["The Journal of Physiology, Volume 604, Issue 8, Page 3297-3313, 15 April 2026. ", "\nAbstract figure legend Higher pulmonary microvascular function may contribute to higher rest and exercise diffusing capacity (DLCO), pulmonary capillary blood volume (VC) and membrane diffusing capacity (DM) in trained individuals. We hypothesized that pulmonary vasodilatation with sildenafil would increase resting and exercise DLCO, VC and DM in untrained (UT) individuals, whereas trained (T) individuals would have a smaller response. This double‐blind randomized crossover trial recruited n = 24 healthy participants into UT and T groups based on V̇O2peak$\\dot{V}{{{\\mathrm{O}}}_{2{\\mathrm{peak}}}}$. Rest and exercise DLCO (cycle ergometry; 60 W, 30%, 60% and 90% of V̇O2peak$\\dot{V}{{{\\mathrm{O}}}_{2{\\mathrm{peak}}}}$) was measured following oral sildenafil (50 mg) or placebo (block randomized) and evaluated using one‐way ANOVA and linear mixed effects modelling. Despite effective pulmonary vasodilatation sildenafil did not impact rest or exercise DLCO, VC or DM in either group. Thus there was no evidence that improved nitric oxide‐mediated pulmonary vasodilatory function would explain the greater DLCO observed in trained individuals. Created using BioRender. Ehnes, C. (2026) https://BioRender.com/43rxsl5.\n\n\n\n\n\n\n\n\n\nAbstract\nHigher pulmonary microvascular function may contribute to higher rest and exercise diffusing capacity (DLCO), pulmonary capillary blood volume (VC) and membrane diffusing capacity (DM) in trained individuals. We hypothesized that pulmonary vasodilatation with sildenafil would increase resting and exercise DLCO, VC and DM in untrained (UT) individuals, whereas trained (T) individuals would have a smaller response. This double‐blind randomized crossover trial recruited n = 24 healthy participants (nine females) into UT and T groups (n = 12 each) based on V̇O2peak$\\dot{V}{{{\\mathrm{O}}}_{2{\\mathrm{peak}}}}$ (mean ± SD V̇O2peak$\\dot{V}{{{\\mathrm{O}}}_{2{\\mathrm{peak}}}}$ = 37.5 ± 3.8 and 65.3 ± 6.7 mL.kg−1.min−1, respectively). Rest and exercise DLCO (cycle ergometry; 60 W, 30%, 60% and 90% of V̇O2peak$\\dot{V}{{{\\mathrm{O}}}_{2{\\mathrm{peak}}}}$) was measured following oral sildenafil (50 mg) or placebo (block randomized) and evaluated using one‐way ANOVA and linear mixed effects modelling. At rest, right ventricular systolic pressure was reduced with sildenafil across groups (mean ∆ = −2.1 mmHg; P = 0.01), indicating effective pulmonary vasodilatation. No group, drug or drug by group interaction effect was detected in resting DLCO, VC or DM (all Pgroup > 0.058). T had higher exercise DLCO during all workloads (all Pgroup < 0.031) and higher VC in relative workloads (Pgroup = 0.006). Sildenafil did not impact exercise DLCO, VC or DM at any workload (all Pdrug > 0.395), with no significant drug by group interaction (all Pinteraction > 0.086). As sildenafil did not impact rest or exercise DLCO, VC or DM in either group, there was no evidence that improved nitric oxide‐mediated pulmonary vasodilatory function would explain the greater DLCO observed in trained individuals.\n\n\n\n\n\n\n\n\n\nKey points\n\nHigher pulmonary vascular function may explain why trained individuals have higher pulmonary diffusing capacity for carbon monoxide (DLCO) compared to untrained individuals.\nThis double‐blind randomized crossover trial investigated whether pulmonary vasodilatation with sildenafil would elucidate changes in resting and exercise DLCO within trained and untrained groups.\nTrained individuals had higher DLCO, but sildenafil did not elicit alterations in DLCO in either group.\nOur findings suggest that improved nitric oxide‐mediated pulmonary vasodilatation is not likely the primary mechanism responsible for the greater DLCO observed in trained individuals.\nFuture work should investigate which mechanism(s) are responsible for the higher DLCO in trained individuals.\n\n\n"]