Nitric Oxide and Oxygen Delivery Among Tibetans

Case Western Reserve University, Cleveland OH

Investigators

Abstract

This project will investigate a newly proposed mechanism by which humans can adapt to life in an extreme environment. Tibetans have lived at high altitudes for millennia and have been demonstrated to possess a number of adaptations for dealing with life on the Tibetan Plateau and in the Himalayan Mountains. The proposed research is designed to test the hypothesis that the high levels of exhaled nitric oxide produced by Tibetan high-altitude natives are responses that improve functional capacity in their environment where there are fewer oxygen molecules in every breath, a situation called high-altitude hypoxia. Based on the known effects of nitric oxide, it is hypothesized that high levels of nitric oxide in the lungs helps in two ways. First, it may offset the high-altitude hypoxia by enabling the extraction of a larger proportion of the oxygen in the inspired air. Second, it may improve oxygen delivery by increasing blood flow throughout the body. The recent finding that high-altitude native Tibetans exhale more than twice as much nitric oxide as sea-level natives at sea level requires explanation because a large body of evidence predicts less, rather than more, synthesis of nitric oxide under hypoxic conditions. The consistent finding of high pulmonary nitric oxide in both Tibetan and Andean indigenous high-altitude populations suggests an adaptive, beneficial function. The hypotheses will be tested with a sample of 91 high-altitude natives of the Tibet Autonomous Region living at 4200m (~ 14,000') altitude. The study participants will be healthy, not pregnant, non-smokers, 18-55 years of age. The concentration of nitric oxide in exhaled breath will be measured and it is expected that there will be a wide range of variation including values two to three times higher than those found at sea level. The hypothesis of greater oxygen extraction will be tested by measuring the difference in the percent of oxygen in inspired air (20.9%) and exhaled air (to be measured). The hypothesis of greater blood flow will be tested noninvasively by quantifying blood flow in the lungs and in the forearm. The anticipated outcome is a positive association between exhaled nitric oxide and oxygen extraction, pulmonary blood flow, forearm blood flow at rest and in response to exercise and in response to breathing 50% oxygen (without the stress of hypoxia). These findings would indicate that Tibetan highlanders use elevated nitric oxide in the lungs to offset high-altitude hypoxia and to deliver adequate oxygen to body tissues. Pulmonary nitric oxide appears central to understanding human adaptation to high altitude and hypoxia. Nitric oxide biology has implications for explaining how Tibetan high-altitude natives can achieve sea-level values for necessary biological processes that require oxygen, such as basal metabolism and physical work capacity, although they live in an environment where ambient oxygen is severely limited relative to sea level. The Tibetan case contributes to basic knowledge of nitric oxide biology because healthy people produce amounts that would be considered pathological at sea level. The proposed research contributes new knowledge to a central question in physical anthropology: the causes and consequences of human biological variation. The significance of the proposed research lies in improving understanding of how people adjust to life with hypoxia. It directly investigates why the Tibetan population inhabiting a stressful, high-altitude environment has very distinctive biological features and also has implications for understanding the responses of sea-level visitors to altitude whether they are vacationers in the Rockies or military personnel serving in mountainous areas, and for understanding the pathophysiology of patients with diseases that cause hypoxia .