Marinkovic_2025_Int.J.Mol.Sci_26_

Autonomic imbalance is one of the major pathological disturbances in chronic heart failure (CHF). Additionally, enhanced oxidative stress and inflammation are considered to be the main contributors to the disease progression. A growing body of evidence suggests cholinergic stimulation as a potential therapeutic approach in CHF, since it corrects the autonomic imbalance and alters the inflammatory response via the cholinergic anti-inflammatory pathway. Although previous research has provided some insights into the potential mechanisms behind these effects, there is a gap in knowledge regarding different cholinergic stimulation methods and their specific mechanisms of action. In the present study, an isoprenaline model (5 mg/kg/day s.c. for 7 days, followed by 4 weeks of CHF development) was used. Afterwards, rats received pyridostigmine (22 mg/kg/day in tap water for 14 days) or no treatment. Pyridostigmine treatment prevented the progression of CHF, decreasing chamber wall thinning ( PWDd, PWDs) and left ventricle dilatation ( LVIDd, LVIDs), thus improving cardiac contractile function ( EF). Additionally, pyridostigmine improved antioxidative status ( TBARS, NO(2)(-); CAT, GSH) and significantly reduced cardiac fibrosis development, confirmed by pathohistological findings and biochemical marker reduction ( MMP2, MMP9). However, further investigations are needed to fully understand the exact cellular mechanisms involved in the CHF attenuation via pyridostigmine.