Inhibitors of hypoxic pulmonary vasoconstriction prevent high-altitude pulmonary edema in rats

Abstract

Objective: Rapid ascent to high altitude causes hypoxic pulmonary vasoconstriction (HPV) and leads to high-altitude pulmonary edema (HAPE) in susceptible humans. Vasodilating agents lessen HAPE (as evidenced by radiographic and gas exchange measurements), but data establishing their effectiveness on alveolar protein content and hemorrhage are lacking. This study was designed to assess whether preventing HPV reduces the alveolar-capillary barrier leak characteristic of HAPE.

Methods: Rats were pretreated with saline (control group) or acetazolamide (20 mg/kg) or nickel chloride (60 mg/kg) (experimental groups) to prevent HPV and were exposed to high altitude (0.5 atm for 24 hours) in a hypobaric chamber. High-altitude pulmonary edema was then assessed by gravimetric analysis of heart and lung tissue, a visual score of lung hemorrhage, and measurement of protein content in bronchoalveolar lavage fluid.

Results: Saline-treated rats developed a mild protein leak indicative of early HAPE that was prevented by inhibition of HPV: protein in bronchoalevolar lavage fluid of saline-treated rats, 21.6 +/- 3.2 mg/dL (mean +/- SEM); HPV-inhibited rats, 12.6 +/- 0.7 mg/dL; air-exposed rats, 13.4 +/- 1.4 mg/ dL (P < .05 saline vs other groups, analysis of variance [ANOVA]). The lungs of saline-treated rats were also mildly hemorrhagic (3.4 +/- 0.9 on a scale of 1-9, where 1 is normal), and the lungs of HPV-inhibited rats appeared normal (1.2 +/- 0.1) (P = .032). Finally, right ventricle weight (adjusted for initial body weight) increased in saline-treated rats: saline-treated, 0.64 +/- 0.02; HPV-inhibited, 0.56 +/- 0.02; air-exposed, 0.59 +/- 0.02 (P < .05, saline vs HPV-inhibited group).

Conclusion: The results demonstrate that treatment with NiCl2 or acetazolamide prevents HAPE in rats and are consistent with a role for elevated pulmonary artery pressure in the pathogenesis of HAPE.