Hypothesis for the research What is the potential mechanism by which BDs would be able to ameliorate the exertional symptoms in patients with stable PAH, and, which BDs would be the best candidate in achieving that? Regardless of the BDs administered, our team anticipates that the potential mechanism by which BDs are able to ameliorate the exertional symptoms in patients with stable PAH would be the reduction and/or delay of the rate of onset of DH-induced critical ventilatory constraints during exercise. In contrast, the nature of the specific BD (β2-agonist or anticholinergic) would be important in determining the mechanism by which the reduction in DH-induced critical ventilatory constraints can be achieved. BDs have been extensively studied in COPD patients, and to less extent in CHF patients. Little is known in PAH patients. Spiekerkoetter and colleagues have recently pointed out that inhaled β2-agonists are able to cause a mild but significant increase in resting FEV1, FEF50% and FEF75% in PAH patients. They also showed that inhalation of β2-agonists determined a significant increase in resting cardiac output accompanied by an increase in stroke volume and a decrease in pulmonary and systemic vascular resistance, in the presence of no change in heart rate. To date, no information is available on the effects of inhaled β2-agonists on the ventilatory, mechanical and perceptual responses to exercise in PAH patients. It can be argued that β2-agonists may reduce and/or delay the rate of onset of DH-induced critical ventilatory constraints by 1) reducing the ventilatory demand in response to exercise, and/or by 2) modifying the shape and limits of the maximal flow-volume loop (MFVL). In the first case, the improved cardiac function and concurrent ventilation-perfusion relations following β2-agonists would reduce the ventilatory demand, thereby reducing the rate of DH and enhancing VT expansion during exercise. This, in turn, would be expected to reduce the perceived exertional dyspnoea, as clearly shown in patients with COPD following BDs. In the second case, β2-agonists would increase the maximal volume-corrected expiratory flow rates in the effort-independent mid-volume range where tidal breathing occurs (i.e., increase in FEF50% and FEF75%), as it has been shown in CHF. This means that PAH patients would now accomplish the required alveolar ventilation at a lower operating lung volume and, therefore, at a reduced oxygen cost of breathing during exercise. The corollary of this will be that PAH patients would increase their end-expiratory lung volume (i.e., DH) to less extent after inhalation of β2-agonist than before, and this is likely to have salutary sensory consequences (i.e., reduction in dyspnoea intensity) for patients with PAH, as clearly shown in patients with COPD. Inhaled anticholinergic agents have not yet been studied, neither at rest nor during exercise in PAH. Inhalation of anticholinergic agents would increase the maximal volume-corrected expiratory flow rates in the effort-independent mid-volume range where tidal breathing occurs, without interfering with the cardiac and pulmonary vascular functions, as it has been shown in patients with CHF. The attendant increase in FEF50% and FEF75% (where tidal breathing occurs) following inhaled anticholinergic agents would cause VT to be accommodated at a lower operating lung volume, thus reducing the extent of DH and the concurrent ventilatory constraints imposed by the accelerated ventilatory response to exercise. This, in turn, is likely to have salutary sensory consequences (i.e., reduction in dyspnoea intensity) for patients with PAH. The interest of our study in dyspnoea evaluation after BDs in PAH patients is, therefore, evident and appealing, for at least two reasons: 1) there is no information in the literature about the effect of pharmacological interventions on dyspnoea intensity (measured by Borg score) during cycle exercise in PAH population, and 2) investigators do not know how much will the dyspnoea intensity (measured by Borg score) change after BD administration in PAH population because no Minimally Clinically Important Difference (MCID) has been established for measurements of dyspnoea intensity. Nonetheless, based on COPD studies, short-term post-intervention changes in dyspnoea intensity of ~1 Borg unit at a standardized exercise time or V'E appear to be clinically meaningful, therefore our team can assume that this MCID may also apply to PAH patients undergoing cycle exercise testing after BD interventions.