Life-long consequences of postnatal normoxia exposure in rats raised at high altitude

Abstract

We tested the hypothesis that exposure of high-altitude (HA) rats to a period of postnatal normoxia has long-term consequences on the ventilatory and hematological acclimatization in adults. Male and female HA rats (3,600 m, PO2 Ӎ 100 Torr; La Paz, Bolivia) were exposed to normal room air [HA control (HACont)] or enriched oxygen (32% O2; PO2 Ӎ 160 Torr) from 1 day before to 15 days after birth [HA postnatal normoxia (HApNorm)]. Hematocrit and hemoglobin values were assessed at 2, 12, and 32 wk of age. Cardiac and lung morphology were assessed at 12 wk by measuring right ventricular hypertrophy (pulmonary hypertension index) and lung air space-to-tissue ratio (indicative of alveolarization). Respiratory parameters under baseline conditions and in response to 32% O2 for 10 min (relieving the ambient hypoxic stimulus) were measured by whole body plethysmography at 12 wk. Finally, we performed a survival analysis up to 600 days of age. Compared with HACont, HApNorm rats had reduced hematocrit and hemoglobin levels at all ages (both sexes); reduced right ventricular hypertrophy (both sexes); lower air space-to-tissue ratio in the lungs (males only); reduced CO2 production rate, but higher oxygen uptake (males only); and similar respiratory frequency, tidal volume, and minute ventilation. When breathing 32% O2, HApNorm male rats had a stronger decrease of minute ventilation than HACont. HApNorm rats had a marked tendency toward longer survival throughout the study. We conclude that exposure to ambient hypoxia during postnatal development in HA rats has deleterious consequences on acclimatization to hypoxia as adults. development; lungs; breathing POSTNATAL DEVELOPMENT IN MAMMALS is a key period during which environmental stimuli induce immediate physiological responses, but also modulate development, leading to long-lasting physiological alterations in adulthood. Along with other nutrients, oxygen is crucial for adequate development. It is well documented that postnatal hypoxia blunts growth (16) and induces several alterations of the respiratory system in adults. In rats and mice, postnatal hypoxia results in a lung tissue with fewer but larger alveoli, reduced surface-exchange area, limitations of respiratory gas exchange, and signs of pulmonary hypertension (6,31,50). Similarly, adequate development of the respiratory control system is also dependent on postnatal oxygen level. Exposure to hypoxia during early life delays the postnatal maturation of ventilatory response to hypoxia (17, 21), reduces respiratory chemoreflex in adult rats (3,39), and reduces carotid body responses to hypoxia and hypercapnia (25). Typically, the period during which neonatal hypoxia induces such long-term changes includes the first 2 wk of postnatal development (3,31,39,50). These experimental studies linking postnatal hypoxia with blunted chemoreflex responses help to explain results from human studies, showing that minute ventilation (V E), but also hypoxic ventilatory response are decreased in high-altitude residents compared with se...

Divergent physiological responses in laboratory rats and mice raised at high altitude

“…While this is higher than values normally reported at sea level (around 20%; Ciuclan et al, 2011), it is much lower than the values reported in rats in our present and past (Lumbroso et al, 2012) studies. Protection against elevated pulmonary hypertension is common in species adapted to high altitude, which demonstrate thinner pulmonary vessel walls with a reduced number of muscular cells (Tucker and Rhodes, 2001).…”

“…In rats, females had lower mass-corrected f R than males, but V T and V˙E were similar (either mass-specific or mass-corrected data). Higher values of V˙E and V T in females compared with males likely reflects the respiratory stimulant effect of ovarian steroids (Joseph et al, 2002), and have been reported in our previous studies (Lumbroso et al, 2012). The fact that sex-specific effects were not reported in the present study in rats might be related to the reduced sample size (six males, six females), while we compared 17 males with 16 females in our previous study (Lumbroso et al, 2012).…”

“…Rats showed a higher respiratory exchange ratio (V˙C O2 /V˙O 2 ) than mice. We previously reported elevated values in high altitude rats (Lumbroso et al, 2012). High values of the respiratory exchange ratio indicate that energy production is mostly accomplished by oxidation of glucose molecules, which is an effective way to optimize synthesis of ATP under low oxygen availability (Hochachka and Somero, 2002) as glucose oxidation produces the highest ratio of ATP synthesized for each molecule of O 2 consumed compared with other metabolites.…”

“…Rectal temperature was measured immediately at the end of the last hypoxic exposure. V T was calculated from the integrated flow trace as previously described (Lumbroso and Joseph, 2009;Lumbroso et al, 2012), by using standard equations (Bartlett and Tenney, 1970). All values were obtained while the animal had a stable breathing pattern during baseline recordings and within the last 3 min of each condition.…”

“…These animals present elevated Hct and Hb levels, a right ventricular hypertrophy (a sign of pulmonary hypertension), an altered alveolar structure with enlarged airspaces in the lungs, and impaired respiratory control (Lumbroso et al, 2012). Considering that elevated Hct and pulmonary hypertension impair survival and lead to right heart failure (Lumbroso et al, 2012;Naeije and Manes, 2014;Storz et al, 2010b), this might explain why rats have not been able to establish stable colonies in high altitude regions under natural conditions.…”