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. 2007 Nov 6;104(45):17593-8.
doi: 10.1073/pnas.0707462104. Epub 2007 Oct 30.

Higher blood flow and circulating NO products offset high-altitude hypoxia among Tibetans

S C Erzurum  1 , S Ghosh, A J Janocha, W Xu, S Bauer, N S Bryan, J Tejero, C Hemann, R Hille, D J Stuehr, M Feelisch, C M Beall
Affiliations

Higher blood flow and circulating NO products offset high-altitude hypoxia among Tibetans

S C Erzurum et al. Proc Natl Acad Sci U S A. .

Abstract

The low barometric pressure at high altitude causes lower arterial oxygen content among Tibetan highlanders, who maintain normal levels of oxygen use as indicated by basal and maximal oxygen consumption levels that are consistent with sea level predictions. This study tested the hypothesis that Tibetans resident at 4,200 m offset physiological hypoxia and achieve normal oxygen delivery by means of higher blood flow enabled by higher levels of bioactive forms of NO, the main endothelial factor regulating blood flow and vascular resistance. The natural experimental study design compared Tibetans at 4,200 m and U.S. residents at 206 m. Eighty-eight Tibetan and 50 U.S. resident volunteers (18-56 years of age, healthy, nonsmoking, nonhypertensive, not pregnant, with normal pulmonary function) participated. Forearm blood flow, an indicator of systemic blood flow, was measured noninvasively by using plethysmography at rest, after breathing supplemental oxygen, and after exercise. The Tibetans had more than double the forearm blood flow of low-altitude residents, resulting in greater than sea level oxygen delivery to tissues. In comparison to sea level controls, Tibetans had >10-fold-higher circulating concentrations of bioactive NO products, including plasma and red blood cell nitrate and nitroso proteins and plasma nitrite, but lower concentrations of iron nitrosyl complexes (HbFeIINO) in red blood cells. This suggests that NO production is increased and that metabolic pathways controlling formation of NO products are regulated differently among Tibetans. These findings shift attention from the traditional focus on pulmonary and hematological systems to vascular factors contributing to adaptation to high-altitude hypoxia.

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Conflict of interest statement

The authors declare no conflict of interest.%

Figures

Fig. 1.
Fig. 1.
Hemodynamics and oxygen delivery among Tibetan and sea level populations. (A and B) Tibetan forearm blood flow (A) and oxygen delivery (B) were greater than sea level controls. (C) The greater forearm blood flow of Tibetans compared with the sea level population accounts for the greater oxygen delivery (R2 = 0.96 and P < 0.001). (D) Higher hemoglobin concentrations of Tibetans as compared with sea level population contributes modestly to greater oxygen delivery (R2 = 0.13 and P < 0.001).
Fig. 2.
Fig. 2.
NO products in the circulation of Tibetan and sea level populations. (A) Amperometric detection (pA) of plasma NO release from nitrite. Arrows identify sample injections. (B and C) Tibetan nitrite (B) and nitrate (C) levels in plasma samples were higher than sea level controls (all P < 0.001). (D) EPR determination of HbFeIINO in red blood cell samples. EPR spectra of the tetranitrosyl HbFeIINO standard is shown in Left. EPR spectra of blood obtained from a Tibetan participant (Right) revealed lower levels of HbFeIINO complex than blood obtained from a sea level volunteer (Center). Data shown are representative of the mean values of the population samples (P < 0.03).
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