Cholinergic stimulation with pyridostigmine increases heart rate variability and baroreflex sensitivity in rats

Objective: Impaired parasympathetic modulation increases the risk for sudden death in patients with heart diseases. Therefore, cholinergic stimulation may have a potential protective role. The aim of this study was to verify the effects of pyridostigmine bromide, a reversible cholinesterase inhibitor, on heart rate (HR), blood pressure (BP), HR and BP variability, and baroreflex sensitivity (BS). Methods: Male Wistar rats were divided in two groups: (1) treated with pyridostigmine in drinking water (7 days, n=10; PYR) and (2) a control group (n=12; CTR). BP was recorded in freely moving rats, and HR and BP variability were quantified by the standard deviation (S.D.) of the mean values during a 30-min period and by spectral analysis. BS was assessed by the ratio between pulse interval and BP power spectra (spontaneous BS) and also by the changes on HR produced by phenylephrine and sodium nitroprusside-induced BP changes. Results: Treated rats had a PYR intake of 7.91±1.90 mg/day (≈31 mg/kg/day). There were no differences between groups concerning resting HR (P=0.158), systolic BP (P=0.481), and BP variability (P=0.201). On the other hand, treatment with PYR increased HR variability on the time domain (S.D.—PYR: 13.5±5.3 ms vs. CTR: 9.9±3.6 ms; P=0.034) and frequency domain (Total power—PYR: 208.3±157.7 ms2 vs. CTR: 109.2±65.6 ms2; P=0.030). BS was also augmented with PYR for both the spontaneous method (High frequency band—PYR: 2.55±1.06 ms/mm Hg vs. CTR: 1.85±0.60 ms/mm Hg; P=0.033) and the drug-induced reflex bradycardia (PYR: 2.48±1.02 bpm/mm Hg vs. CTR: 1.54±0.58 bpm/mm Hg; P=0.024) and reflex tachycardia (PYR: 4.08±1.04 bpm/mm Hg vs. CTR: 2.95±1.30 bpm/mm Hg; P=0.037). Conclusions: In conclusion, treatment with pyridostigmine increased HR variability and BS in normal rats with no modifications on basal hemodynamic parameters. Considering that reduced HR variability and baroreflex sensitivity are independent risk factors in heart disease, the present results support the concept that cholinergic stimulation with pyridostigmine may become a therapeutic option for vagal dysfunction.