ABSTRACT
BACKGROUND: Parasympathetic dysfunction is an independent risk factor for mortality in heart failure for which there is no specific pharmacologic treatment. This article aims to determine the effect of pyridostigmine, an anticholinesterase agent, on the integrated physiologic responses to dynamic exercise in heart failure. METHODS AND RESULTS: Patients with chronic heart failure (n = 23; 9 female; age = 48 +/- 12 years) were submitted to 3 maximal cardiopulmonary exercise tests on treadmill in different days. The first test was used for adaptation and to determine exercise tolerance. The other tests were performed after oral administration of pyridostigmine (45 mg, 3 times/day, for 24 hours) or placebo, in random order. All patients were taking their usual medication. Pyridostigmine reduced cholinesterase activity by 30%, inhibited the chronotropic response throughout exercise, up to 60% of maximal effort (pyridostigmine = 108 +/- 3 beats/min vs. placebo = 113 +/- 3 beats/min; P = .040), and improved heart rate reserve (pyridostigmine = 73 +/- 5 beats/min vs. placebo = 69 +/- 5 beats/min; P = 0.035) and heart rate recovery in the first minute after exercise (pyridostigmine = 25 +/- 2 beats/min vs. placebo = 22 +/- 2 beats/min; P = .005), whereas peak heart rate was similar to placebo. Oxygen pulse, an indirect indicator of stroke volume, was higher under pyridostigmine during submaximal exercise. CONCLUSIONS: Pyridostigmine was well tolerated by heart failure patients, leading to improved hemodynamic profile during dynamic exercise.
Subject(s)
Acetylcholinesterase/drug effects , Autonomic Nervous System/physiopathology , Cholinesterase Inhibitors/therapeutic use , Heart Failure/physiopathology , Hemodynamics , Pyridostigmine Bromide/therapeutic use , Receptors, Cholinergic/metabolism , Adaptation, Physiological , Analysis of Variance , Cross-Over Studies , Double-Blind Method , Exercise Test , Female , Heart Failure/drug therapy , Heart Failure/metabolism , Heart Failure/rehabilitation , Humans , Male , Middle Aged , Risk Factors , Stroke VolumeABSTRACT
Activation of the sympathetic nervous system plays a major role in the pathogenesis and prognosis of cardiovascular diseases. Rilmenidine is an I(1)-imidazoline receptor agonist that reduces blood pressure by modulation of central sympathetic activity, but the effects of low-dose rilmenidine on the hemodynamic responses to physiological maneuvers that increase adrenergic drive is not known. To assess the effects of low-dose rilmenidine on the hemodynamic responses to stress, 32 healthy subjects (20-56 years old) underwent acute physical exercise (n = 15, individualized ramp protocol on treadmill) and mental stress (n = 17, word color Stroop and mental arithmetics tests) two hours after the oral administration of 0.5 mg of rilmenidine (RIL) or placebo (PLA) following a randomized, double-blind, placebo controlled crossover study. No subject complained of any side effect. Rilmenidine reduced peak exercise heart rate (PLA: 187 +/- 7; RIL: 181 +/- 9 bpm; P = 0.003), but did not modify peak aerobic power (VO(2max) - PLA: 41.7 +/- 6.2; RIL: 42.3 +/- 6.7 ml/kg/min; P = 0.26). During mental stress, rilmenidine inhibited the peak systolic (PLA: 123 +/- 10; RIL: 114 +/- 8 mmHg; P = 0.02) and diastolic (PLA: 86 +/- 7; RIL: 81 +/- 7 mmHg; P <0.05) blood pressure responses. In conclusion, rilmenidine reduced the hemodynamic response to physical and mental stress stimuli without limiting exercise capacity. These results support the concept that rilmenidine, at a dose lower than the ones recommended to treat hypertension, reduced the myocardial oxygen demand to stress and may carry potential clinical impact.
