Nitric oxide in adaptation to altitude

Abstract

This review summarizes published information on the levels of nitric oxide gas (NO) in the lungs and NO-derived liquid-phase molecules in the acclimatization of visitors newly arrived at altitudes of 2500 m or more and adaptation of populations whose ancestors arrived thousands of years ago. Studies of acutely exposed visitors to high altitude focus on the first 24-48 h with just a few extending to days or weeks. Among healthy visitors, NO levels in the lung, plasma, and/or red blood cells fell within 2h, but then returned toward baseline or slightly higher by 48 h and increased above baseline by 5 days. Among visitors ill with high-altitude pulmonary edema at the time of the study or in the past, NO levels were lower than those of their healthy counterparts. As for highland populations, Tibetans had NO levels in the lung, plasma, and red blood cells that were at least double and in some cases orders of magnitude greater than other populations regardless of altitude. Red blood cell-associated nitrogen oxides were more than 200 times higher. Other highland populations had generally higher levels although not to the degree shown by Tibetans. Overall, responses of those acclimatized and those presumed to be adapted are in the same direction, although the Tibetans have much larger responses. Missing are long-term data on lowlanders at altitude showing how similar they become to the Tibetan phenotype. Also missing are data on Tibetans at low altitude to see the extent to which their phenotype is a response to the immediate environment or expressed constitutively. The mechanisms causing the visitors' and the Tibetans' high levels of NO and NO-derived molecules at altitude remain unknown. Limited data suggest processes including hypoxic upregulation of NO synthase gene expression, hemoglobin-NO reactions, and genetic variation. Gains in understanding will require integrating appropriate methods and measurement techniques with indicators of adaptive function under hypoxic stress.

Figure 1. Measures of NO in exhaled breath from the airway or the vital capacity can lead to different inferences about altitude effects. Tibetans at 4200m had less NO in gases collected from the proximal conducting airways and substantially more in gases collected from the entire exhaled breath than a low-altitude sample

A. A low altitude U.S. sample exhaled more NO and a wider range of values from the conducting airways (measured online at a flow rate of 50 ml/s into the NO analyzer) than a Tibetan sample at 4200m that in turn exhaled more than a Tibetan sample at 4700m. The x-axis marks intervals of 5nm Hg NO and the y-axis the percent of observations in the interval or lower. B. A Tibetan sample at 4200m contained more NO in the vital capacity volume collected from exhaled breath and a wider range of values in the total lung exhalate (measured in the total volume of breath exhaled into a mylar collection bag after a 15s breathhold, i.e. offline) than a Tibetan sample at 4700m that in turn exhaled more than a low-altitude U.S. sample.

Figure 2. Units of reporting change comparisons of NO across altitudes. The first comparison leads to the inference that Tibetans have uniquely high values while the second leads to the inference that highlanders generally have high values

Top. Tibetans at 4200m exhaled more NO than Bolivian Aymara at 3900m who did not differ significantly from a U.S. low-altitude sample when reported as partial pressure of NO in vital capacity exhalate. The respective geometric means were 8.7 nmHg with a range of 2.6 to 26 among Tibetans, 4.6 nmHg with a range of 1.3 to 14.7 nmHg among Aymara, and 5.5 nmHg with a range from 3.3 to 10.8 nmHg among lowlanders. Bottom. Tibetans at 4200m exhaled more NO than Bolivian Aymara at 3900m who in turn exhaled more than a U.S. low-altitude sample when reported as the concentration of NO in exhalate. The respective geometric means were 18.6 ppb with a range of 5.5 to 55.7 among Tibetans, 9.5 ppb with a range of 2.7 to 30.3 ppb among Aymara, and 7.5 ppb with a range from 4.5 to 14.6 ppb among lowlanders. Redrawn from [1] with permission of the publishers.

Figure 3. Inhalation of NO lowers pulmonary artery pressure at high altitude and shows that hypoxic pulmonary vasoconstriction is vasoreactive

A. Pulmonary artery pressure (systolic except for case #1 that is mean arterial pressure) fell after breathing 30–40 ppm NO for 15–40 minutes at 3600–4665m altitude [–5]. Sample #1 was composed of Indian soldiers at 3600m with HAPE (high-altitude pulmonary edema) [6], #2 were HAPE susceptible lowlanders with HAPE, #3 were HAPE susceptible lowlanders without HAPE, #4 were HAPE resistant lowlanders all at 4559m [5], #5 are lowlanders, age 21 years, who suffered perinatal hypoxia and #6 were those who did not at 4559m [7], and #7 were Bolivian Aymara highlanders, age 13–14 years, whose mothers had pre-eclampsia and #8 are those mothers had normal pregancies at 3600m [4]. Effect size, d, of NO on pressures is shown. B. Pulmonary artery pressure after NO inhalation at 3600–4559m (shown on y-axis) declines from high altitude baseline (shown on x-axis). The post-treatment levels are directly associated with pre-treatment levels and the decline across studies is 28% based on linear regression analyses.

Figure 4. HAPE resistant people, whose previous exposure to altitude did not incur HAPE, have generally less reduction of NO or even an increase when re-exposed to altitude than HAPE susceptible people

Figure 4A. Total lung NO falls in the first hours at altitudes above 4000m and then trends slightly toward baseline values among HAPE susceptible individuals and returns to baseline by 38 hours among HAPE resistant individuals [8, 9]. Figure 4B. Healthy HAPE resistant individuals showed increased nitrogen oxides in bronchoalveolar lavage (BAL) fluid at 12 hours. In contrast HAPE susceptible individuals had reductions of nitrogen oxides at altitude regardless of whether or not they suffered from HAPE during this particular study [10].

Figure 5. Plasma NO_2⁻ fell as nitrogen oxide-derived products (NO) in plasma and associated with erythrocytes increased over 20 hours at 4559. [11]

A. Arterial and venous plasma NO_2⁻ and venous S-nitrosothiol (RSNO) concentrations among healthy people generally fell at 3 and 20 hours at 4559m but arterial RSNO values increased strikingly, which may reflect synthesis and/or greater hemoglobin-NO interactions [11]. Arterial-venous differences uniformly decreased. B. Arterial and venous erythrocyte (RBC)-nitrogen oxides [(nitrite, nitrosyl hemoglobin (FeNO) and S-nitrosohemoglobin (SNO:Hb)] and total nitrogen oxides (sum of those in plasma plus those associated with the erythrocytes) at 3 and 20 hours at 4559m among healthy people [11]. Erythrocyte-associated nitrogen oxides increased while plasma NO_2⁻ fell. The arterial-venous differences in erythrocyte nitrogen oxides increased, suggesting greater offloading of NO to tissues at altitude.

Figure 6

Tibetan and Andean highlanders show higher vital capacity NO levels compared with sea level. Tibetans at the same altitude have lower airway NO levels. Among Tibetans, samples at 4700m have lower NO values in both compartments than those at 4200m. The lower values of airway NO may be related to decreased local production of NO by airway epithelial type 2 NO synthase due to limitation of oxygen substrate to the enzyme while higher total lung NO may be related to increasing values of circulating nitrogen products. Source [1, 12]

Figure 7

Tibetans have very high and other highlanders have high levels of plasma or serum nitrogen oxides compared with lowlanders at low altitude [–15].