Cardioprotective Effects of Pyridostigmine in Isoprenaline-Induced Heart Failure

Abstract

 Introduction: Autonomic nervous system (ANS) imbalance is a central pathophysiological mechanism in the development of chronic heart failure (CHF). Sympathetic dominance is initially compensated, but eventually leads to instability, oxidative stress, inflammation, and myocardial fibrosis, accelerating disease progression.

 Aim: To investigate the potential protective effects of the acetylcholinesterase inhibitor pyridostigmine in a rat model of CHF.

 Materials and Methods: Male Wistar albino rats were used. CHF was induced by subcutaneous (s.c.) administration of 5 mg/kg/day of isoprenaline for 7 days, while control groups received s.c. saline solution (0.9% NaCl). The development of heart failure was monitored over 4 weeks. After the establishment of the CHF model, animals were randomized into four experimental groups: Control, Iso, Pyr, and Iso+Pyr. Animals in the Control and Iso groups drank tap water, while animals in the Pyr and Iso+Pyr groups received pyridostigmine (22 mg/kg/day) dissolved in water for 14 days. At the end of the experiment, final echocardiographic (ECHO) and electrocardiographic (ECG) measurements were performed. Animals were then anesthetized with a combination of ketamine (90 mg/kg) and xylazine (10 mg/kg), sacrificed by exsanguination, and blood and tissue samples were collected for biochemical and pathohistological analysis.

 Results: Pyridostigmine therapy significantly slowed the progression of CHF, reducing left ventricular dilation (decline LVIDd and LVIDs), posterior wall thickening (rise PWDd and PWDs), and improved overall cardiac contractility, as evidenced by an increase in ejection fraction (↑EF). Besides functional effects, a significant improvement in antioxidant status was observed, evidenced by a reduction in thiobarbituric acid reactive substances (TBARS) and nitrites, along with increased catalase (CA) and glutathione (GSH) activity. Histopathological analysis showed a significant reduction in interstitial fibrosis and cellular inflammation in the pyridostigmine-treated group. Additionally, a decrease in the expression of matrix metalloproteinases MMP-2 and MMP-9 was observed.  

Conclusion: The results indicate that administration of pyridostigmine at 22 mg/kg/day significantly slowed the progression of isoprenaline-induced CHF in rats.