Cholinergic stimulation with pyridostigmine protects myocardial infarcted rats against ischemic-induced arrhythmias and preserves connexin43 protein

Abstract

Fazan R Jr. Cholinergic stimulation with pyridostigmine protects myocardial infarcted rats against ischemic-induced arrhythmias and preserves connexin43 protein. Am J Physiol Heart Circ Physiol 308: H101-H107, 2015. First published November 21, 2014; doi:10.1152/ajpheart.00591.2014.-We investigated the effects of acute pyridostigmine (PYR) treatment, an acetylcholinesterase inhibitor, on arterial pressure (AP), heart rate (HR), cardiac sympathovagal balance, and the incidence of arrhythmias during the first 4 h after myocardial infarction (MI) in anesthetized rats. Male Wistar rats were implanted with catheters into the femoral artery and vein for AP recordings and drug administration. Rats received the autonomic receptor blockers methyl-atropine (1 mg/kg iv) and propranolol (2 mg/kg iv) at intervals of 15 min, 1 h after saline (n ϭ 16) or PYR (0.25 mg/kg iv, n ϭ 18), to indirectly assess sympathovagal balance. Acute treatment with PYR increased cardiac vagal (86 Ϯ 7 vs. 44 Ϯ 5 beats/min) and decreased sympathetic tone (Ϫ31 Ϯ 8 vs. Ϫ69 Ϯ 7 beats/min). Different animals were implanted with ECG electrodes and catheters. A large MI was induced via left coronary artery ligation after basal recordings. Rats received PYR (n ϭ 14) or saline (n ϭ 14) 10 -15 min after MI, and the recordings lasted up to 4 h. In part of the animals, hearts were removed for connexin43 quantification after all procedures. MI elicited a fall in AP (Ϫ45 Ϯ 5 mmHg), a progressive rise in HR (26 Ϯ 14 beats/min), and an increase in corrected QT interval (33 Ϯ 13 ms). PYR elicited a prompt bradycardia (Ϫ50 Ϯ 14 beats/min) that returned to basal levels over time, and it prevented the lengthening of the corrected QT interval. Treatment with PYR increased by ϳ20% the occurrence of rats free of arrhythmias after MI. MI markedly decreased connexin43 in left ventricles, and PYR treatment partially prevented this decrease. parasympathetic stimulation; anticholinesterase agent; myocardial infarction; autonomic imbalance; arrhythmias MYOCARDIAL INFARCTION (MI) is a key component of the burden of cardiovascular disease and one of the leading causes of death in high-or middle-income countries (49, 61). Epidemiological evidence establishes that 50% of MI patients do not survive the first hour after MI before receiving any medical support (37) and that ventricular arrhythmia causes most of these deaths (60). These observations are corroborated by experiments in animal models of MI (25,28,44). Myocardial ischemia and MI are often accompanied by a marked autonomic imbalance that is characterized by sympathetic overactivity (38, 60) and vagal attenuation (54).

Cardiac sympatho-vagal balance and ventricular arrhythmia

“…Historically, pharmacological approaches such as cholinesterase inhibition (Behling et al, 2003, Santos-Almeida et al, 2015) have also been limited. Therefore the sympatho-adrenal axis has been the principal target for established pharmacotherapies such as β-blockers and ACE inhibitors, with both achieving significant reductions in morbidity and mortality (ISIS-1, 1986, CONSENSUS, 1987, Pfeffer et al, 1992, CIBIS-II, 1999).…”

The effects of acetylcholinesterase inhibitors on the heart in acute myocardial infarction and heart failure: From cells to patient reports

“…44 The underlying mechanism used by donepezil on ACh synthesis remains unclear, however, and further studies are needed to elucidate this. 26,46 Pyridostigmine improved heart rate variability and baroreflex sensitivity, but did not affect heart rate in normal rats after oral administration for 7 days. 45 However, the synthesis of ACh via α7nAChR in cardiomyocytes has never been investigated.…”

“…45 However, the synthesis of ACh via α7nAChR in cardiomyocytes has never been investigated. 26 The bradycardic effect of pyridostigmine in normal rats may depend on dose, route or duration of pyridostigmine administration. AChE inhibitors are known to prevent ACh degradation, mimicking activation of the cholinergic system.…”

“…21 However, further clinical studies are needed to warrant its clinical use. [26][27][28][29][30][31][32][33][34][35][36][37][38][39] Despite its potential clinical benefits for CVDs patients, the role of AChE inhibitors in AMI and heart failure remediation remains unclear. 22,23 Use of AChE inhibitors is a non-invasive intervention which increases the parasympathetic activity.…”

Future perspectives of a cardiac non-neuronal acetylcholine system targeting cardiovascular diseases as an adjunctive tool for metabolic intervention

“…In contrast to donepezil that crosses blood brain barrier and therefore affects central cholinergic signaling, pyridostigmine that does not cross blood brain barrier and works as a peripheral acetylcholinesterase inhibitor has been also utilized to investigate the effects of the acetylcholinesterase inhibition on cardiovascular diseases by Salgado HC et al [30][31][32]. They have clarified that even the peripheral acetylcholinesterase inhibitor possessed anti-heart failure effects and suppressed aggravation of cardiac dysfunction induced by myocardial infarction, suggesting that pyridostigmine without its central cholinergic regulation has a comparable outcome with donepezil, protecting the subjected cardiac function, and the peripheral cholinergic system may be also important for the modification through NNA.…”