Long‐term administration of pyridostigmine attenuates pressure overload‐induced cardiac hypertrophy by inhibiting calcineurin signalling

Abstract

Cardiac hypertrophy is associated with autonomic imbalance, characterized by enhanced sympathetic activity and withdrawal of parasympathetic control. Increased parasympathetic function improves ventricular performance. However, whether pyridostigmine, a reversible acetylcholinesterase inhibitor, can offset cardiac hypertrophy induced by pressure overload remains unclear. Hence, this study aimed to determine whether pyridostigmine can ameliorate pressure overload‐induced cardiac hypertrophy and identify the underlying mechanisms. Rats were subjected to either sham or constriction of abdominal aorta surgery and treated with or without pyridostigmine for 8 weeks. Vagal activity and cardiac function were determined using PowerLab. Cardiac hypertrophy was evaluated using various histological stains. Protein markers for cardiac hypertrophy were quantitated by Western blot and immunoprecipitation. Pressure overload resulted in a marked reduction in vagal discharge and a profound increase in cardiac hypertrophy index and cardiac dysfunction. Pyridostigmine increased the acetylcholine levels by inhibiting acetylcholinesterase in rats with pressure overload. Pyridostigmine significantly attenuated cardiac hypertrophy based on reduction in left ventricular weight/body weight, suppression of the levels of atrial natriuretic peptide, brain natriuretic peptide and β‐myosin heavy chain, and a reduction in cardiac fibrosis. These effects were accompanied by marked improvement of cardiac function. Additionally, pyridostigmine inhibited the CaN/NFAT3/GATA4 pathway and suppressed Orai1/STIM1 complex formation. In conclusion, pressure overload resulted in cardiac hypertrophy, cardiac dysfunction and a significant reduction in vagal discharge. Pyridostigmine attenuated cardiac hypertrophy and improved cardiac function, which was related to improved cholinergic transmission efficiency (decreased acetylcholinesterase and increased acetylcholine), inhibition of the CaN/NFAT3/GATA4 pathway and suppression of the interaction of Orai1/STIM1.

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

“…55 In m 2 AChR knockdown cardiac fibroblasts, increased expression of TGF-β1, phosphorylated Smad3, and collagen I was observed. 54 In that report, it was stated that the beneficial effects of pyridostigmine were abolished by atropine, suggesting that anti-hypertrophic effects of pyridostigmine occurred through activation of mAChRs. 55 Interestingly, donepezil has been shown to attenuate the volume fraction of collagen through inhibition of the TGF-β1/Smad2 signalling pathways via α7nAChR in heart transplantation induced I/R injury rats.…”

“…33,36,104 In pressure overloadinduced cardiac hypertrophy rats, pyridostigmine attenuated cardiac hypertrophy via inhibition of the calcineurin/nuclear factor activated T cells 3/GATA4 signalling pathway and prevention of Ca 2+ -release-activated Ca 2+ channel protein 1 (Orai1)/stromal interaction molecule 1 (STIM1) complex formation. 54 In that report, it was stated that the beneficial effects of pyridostigmine were abolished by atropine, suggesting that anti-hypertrophic effects of pyridostigmine occurred through activation of mAChRs. The possible mechanisms used by AChE inhibitors in cardiac remodelling are summarized in both Figures 2 and 3.…”

“…14 Use of an AChE inhibitor has been shown to improve cardiac autonomic balance by increasing parasympathetic tone and suppressing sympathetic tone in rats with MI. 13,36,[54][55][56] Heart rate variability is an indirect method that is used to determine cardiac autonomic function. 53 Several studies reported that AChE inhibitors suppress neurohumoral activation and sympathetic tone, thus improving cardiac autonomic function and cardiac remodelling in MI rats.…”

“…53 Several studies reported that AChE inhibitors suppress neurohumoral activation and sympathetic tone, thus improving cardiac autonomic function and cardiac remodelling in MI rats. 13,36,[54][55][56] Heart rate variability is an indirect method that is used to determine cardiac autonomic function. 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.…”

Pharmacological Modulation of Vagal Nerve Activity in Cardiovascular Diseases

“…HRV is the variation over time of the period between consecutive heartbeats [ 23 ]. Other methods, such as the ACh level in the blood measured by microdialysis [ 6 ], cardiac automatic nerves and cholinergic nerve distribution by immunohistochemistry [ 24 ], autonomic tone and intrinsic heart rate by administration of atropine and propranolol [ 25 , 26 ] or neuronal/vagal discharge measured by a biological signal analytical system [ 27 ], can also be used to evaluate vagal activity in experiments (Fig. 1 ).…”