Voluntary physical activity does not improve with attenuated vascular permeability in a model of acute mountain sickness

Abstract

Acute mountain sickness (AMS) affects > 60% of individuals ascending to altitude, yet the etiology is unclear. Symptoms include lethargy, inactivity, headache, and in severe cases pulmonary or cerebral edema. Pulmonary and cerebral edema are characterized by leakage of fluid from the vascular space into pulmonary and cerebral tissues. Current treatments for AMS are targeted at vasodilation, enhancing fluid clearance, and increasing ventilation. Hypothesis We postulated that decreasing the vascular permeability that gives rise to pulmonary and cerebral edema would result in a return of physical activity (PA) to normoxic levels. Methods Adult male SD rats were acclimated to voluntary PA for at least one wk using running wheels. Rats were then exposed to48 hrs of 14,000ft simulated altitude and treated with combinations of compounds to decrease vascular leak including endothelin receptor (ETr) antagonists, Nrf2 activators, carbonic anhydrase (CA) inhibitors, Ca++ channel blockers, and phosphodiesterase (PDE) inhibitors. PA was assessed continuously while pulmonary and cerebral vascular leak were assessed at the end of 48 hrs. Results Treatment with ETr antagonists, Nrf2 activators, CA inhibitors, and Ca++ channel blockers significantly decreased vascular leak, without increasing physical activity. Conversely, treatment with a PDE inhibitor significantly increased PA without decreasing permeability. Conclusion While it is possible to pharmacologically attenuate the hypoxia-induced increase in vascular permeability and attenuate the decrement in physical activity, these two findings are divergent. In our model, decreasing vascular permeability does not result in improvement in voluntary physical activity in hypobaric hypoxia.