Ecological studies show that mice can be found at high altitude (HAup to 4000 m) while rats are absent at these altitudes, and there are no data to explain this discrepancy. We used adult laboratory rats and mice that have been raised for more than 30 generations in La Paz, Bolivia (3600 m), and compared their hematocrit levels, right ventricular hypertrophy (index of pulmonary hypertension) and alveolar surface area in the lungs. We also used whole-body plethysmography, indirect calorimetry and pulse oxymetry to measure ventilation, metabolic rate (O 2 consumption and CO 2 production), heart rate and pulse oxymetry oxygen saturation (p O2,sat ) under ambient conditions, and in response to exposure to sea level P O2 (32% O 2 =160 mmHg for 10 min) and hypoxia (18% and 15% O 2 =90 and 75 mmHg for 10 min each). The variables used for comparisons between species were corrected for body mass using standard allometric equations, and are termed mass-corrected variables. Under baseline, compared with rats, adult mice had similar levels of p O2,sat , but lower hematocrit and hemoglobin levels, reduced right ventricular hypertrophy and higher mass-corrected alveolar surface area, tidal volume and metabolic rate. In response to sea level P O2 and hypoxia, mice and rats had similar changes of ventilation, but metabolic rate decreased much more in hypoxia in mice, while p O2,sat remained higher in mice. We conclude that laboratory mice and rats that have been raised at HA for >30 generations have different physiological responses to altitude. These differences might explain the different altitude distribution observed in wild rats and mice.

Compared with mice, adult rats living at 3,600 m above sea level (SL—La Paz, Bolivia) have high hematocrit, signs of pulmonary hypertension, and low lung volume with reduced alveolar surface area. This phenotype is associated with chronic mountain sickness in humans living at high altitude (HA). We tested the hypothesis that this phenotype is associated with impaired gas exchange and oxidative stress in the lungs. We used rats and mice (3 months old) living at HA (La Paz) and SL (Quebec City, Canada) to measure arterial oxygen saturation under graded levels of hypoxia (by pulse oximetry), the alveolar surface area in lung slices and the activity of pro- (NADPH and xanthine oxidases—NOX and XO) and anti- (superoxide dismutase, and glutathione peroxidase—SOD and GPx) oxidant enzymes in cytosolic and mitochondrial lung protein extracts. HA rats have a lower arterial oxygen saturation and reduced alveolar surface area compared to HA mice and SL rats. Enzymatic activities (NOX, XO, SOD, and GPx) in the cytosol were similar between HA and SL animals, but SOD and GPx activities in the mitochondria were 2–3 times higher in HA vs. SL rats, and only marginally higher in HA mice vs. SL mice. Furthermore, the maximum activity of cytochrome oxidase-c (COX) measured in mitochondrial lung extracts was also 2 times higher in HA rats compared with SL rats, while there was only a small increase in HA mice vs. SL mice. Interestingly, compared with SL controls, alterations in lung morphology are not observed for young rats at HA (15 days after birth), and enzymatic activities are only slightly altered. These results suggest that rats living at HA have a gradual reduction of their alveolar surface area beyond the postnatal period. We can speculate that the elevation of SOD, GPx, and COX activities in the lung mitochondria are not sufficient to compensate for oxidative stress, leading to damage of the lung tissue in rats.

We used pulse oximetry to measure arterial oxygen saturation (SpO2) and heart rate (HR) in 4 and 14 day‐old rats raised at HA (La Paz, Bolivia, 3,600 m/12,000ft) or at sea level (SL, Québec, Canada). SpO2 and HR were measured at 5 different levels of inspired PO2 (PiO2: 160 ‐ 60 mmHg – 10 min each), in awake rats maintained in a chamber flushed with room air or the desired gas mixtures. When exposed to a PiO2 of 160 mmHg, P4 HA rats had a similar SpO2 than P4 SL, but a lower HR. At lower PiO2, HA rats maintained a much higher SpO2 than SL rats. HR increased in HA rats (but not in SL rats) at low PiO2. Contrastingly, P14 HA rats exposed to a PiO2 of 160 mmHg had a lower SpO2 than SL (93.7±1.1% vs. 98.8±0.1%, p<0.0001), and similar SpO2 at lower PiO2. HR was higher in P14 HA rats vs. SL rats at all PiO2 levels. A group of SL rats was raised in hypoxia (13.5% O2 – similar to HA PiO2) between P4 and P14. This reduces SpO2 values measured at PiO2 below 160 mmHg, and enhances HR. Male and female rats had similar responses. We conclude that: a) 4‐day old rats raised at HA had efficient responses that help maintaining a high SpO2 under a wide range of PiO2 ‐ b) these responses are no longer apparent in P14. Since rats are not found under natural conditions at HA, success to develop adequate responses to hypoxia during early postnatal development might be critical for genetic adaptation to altitude. Founded by NSERC.