infarction

Abstract

Despite the presence of clinical guidelines recommending that β-blocker treatment be initiated early after reperfused myocardial infarction (RMI), acute myocardial infarction remains a leading cause of chronic heart failure (CHF). In this study, we compared the effects of donepezil, metoprolol, and their combination on the progression of cardiac remodeling in rats with RMI. The animals were randomly assigned to untreated (UT), donepezil-treated (DT), metoprolol-treated (MT), and a combination of donepezil and metoprolol (DMT) groups. On day 8 after surgery, compared to the UT, the DT and DMT significantly improved myocardial salvage, owing to the suppression of macrophage infiltration and apoptosis. After the 10-week treatment, the DT and DMT exhibited decreased heart rate, reduced myocardial infarct size, attenuated cardiac dysfunction, and decreased plasma levels of brain natriuretic peptide and catecholamine, thereby preventing subsequent CHF. These results suggest that donepezil monotherapy or combined therapy with β-blocker may be an alternative pharmacotherapy post-RMI.

The role of β‐adrenergic receptors in the regulation of cardiac tolerance to ischemia/reperfusion. Why do β‐adrenergic receptor agonists and antagonists protect the heart?

“…It is possible that these kinases are involved in the infarct‐limiting effect of bisoprolol. Rats ( n = 6) were subjected to CAO (30 min) and reperfusion [74]. Metoprolol was infused 1 h after the onset of reperfusion at a dose of 70 mg/kg/day.…”

“…Metoprolol was infused 1 h after the onset of reperfusion at a dose of 70 mg/kg/day. It did not alter infarct size [74]. It should be noted that reperfusion cardiac injury developed very rapidly [6].…”

Targeting immunometabolism during cardiorenal injury: roles of conventional and alternative macrophage metabolic fuels

“…Meanwhile, parasympathetic activation of α7 nicotinic acetylcholine receptor (α 7nAChR) by acetylcholine mediates anti-inflammatory responses in macrophages, mainly via inhibition of signaling pathways including NF-κB, STAT3, and heme oxygenase ( Baez-Pagan et al, 2015 ). Increasing parasympathetic activity using drugs that inhibit acetylcholinesterase (e.g., donepezil) protects the heart against cardiac remodeling and improves prognosis in heart failure induced by ischemia/reperfusion injury ( Li et al, 2020 ; Li et al, 2022b ). This cardiac protective effect can be prevented by blockade of peripheral α7nAChR (183), indicating that the α7nAChR is also critical for the cardiac protection conferred by the cholinergic anti-inflammatory pathway.…”

Pharmacological stimulation of the parasympathetic system – a promising means of cardioprotection in heart failure

“…Hypothetically, since donepezil seems to be well tolerated in clinical trials with Alzheimer´s disease, it could be considered an alternative to BB, in cases when BB is poorly tolerated or contraindicated. The combination of donepezil with BB may also be of benefit [11]. However, one should bear in mind the combined treatment with RAAS inhibitors, where the simultaneous administration of ACEI and ARB brought only restricted benefit and accelerated side effects.…”