The Effect of Inhaled Nitric Oxide on Maximal Oxygen Consumption During Exercise in Hypoxia

Background

During exercise in hypoxic conditions, maximal exercise capacity, as determined by maximal oxygen uptake (V̇O2max), is reduced progressively as inspired oxygen tension falls. It is generally assumed that this reduction in V̇O2max results entirely from a reduction in arterial oxygen content. However, previous work in severe cases of hypoxia have demonstrated a larger than expected reduction in V̇O2max. Further, the hypoxia-induced impairment in V̇O2max could not be explained entirely by the reduced inspired O2 tension and suggest that other mechanisms contribute to the drop in V̇O2max. Previous research showed that impaired pulmonary gas-exchange and reduced peak cardiac output, in addition to the reduced arterial oxygen content, were key contributors to the impaired V̇O2max in severe hypoxia (10.5% inspired oxygen). The reason for the gas-exchange impairment and reduced cardiac output is currently unclear, however, it has been hypothesized that hypoxic pulmonary vasoconstriction (HPV) may increase pulmonary vascular resistance and pulmonary artery pressure during very heavy exercise. HPV-mediated increases in pulmonary vascular resistance would increase right heart work and potentially impair the pumping capacity of the heart, leading to a reduction in stroke volume and, ultimately, cardiac output. HPV has been detected, even in mild hypoxia (15-18% inspired oxygen), in healthy humans. Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator and has been shown to reduce pulmonary vascular resistance during exercise in patients with pulmonary vascular dysfunction (i.e. chronic obstructive pulmonary disease). Further, iNO has been shown to release HPV in healthy individuals. If iNO can prevent HPV, this would mitigate the increase in pulmonary vascular resistance in moderate (~13.6% inspired oxygen) and more severe (~12.1% inspired oxygen) hypoxia and improve V̇O2max during hypoxic exercise. Therefore, we hypothesize that the iNO will improve V̇O2max during exercise in moderate and severe hypoxia, secondary to reduced pulmonary artery systolic pressure leading to increased stroke volume and peak cardiac output. Further, larger improvements in V̇O2max, with iNO, will be observed in severe hypoxia conditions, when compared to the iNO-mediated change in V̇O2max in moderate hypoxia. This would provide conclusive evidence that the pulmonary vasculature is a key contributor to reduced V̇O2max in both moderate and severe hypoxic conditions.

Trial Objectives

Purpose: To examine the effect of iNO on maximal oxygen consumption (V̇O2max) during exercise in hypoxia.

Hypothesis: Inhaled NO will improve V̇O2max during hypoxic exercise, secondary to increased stroke volume and peak cardiac output. A larger improvement in V̇O2max, with iNO, will be observed in more severe hypoxia conditions, when compared to the iNO-mediated change in V̇O2max in moderate hypoxia.