Effects of sildenafil on gas exchange, ventilatory, and sensory responses to exercise in subjects with mild-to-moderate COPD: A randomized cross-over trial

• Published in: Respiratory physiology & neurobiology 2025-01, Vol.331, p.104359, Article 104359
• Main Authors: Gass, Ricardo, Plachi, Franciele, Silva, Fernanda O.B., Nolasco, Talmir, Tonetto, Mateus Samuel, Goelzer, Leandro S., Muller, Paulo T., Knorst, Marli M., Neder, J. Alberto, Berton, Danilo C.
• Format: Article
• Language: English
• Subjects: Aged; Chronic Obstructive Pulmonary Disease; Cross-Over Studies; Dyspnea; Dyspnea - drug therapy; Dyspnea - physiopathology; Exercise - physiology; Exercise Test; Exercise Tolerance - drug effects; Exercise Tolerance - physiology; Female; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors 5; Pulmonary Disease, Chronic Obstructive - drug therapy; Pulmonary Disease, Chronic Obstructive - physiopathology; Pulmonary Disease, Chronic Obstructive - therapy; Pulmonary Gas Exchange - drug effects; Pulmonary Gas Exchange - physiology; Pulmonary Ventilation - drug effects; Pulmonary Ventilation - physiology; Sildenafil Citrate - administration & dosage; Sildenafil Citrate - pharmacology; Vasodilator Agents - administration & dosage; Vasodilator Agents - pharmacology
• ISSN: 1569-9048; 1878-1519; 1878-1519
• DOI: 10.1016/j.resp.2024.104359

Excess exercise ventilation (high ventilation (V̇E)/carbon dioxide output (V̇CO2)) contributes significantly to dyspnea and exercise intolerance since the earlier stages of chronic obstructive pulmonary disease (COPD). A selective pulmonary vasodilator (inhaled nitric oxide) has shown to increase exercise tolerance secondary to lower V̇E/V̇CO2 and dyspnea in this patient population. We aimed to assess whether a clinically more practical option - oral sildenafil - would be associated with similar beneficial effects. In a randomized, placebo-controlled study, twenty-four patients with mild-to-moderate COPD completed, on different days, two incremental cardiopulmonary exercise tests (CPET) one hour after sildenafil or placebo. Eleven healthy participants performed a CPET in a non-interventional visit for comparative purposes with patients when receiving placebo. Patients (FEV1= 69.4 ± 13.5 % predicted) showed higher ventilatory demands (V̇E/V̇CO2), worse pulmonary gas exchange, and higher dyspnea during exercise compared to controls (FEV1= 98.3 ±11.6 % predicted). Contrary to our expectations, however, sildenafil (50 mg; N= 15) did not change exertional V̇E/V̇CO2, dead space/tidal volume ratio, operating lung volumes, dyspnea, or exercise tolerance compared to placebo (P>0.05). Due to the lack of significant beneficial effects, nine additional patients were trialed with a higher dose (100 mg). Similarly, active intervention was not associated with positive physiological or sensory effects. In conclusion, acute oral sildenafil (50 or 100 mg) failed to improve gas exchange efficiency or excess exercise ventilation in patients with predominantly moderate COPD. The current study does not endorse a therapeutic role for sildenafil to mitigate exertional dyspnea in this specific patient subpopulation. Clinical trial registry: https://ensaiosclinicos.gov.br/rg/RBR-4qhkf4 Web of Science Researcher ID: O-7665–2019 •Increased “wasted” ventilation heightens ventilatory drive since the early stages of COPD.•A high ventilatory demand has been consistently linked with dyspnea in these patients.•Acute sildenafil did not reduce the “wasted” ventilation in mild-moderate COPD.•Exertional ventilatory demands were also not affected by this intervention.•Sildenafil was not found to be effective in reducing exertional dyspnea in this subgroup.