Increase in cholinergic modulation with pyridostigmine induces anti-inflammatory cell recruitment soon after acute myocardial infarction in rats

Abstract

-We tested the hypothesis that an increase in the anti-inflammatory cholinergic pathway, when induced by pyridostigmine (PY), may modulate subtypes of lymphocytes (CD4ϩ, CD8ϩ, FOXP3ϩ) and macrophages (M1/M2) soon after myocardial infarction (MI) in rats. Wistar rats, randomly allocated to receive PY (40 mg·kg Ϫ1 ·day Ϫ1 ) in drinking water or to stay without treatment, were followed for 4 days and then were subjected to ligation of the left coronary artery. The groupsdenominated as the pyridostigmine-treated infarcted (IP) and infarcted control (I) groups-were submitted to euthanasia 3 days after MI; the heart was removed for immunohistochemistry, and the peripheral blood and spleen were collected for flow cytometry analysis. Noninfarcted and untreated rats were used as controls (C Group). Echocardiographic measurements were registered on the second day after MI, and heart rate variability was measured on the third day after MI. The infarcted groups had similar MI areas, degrees of systolic dysfunction, blood pressures, and heart rates. Compared with the I Group, the IP Group showed a significant higher parasympathetic modulation and a lower sympathetic modulation, which were associated with a small, but significant, increase in diastolic function. The IP Group showed a significant increase in M2 macrophages and FOXP3 ϩ cells in the infarcted and peri-infarcted areas, a significantly higher frequency of circulating Treg cells (CD4 ϩ CD25 ϩ FOXP3 ϩ ), and a less extreme decrease in conventional T cells (CD25 ϩ FOXP3 Ϫ ) compared with the I Group. Therefore, increasing cholinergic modulation with PY induces greater anti-inflammatory cell recruitment soon after MY in rats. myocardial infarction; T lymphocytes; macrophage activation; anticholinesterase drugs; cholinergic anti-inflammatory reflex

Nicotinic Acetylcholine Receptor-Mediated Protection of the Rat Heart Exposed to Ischemia Reperfusion

“…Furthermore, targeting nicotinic cholinergic receptor pathways by pharmacologic means or neuromodulation has the added benefit of dampening subsequent systemic inflammatory responses in which cytokines released from damaged tissue promote leukocyte trafficking to the site of injury (3,37,50).…”

“…Furthermore, vagus nerve stimulation in animal studies and in patients with heart failure has shown improvement in cardiac function, suggesting that cholinergic-pathway activation may provide therapeutic benefit (5,18,45,53,). Other studies using drugs to augment the parasympathetic nervous system or influence vagal tone, including acetylcholinesterase inhibitors such as donepezil or pyridostigmine, show evidence of improved ventricular remodeling and autonomic function in animal models of heart failure or after myocardial infarction (13,26,32,37,42). Studies of patients treated with these drugs for Alzheimer's dementia have reported reduced adverse cardiac events, including myocardial infarction and death (31).…”

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

“…53 Several studies reported that AChE inhibitors suppress neurohumoral activation and sympathetic tone, thus improving cardiac autonomic function and cardiac remodelling in MI rats. 28,30,31,36,38,56 Similarly, pyridostigmine increased baroreflex sensitivity in MI rats. It has been shown that the high frequency (HF) component is a marker of parasympathetic tone, whereas the low frequency (LF) component is considered a marker of sympathetic and parasympathetic activity.…”

“…85 Innate and adaptive immune cells are involved in initiating the wound healing process. 28 Moreover, treatment with pyridostigmine for 7 days following MI, substantially augmented the M2-macrophages in the left ventricle, while, recruitment of regulatory T lymphocytes was not observed at the 7-day time point following MI. On the other hand, M2-macrophages with an anti-inflammatory profile predominate after 5 days.…”

“…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.…”