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Different solutions to restoring oxygen delivery at altitude

Populations resident to high altitude have adapted to the demands of performance in low oxygen environments in different ways. The article by Ivy et al. provides new data allowing the authors to speculate on what specifically may have led to these alternate solutions. Sojourners to altitude exhibit increases in ventilation, heart rate and red cell mass (increased Hct and [Hb]) all of which enhance O2 delivery to tissues. There is a further time-dependent increase in ventilation (ventilatory acclimatization to hypoxia) and heart rate resulting from increases in the sensitivity of sensory input from the carotid body as well as changes in sensitivity at other sites within the central nervous system. These responses are energetically costly and lead to significant increases in basal metabolic rate. Thus, paradoxically, as O2 becomes limited, more O2 is required for basic physiological processes. Associated with this are reductions in sleep quality and metabolic scope as reflected by reductions in exercise performance. High-altitude residents that are chronically exposed to hypoxia, not surprisingly, show adaptive changes that offset the stress of hypoxia and restore oxygen delivery allowing individuals to achieve a full range of metabolic activities. Not all of the changes seen in high-altitude resident populations are the same, however. Tibetan high-altitude natives retain a high level of resting ventilation and an enhanced hypoxic ventilatory response, but Andean high-altitude natives do not. Andeans, on the other hand, exhibit an increased alveolar capillary density resulting in increases in pulmonary diffusion capacity and a reduction in the alveolar-arterial O2 partial pressure difference. 3 In high-altitude Tibetan natives, Hct and [Hb] levels are similar to low-altitude populations, whereas high-altitude Andean natives retain a high Hct and [Hb]. The net results of these changes in both populations are arterial oxygen contents that approach sea-level values. Indeed, the Andean high-altitude population actually has a higher arterial oxygen content than sea-level natives at sea level. Similar data for resting ventilation and hypoxic ventilatory responses have also been obtained in animal studies. In plateau pika (Ochotona curzoniae) and barheaded geese (Anser indicus), total and/or alveolar ventilation is similar or enhanced compared to lowaltitude species just as it is in the Tibetan natives. By contrast, guinea-pigs (Cavia porcellus) and Andean geese (Chloephaga melanoptera) exhibit a blunted hypoxic ventilatory response similar to Andean natives, and Andean geese have the highest respiratory surface per unit body mass reported in birds along with a relatively thin blood-gas barrier and a pulmonary capillary blood volume per unit body mass that is the highest reported in non-diving birds. As a result, their mass-specific morphometric pulmonary diffusing capacity is among the highest reported in birds. In the present issue, Ivy et al. begin to explore the mechanisms underlying these evolved differences in the control of breathing. Sorting out the genotypic basis of phenotypic differences (nature vs. nurture) ideally requires raising offspring from high-altitude populations at low altitude and vice versa and then examining the responses of these individuals when subsequently acclimated to both normoxic and hypoxic environments. Ivy et al. have taken the first step in this process. They bred one species of deer mice native to high-altitude (Peromyscus maniculatus) and a congeneric species native to low altitude (Peromyscus leucopus) in captivity at low altitude. The F1 progeny of each population were raised to adulthood under identical low altitude conditions and then were acclimated to normoxia or hypobaric hypoxia (12 kPa, simulating hypoxia at ~4300 m) for 5 months. Ivy et al. then recorded the effects of stepwise reductions in inspired O2 on ventilation, respiratory water loss, heart rate, arterial O2 saturation, metabolism and growth of the carotid body. The low-altitude species when acclimated to simulated altitude showed the classic responses: significant growth of the carotid bodies and when exposed to acute hypoxia, an enhanced ventilatory response, a more effective breathing pattern (higher tidal volumes and lower breathing frequencies), and increases in heart rate and arterial O2 saturation. The high-altitude species, however, exhibited these characteristics even when raised and held in normoxia, behaving like the plateau pika, barheaded geese and Tibetan natives. This suggests that the acclimation response exhibited by the low-altitude mice has become fixed (genetic