Immersion pulmonary edema (IPE) can occur in otherwise healthy swimmers and divers, likely because of stress failure of pulmonary capillaries secondary to increased pulmonary vascular pressures. Prior studies have revealed progressive increase in ventilation [minute ventilation (Ve)] during prolonged immersed exercise. We hypothesized that this increase occurs because of development of metabolic acidosis with concomitant rise in mean pulmonary artery pressure (MPAP) and that hyperoxia attenuates this increase. Ten subjects were studied at rest and during 16 min of exercise submersed at 1 atm absolute (ATA) breathing air and at 4.7 ATA in normoxia and hyperoxia [inspired P(O(2)) (Pi(O(2))) 1.75 ATA]. Ve increased from early (E, 6th minute) to late (L, 16th minute) exercise at 1 ATA (64.1 +/- 8.6 to 71.7 +/- 10.9 l/min BTPS; P < 0.001), with no change in arterial pH or Pco(2). MPAP decreased from E to L at 1 ATA (26.7 +/- 5.8 to 22.7 +/- 5.2 mmHg; P = 0.003). Ve and MPAP did not change from E to L at 4.7 ATA. Hyperoxia reduced Ve (62.6 +/- 10.5 to 53.1 +/- 6.1 l/min BTPS; P < 0.0001) and MPAP (29.7 +/- 7.4 to 25.1 +/- 5.7 mmHg, P = 0.002). Variability in MPAP among subjects was wide (range 14.1-42.1 mmHg during surface and depth exercise). Alveolar-arterial Po(2) difference increased from E to L in normoxia, consistent with increased lung water. We conclude that increased Ve at 1 ATA is not due to acidosis and is more consistent with respiratory muscle fatigue and that progressive pulmonary vascular hypertension does not occur during prolonged immersed exercise. Wide variation in MPAP among healthy subjects is consistent with variable individual susceptibility to IPE.

The heme oxygenase-1 (HO-1)/carbon monoxide (CO) system induces mitochondrial biogenesis, but its biological impact in human skeletal muscle is uncertain. The enzyme system generates CO, which stimulates mitochondrial proliferation in normal muscle. Here we examined whether CO breathing can be used to produce a coordinated metabolic and vascular response in human skeletal muscle. In 19 healthy subjects, we performed vastus lateralis muscle biopsies and tested one-legged maximal O2 uptake (V̇o2max) before and after breathing air or CO (200 ppm) for 1 h daily for 5 days. In response to CO, there was robust HO-1 induction along with increased mRNA levels for nuclear-encoded mitochondrial transcription factor A (Tfam), cytochrome c, cytochrome oxidase subunit IV (COX IV), and mitochondrial-encoded COX I and NADH dehydrogenase subunit 1 (NDI). CO breathing did not increase V̇o2max (1.96 ± 0.51 pre-CO, 1.87 ± 0.50 post-CO l/min; P = not significant) but did increase muscle citrate synthase, mitochondrial density (139.0 ± 34.9 pre-CO, 219.0 ± 36.2 post-CO; no. of mitochondrial profiles/field), myoglobin content and glucose transporter (GLUT4) protein level and led to GLUT4 localization to the myocyte membrane, all consistent with expansion of the tissue O2 transport system. These responses were attended by increased cluster of differentiation 31 (CD31)-positive muscle capillaries (1.78 ± 0.16 pre-CO, 2.37 ± 0.59 post-CO; capillaries/muscle fiber), implying the enrichment of microvascular O2 reserve. The findings support that induction of the HO-1/CO system by CO not only improves muscle mitochondrial density, but regulates myoglobin content, GLUT4 localization, and capillarity in accordance with current concepts of skeletal muscle plasticity.