Enhancement of heart rate variability by cholinergic stimulation with pyridostigmine in healthy subjects

Abstract

The purpose of this study was to determine the effect of the oral administration of pyridostigmine bromide on indices of heart rate variability (HRV) in healthy young volunteers. Seventeen healthy participants (11 men, 6 women; aged 27 +/- 8 y) submitted to a randomized, crossover, double-blind protocol, in which they received 30 mg pyridostigmine bromide (PYR) or placebo orally at 8-hour intervals for 24 hours, on two separate days. Venous blood samples were collected 2 and 24 hours after the first dose for determination of serum cholinesterase activity. Holter tapes were recorded during the 24-hour period and analyzed using a semiautomatic technique to evaluate time- and frequency-domain indices of HRV and to build three-dimensional return maps for later quantification. Symptoms were mild and occurred similarly during administration of PYR and placebo (p = 0.140). Serum cholinesterase activity was reduced by 15% at 2 hours (p = 0.013) and by 14% at 24 hours (p = 0.010) after the first dose of PYR, but not after administration of placebo. Pyridostigmine administration caused a significant increase in the mean 24-hour R-R interval (placebo: 814 +/- 20 msec; PYR: 844 +/- 18 msec; p = 0.003) and in time-domain indices of HRV, such as the standard deviation of all R-R intervals (SDNN; placebo: 151 +/- 9 msec; PYR: 164 +/- 9 msec; p = 0.017), and the percentage of pairs of adjacent R-R intervals differing by more than 50 msec (pNN50; placebo: 12.8 +/- 1.8%; PYR: 13.9 +/- 1.5%; p = 0.029). Pyridostigmine had no significant effect on frequency-domain indices of HRV, but resulted in significant increase in P2, a parasympathetic index derived from the three-dimensional return map (placebo: 93 +/- 13 msec; PYR: 98 +/- 13 ms; p = 0.029). In conclusion, low-dose pyridostigmine reduced mean heart rate and increased HRV during a 24-hour period in healthy young subjects.

Cholinergic stimulation with pyridostigmine reduces the QTc interval in coronary artery disease

“…Previous studies specifically investigating the hemodynamic changes induced by pyridostigmine have shown that a single dose of the drug decreases resting (12) and exercise (13) heart rate and reduces QTc dispersion (14) in healthy individuals without impairing exercise tolerance. When given at 8-h intervals, pyridostigmine elicited sustained 24-h bradycardia and augmented heart rate variability (15). These effects were obtained without impairment of systolic or diastolic cardiac functions (16).…”

Increase in parasympathetic tone by pyridostigmine prevents ventricular dysfunction during the onset of heart failure

“…PYR increased HR variability in normal rats (63), healthy humans (47), and HF patients (5). In healthy humans, PYR given during a 1-or 2-day period produced bradycardia (20,46) without modifying cardiac function (18).…”

Acute electrophysiologic consequences of pyridostigmine inhibition of cholinesterase in humans

“…When administered to patients with coronary artery disease, pyridostigmine reduced the QTc interval at rest (29) and its recovery from maximal effort (14). Heart rate variability, an established method for analysis of autonomic modulation, was also increased when pyridostigmine was used by healthy volunteers (15) and heart failure patients, reducing ventricular arrhythmia density in the latter (17). The electrophysiologic mechanisms involved in these effects are currently unknown.…”

“…Albeit exhibiting promising effects, edrophonium needs to be administered intravenously, precluding its prescription for regular use. Therefore, pyridostigmine, which can be administered orally and causes a dose-dependent vagomimetic effect with few side effects (13)(14)(15)(16)(17)(18)(19), is a preferable candidate for the treatment of impaired parasympathetic modulation in heart disease. As a drug that elicits a parasympathetic effect, pyridostigmine was expected to cause bradycardia in the present study.…”

“…In addition, it has been shown to counteract the adverse anti-cholinergic effects of disopyramide, such as decreased baseline saliva and tear production (12). We have previously shown that short-term administration of pyridostigmine may be also potentially useful for cardiovascular protection since in healthy individuals and patients with cardiovascular diseases it results in beneficial effects on markers of cardiovascular risk and dysfunction (8,(13)(14)(15)(16)(17)(18)(19).…”