Cholinergic stimulation with pyridostigmine protects against exercise induced myocardial ischaemia

Abstract

Objective: To determine the acute effects of pyridostigmine bromide, a reversible cholinesterase inhibitor, during exercise in patients with coronary artery disease. Design: Double blind, randomised, placebo controlled, crossover study. Setting: Outpatients evaluated in an exercise test laboratory. Patients: 15 patients with exercise induced myocardial ischaemia. Interventions: Maximal cardiopulmonary exercise test on a treadmill according to an individualised ramp protocol on three days. The first day was used for adaptation to the equipment and to determine exercise tolerance and the presence of exercise induced ischaemia. On the other two days, the cardiopulmonary exercise test was performed two hours after oral administration of pyridostigmine (45 mg) or placebo. All patients were taking their usual medication during the experiments. Main outcome measures: Rate-pressure product and oxygen uptake during exercise. Results: Pyridostigmine inhibited the submaximum chronotropic response (p = 0.001), delaying the onset of myocardial ischaemia, which occurred at a similar rate-pressure product (mean (SE) placebo 20.55 (1.08) mm Hg 6 beats/min 10 3 ; pyridostigmine 19.75 (1.28) mm Hg 6 beats/min 10 3 ; p = 0.27) but at a higher exercise intensity (oxygen consumption: placebo 18.6 (1.7) ml/kg/min; pyridostigmine 19.6 (1.8) ml/kg/min; p = 0.03). Also, pyridostigmine increased peak oxygen consumption (placebo 23.6 (2) ml/kg/min; pyridostigmine 24.8 (2) ml/kg/min; p = 0.01) and peak oxygen pulse (placebo 12.9 (1) ml/beat; pyridostigmine 13.6 (1) ml/beat; p = 0.02). Conclusions: Pyridostigmine improved peak exercise tolerance and inhibited the chronotropic response to submaximum exercise, increasing the intensity at which myocardial ischaemia occurred. These results suggest that pyridostigmine can protect against exercise induced myocardial ischaemia.

Donepezil Markedly Improves Long-Term Survival in Rats With Chronic Heart Failure After Extensive Myocardial Infarction

“…Decreased parasympathetic activity is also an independent risk factor after acute myocardial infarction (MI), 14,15 but few studies have investigated an alternative treatment targeting parasympathetic dysfunction. 16 We previously demonstrated that parasympathetic activation by electrical vagal nerve stimulation (VNS) markedly improved the long-term survival of CHF rats by preventing progressive pump failure and cardiac remodeling. 17 Despite potential differences of vagal nerve structure and function between animals effects in CHF, 22 and reported that donepezil increased vagal tone and preserved cardiac function in rats after MI.…”

Acute electrophysiologic consequences of pyridostigmine inhibition of cholinesterase in humans

“…Therefore, pyridostigmine presents a potential anti-arrhythmic effect at higher heart rates, as occurs during physical exercise and mental stress. Accordingly, previous studies have shown a modulatory action of pyridostigmine on cardiovascular reactivity to exercise and stress, both in healthy subjects (18) and in patients with cardiovascular diseases (13,14,19). Whether adverse outcomes can be hampered by pyridostigmine or the sustained release version of the drug leads to a better effective action with lower side affects remains to be determined.…”

“…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).…”

“…In patients with coronary artery disease, pyridostigmine improves the autonomic and hemodynamic responses to exercise (13,14,19), prevents the myocardial dysfunction induced by mental stress (16), and reduces QTc dispersion (18). In a randomized, crossover, placebo-controlled, and double-blind study, pyridostigmine administration increased heart rate variability and reduced ventricular arrhythmia density in patients with heart failure (17), an effect mediated, at least in part, by stimulation of the endogenous nitric oxide pathway (20).…”