Influence of sildenafil on lung diffusion during exposure to acute hypoxia at rest and during exercise in healthy humans

Abstract

We sought to determine the influence of sildenafil on the diffusing capacity of the lungs for carbon monoxide (DL CO ) and the components of DL CO (pulmonary capillary blood volume V c , and alveolar-capillary membrane conductance D M ) at rest and following exercise with normoxia and hypoxia. This double-blind placebo-controlled, cross-over study included 14 healthy subjects (age = 33 ± 11 years, ht = 181 ± 8 cm, weight = 85 ± 14 kg, BMI = 26 ± 3 kg/m 2 , peak normoxic VO 2 = 36 ± 6 ml/kg, mean ± SD). Subjects were randomized to placebo or 100 mg sildenafil 1 h prior to entering a hypoxic tent with an FiO 2 of 12.5% for 90 min. DLCO, V c , and D M were assessed at rest, every 3 min during exercise, at peak exercise, and 10 and 30 min post exercise. Sildenafil attenuated the elevation in PAP at rest and during recovery with exposure to hypoxia, but pulmonary arterial pressure immediately post exercise was not different between sildenafil and placebo. Systemic O 2 saturation and VO 2peak did not differ between the two conditions. DL CO was not different between groups at any time point. V C was higher with exercise in the placebo group, and the difference in D M between sildenafil and placebo was significant only when corrected for changes in V c (D M /V c = 0.57 ± 0.29 vs. 0.41 ± 0.16, P = 0.04). These results suggest no effect of sildenafil on DLCO, but an improvement in D M when corrected for changes in V c during short-term hypoxic exposure with exercise.

Sildenafil does not improve steady state cardiovascular hemodynamics, peak power, or 15-km time trial cycling performance at simulated moderate or high altitudes in men and women

“…Our data agree with the latter concept, since HA values for SV and _ Q at rest (Table 3) and SV peak and _ Q peak (Table 2) were either unaffected or only slightly reduced compared to SL and were not affected by sildenafil. While one study did observe a decline in SV with simulated altitude (*5,800 m, 10% F I O 2 ), most investigations at actual and simulated altitudes between 3,200 and 5,800 m (10-14% F I O 2 ) report unchanged SV at rest and at submaximal, and maximal exercise compared to SL (Faoro et al 2007;Hopkins et al 2003;Peltonen et al 2001;Snyder et al 2008;Stenberg et al 1966). Therefore, it appears likely that the HPV response in the current investigation was not severe enough to reduce SV and _ Q significantly, leaving very little room for sildenafil to exert a positive influence.…”

“…While unavoidable, the absence of such assessment prevented comparisons with _ VO 2 values from SL and previous studies. Differences between _ VO 2peak and W peak response to sildenafil at altitude have been found in untrained ( _ VO 2peak = 36 ± 6 ml kg -1 min -1 ) (Snyder et al 2008) and low-moderately trained ( _ VO 2peak = 45 ± 3 ml kg -1 min -1 ) (Faoro et al 2007) individuals. The comparatively highly trained men and women ( _ VO 2peak = 55.0 ± 1.3 and 42.8 ± 0.6 ml/kg/min, respectively) in this investigation, however, exhibited good correlation (0.8, p = 0.008) between _ VO 2peak and W peak at SL.…”

Improvement in lung diffusion by endothelin A receptor blockade at high altitude

“…In patients with congestive heart failure, sildenafil improved the membrane component of lung diffusion without affecting pulmonary capillary pressure or Vc, which the authors explained by a yet unclear NO-dependent effect on the alveolocapillary membrane (23). In healthy acutely hypoxic volunteers at exercise, sildenafil attenuated the hypoxia-induced increase in PAP and did not affect DL CO but was associated with an increased Dm corrected for Vc (39). These observations are in keeping with the present report of an improvement in the membrane component in diffusing capacity by the intake of the specific endothelin A receptor blocker sitaxsentan.…”

Influence of lung volume, fluid and capillary recruitment during positional changes and exercise on thoracic impedance in heart failure

“…This has been validated previously in our laboratory relative to the traditional method of measuring Vc and Dm at multiple inspired oxygen concentrations (Ceridon et al, 2010). The Roughton and Forster equation is widely used to quantify lung diffusion capacity (DL): where θ is the binding affinity of NO (θ NO ) or CO (θ CO ) to hgb (Snydet et al, 2008; Ceridon et al, 2010). The equations for CO and NO are below;…”

“…In addition, acute exercise has been suggested to cause increases in extravascular lung water through a rise in cardiac output, although this also should expand pulmonary capillary blood volume (Olson et al, 2006). More recently we have adapted a technique in our laboratory that involves the inhalation of small amounts of carbon monoxide (CO) and nitric oxide (NO) simultaneously (Snyder et al, 2008; Ceridon et al, 2010). The resistance to the uptake of CO gas is dependent on the alveolar-capillary membrane (Dm) and subsequently the reaction rates with hgb, which is influenced by the capillary blood volume (Vc).…”