Contribution to the study of sympathetic nervous system modulation of exercise capacity: effects of ß-blocker and ß2-stimulant drugs

Exercise is associated with increases of ventilation, heart rate and blood pressure. Ventilation increases adaptedly to increased oxygen uptake (VO2) and carbon dioxide output (VCO2) and eventually to limit metabolic acidosis occurring above the ventilatory threshold. Cardiac output increases to meet the contracting muscles’ requirement for flow. The increase in cardiac output occurs through increases in both heart rate and stroke volume and is regulated by feed-forward mechanisms: central command and exercise pressor reflex.

Skeletal muscle contraction elicits a reflex increase in sympathetic outflow which causes vasoconstriction contributing to the exercise induced rise in blood pressure. This reflex is triggered by stimulation of metabo- and chemoreceptors. Although the precise stimulus is not known, adrenergic receptor signaling is involved in the cardiovascular and respiratory alterations in response to exercise.

This thesis has been devoted to a better understanding of the functional aspects of sympathetic nervous system activation during dynamic and resistive exercise, with use of β blocker and β2 stimulant interventions The hypotheses were: 1) that β blocker interventions would decrease aerobic exercise capacity by a limitation of maximal cardiac output, but more so the ventilatory responses to exercise because of a decreased chemosensitivity, thereby decreasing dyspnea, and 2) β2 stimulant interventions would slightly increase aerobic exercise capacity by an increase in maximal cardiac output, but also the ventilatory responses because of an increased chemosensitivity, with possible decrease of the ventilatory reserve at exercise and increased dyspnea. Both interventions could affect maximal muscle strength through central effects.

Ventilatory responses to hyperoxic hypercapnia (central chemoreflex) and to isocapnic hypoxia (peripheral chemoreflex) were confronted to measurements of ventilatory equivalents for oxygen (O2) and carbon dioxide (CO2) during standard cardiopulmonary exercise test (CPET). Resting 5 measurements of muscle sympathetic nervous activity (MSNA) were obtained in different conditions with and without pharmacological interventions. Muscle metaboreflex and muscle stength measurements were also considered. Drugs with β blocker or β2 stimulant properties were administered in range of doses used in clinical practice for the teatment of cardiovascular or rerspiratory conditions. The results show that β blockade with bisoprolol slightly reduced maximal exercise capacity as assessed by a maximal oxygen uptake (VO2max) or maximal workload (Wmax), with a decreased maximal heart rate, without significant effect on ventilation (VE) or MSNA responses to hypercapnia, hyperoxia or to isometric muscle contraction or ischemia. Both VE/VO2 and VE/VCO2 slopes were decreased during CPET, which was attributable to β blockade-related hemodynamic changes. On the other hand, stimulation of β2 receptors with salbutamol did not affect exercise capacity as assessed by VO2max or Wmax in spite of increased peripheral chemosensitivity with increased VE/VCO2 slopes and early lactic acidosis. MSNA burst frequency, muscle metaboreflex and maximal isokinetic muscle strength were not affected by salbutamol.

Thus, aerobic exercise capacity in healthy subjects is sensitive to sympathetic nervous system modulation by β blocker or β2 stimulant interventions with drugs at doses prescribed in clinical practice. B blocker intervention has a slight limitation of aerobic exercise capacity and a hemodynamic decrease in ventilation, while β2 stimulant intervention has no change in exercise capacity with associated increased ventilatory responses because of increased chemosensitivity, partly related to early lactic acidosis. None of the studied phamacologic interventions affected MSNA or muscle strength measurements.

We hope that these results might be useful for the understanding of the effects of revalidation to exercise of patients treated with β blocker or β2 stimulant drugs, document the limited ergogenic properties and also side effects of the intake of these substances in healthy exercising subjects.