Key points• Pulmonary transit of agitated contrast (PTAC) occurs during exercise in healthy individuals.• It has been suggested that positive PTAC reflects a greater pulmonary vascular reserve, allowing for the right ventricle to operate at a decreased afterload at high levels of exercise.• In this study, we determined whether individuals with highest maximal aerobic capacity have the greatest pulmonary vascular distensibility, highest PTAC and greatest increase in the capillary blood component of lung diffusing capacity during exercise.• We observed that individuals with highest maximal aerobic capacity have a more distensible pulmonary circulation as observed through greater pulmonary vascular distensibility, greater pulmonary capillary blood volume, and lowest pulmonary vascular resistance at maximal exercise.• Pulmonary vascular distensibility predicts aerobic capacity in healthy individuals.Abstract It has been suggested that shallow slopes of mean pulmonary artery pressure (MPPA)-cardiac output (Q ) relationships and pulmonary transit of agitated contrast during exercise may be associated with a higher maximal aerobic capacity (V O 2 max ). If so, individuals with a higherV O 2 max could also exhibit a higher pulmonary vascular distensibility and increased pulmonary capillary blood volume during exercise. Exercise stress echocardiography was performed with repetitive injections of agitated contrast and measurements of MPPA,Q and lung diffusing capacities for carbon monoxide (D L,CO ) and nitric oxide (D L,NO ) in 24 healthy individuals. A pulmonary vascular distensibility coefficient α was mathematically determined from the slight natural curvilinearity of multipoint MPPA-Q plots. Membrane (D m ) and capillary blood volume (V c ) components of lung diffusing capacity were calculated. Maximal exercise increased MPPA, cardiac index (CI), D L,CO and D L,NO . The slope of the linear best fit of MPPA-CI was 3.2 ± 0.5 mmHg min l −1 m 2 and α was 1.1 ± 0.3% mmHg −1 . A multivariable analysis showed that higher α and greater V c independently predictedV O 2 max . All individuals had markedly positive pulmonary transit of agitated contrast at maximal exercise, with increases proportional to increases in pulmonary capillary pressure and V c . Pulmonary transit of agitated contrast was not related to pulse oximetry arterial oxygen saturation. Therefore, a more distensible pulmonary circulation and a greater pulmonary capillary blood volume are associated with a higherV O 2 max in healthy individuals. Agitated contrast commonly transits through the pulmonary circulation at exercise, in proportion to increased pulmonary capillary pressures.

Altitude exposure is associated with decreased exercise capacity and increased pulmonary vascular resistance (PVR).Echocardiographic measurements of pulmonary haemodynamics and a cardiopulmonary exercise test were performed in 13 healthy subjects at sea level, in normoxia and during acute hypoxic breathing (1 h, 12% oxygen in nitrogen), and in 22 healthy subjects after acclimatisation to an altitude of 5,050 m. The measurements were obtained after randomisation, double-blinded to the intake of placebo or the endothelin A receptor blocker sitaxsentan (100 mg?day -1 for 7 days). Blood and urine were sampled for renal function measurements. Normobaric as well as hypobaric hypoxia increased PVR and decreased maximum workload and oxygen uptake (V9O 2 ,max). Sitaxsentan decreased PVR in acute and chronic hypoxia (both p,0.001), and partly restored V9O 2 ,max, by 30 % in acute hypoxia (p,0.001) and 10% in chronic hypoxia (p,0.05). Sitaxsentan-induced changes in PVR and V9O 2 ,max were correlated (p50.01). Hypoxia decreased glomerular filtration rate and free water clearance, and increased fractional sodium excretion. These indices of renal function were unaffected by sitaxsentan intake.Selective endothelin A receptor blockade with sitaxsentan improves mild pulmonary hypertension and restores exercise capacity without adverse effects on renal function in hypoxic normal subjects.

High altitude (HA)-induced pulmonary hypertension may be due to a free radical-mediated reduction in pulmonary nitric oxide (NO) bioavailability. We hypothesised that the increase in pulmonary artery systolic pressure (PASP) at HA would be associated with a net transpulmonary output of free radicals and corresponding loss of bioactive NO metabolites. Twenty-six mountaineers provided central venous and radial arterial samples at low altitude (LA) and following active ascent to 4559 m (HA). PASP was determined by Doppler echocardiography, pulmonary blood flow by inert gas re-breathing, and vasoactive exchange via the Fick principle. Acute mountain sickness (AMS) and high-altitude pulmonary oedema (HAPE) were diagnosed using clinical questionnaires and chest radiography. Electron paramagnetic resonance spectroscopy, ozone-based chemiluminescence and ELISA were employed for plasma detection of the ascorbate free radical (A •− ), NO metabolites and 3-nitrotyrosine (3-NT). Fourteen subjects were diagnosed with AMS and three of four HAPE-susceptible subjects developed HAPE. Ascent decreased the arterio-central venous concentration difference (a-cv D ) resulting in a net transpulmonary loss of ascorbate, α-tocopherol and bioactive NO metabolites (P < 0.05 vs. LA). This was accompanied by an increased a-cv D and net output of A•− and lipid hydroperoxides (P < 0.05 vs. sea level, SL) that correlated against the rise in PASP (r = 0.56-0.62, P < 0.05) and arterial 3-NT (r = 0.48-0.63, P < 0.05) that was more pronounced in HAPE. These findings suggest that increased PASP and vascular resistance observed at HA are associated with a free radical-mediated reduction in pulmonary NO bioavailability. Abbreviations AMS, acute mountain sickness; HA, high altitude; HAPE, high-altitude pulmonary oedema; HAPE-S, susceptible to high-altitude pulmonary oedema; HPV, hypoxic pulmonary vasoconstriction; LA, low altitude; PASP, pulmonary artery systolic pressure; PBF, pulmonary blood flow; PPF, pulmonary plasma flow; SL, sea level.

The phosphodiesterase-5 inhibitor sildenafil has been reported to improve hypoxic exercise capacity, but the mechanisms accounting for this observation remain incompletely understood. Sixteen healthy subjects were included in a randomized, double-blind, placebo-controlled, cross-over study on the effects of 50-mg sildenafil on echocardiographic indexes of the pulmonary circulation and on cardiopulmonary cycle exercise in normoxia, in acute normobaric hypoxia (fraction of inspired O2, 0.1), and then again after 2 weeks of acclimatization at 5000 m on Mount Chimborazo (Ecuador). In normoxia, sildenafil had no effect on maximum VO2 or O2 saturation. In acute hypoxia, sildenafil increased maximum VO2 from 27 +/- 5 to 32 +/- 6 mL/min/kg and O2 saturation from 62% +/- 6% to 68% +/- 9%. In chronic hypoxia, sildenafil did not affect maximum VO2 or O2 saturation. Resting mean pulmonary artery pressure increased from 16 +/- 3 mmHg in normoxia to 28 +/- 5 mmHg in normobaric hypoxia and 32 +/- 6 mmHg in hypobaric hypoxia. Sildenafil decreased pulmonary vascular resistance by 30% to 50% in these different conditions. We conclude that sildenafil increases exercise capacity in acute normobaric hypoxia and that this is explained by improved arterial oxygenation, rather than by a decrease in right ventricular afterload.

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