Differences in the control of breathing between Andean highlanders and lowlanders after 10 days acclimatization at 3850 m.

We used Duffin's isoxic hyperoxic ( mmHg) and hypoxic ( mmHg) rebreathing tests to compare the control of breathing in eight (7 male) Andean highlanders and six (4 male) acclimatizing Caucasian lowlanders after 10 days at 3850 m. Compared to lowlanders, highlanders had an increased non-chemoreflex drive to breathe, characterized by higher basal ventilation at both hyperoxia (10.5 +/- 0.7 vs. 4.9 +/- 0.5 l min(1), P = 0.002) and hypoxia (13.8 +/- 1.4 vs. 5.7 +/- 0.9 l min(1), P < 0.001). Highlanders had a single ventilatory sensitivity to CO(2) that was lower than that of the lowlanders (P < 0.001), whose response was characterized by two ventilatory sensitivities (VeS1 and VeS2) separated by a patterning threshold. There was no difference in ventilatory recruitment thresholds (VRTs) between populations (P = 0.209). Hypoxia decreased VRT within both populations (highlanders: 36.4 +/- 1.3 to 31.7 +/- 0.7 mmHg, P < 0.001; lowlanders: 35.3 +/- 1.3 to 28.8 +/- 0.9 mmHg, P < 0.001), but it had no effect on basal ventilation (P = 0.12) or on ventilatory sensitivities in either population (P = 0.684). Within lowlanders, VeS2 was substantially greater than VeS1 at both isoxic tensions (hyperoxic: 9.9 +/- 1.7 vs. 2.8 +/- 0.2, P = 0.005; hypoxic: 13.2 +/- 1.9 vs. 2.8 +/- 0.5, P < 0.001), although hypoxia had no effect on either of the sensitivities (P = 0.192). We conclude that the control of breathing in Andean highlanders is different from that in acclimatizing lowlanders, although there are some similarities. Specifically, acclimatizing lowlanders have relatively lower non-chemoreflex drives to breathe, increased ventilatory sensitivities to CO(2), and an altered pattern of ventilatory response to CO(2) with two ventilatory sensitivities separated by a patterning threshold. Similar to highlanders and unlike lowlanders at sea-level, acclimatizing lowlanders respond to hypobaric hypoxia by decreasing their VRT instead of changing their ventilatory sensitivity to CO(2).

Adaptation and mal-adaptation to ambient hypoxia; Andean, Ethiopian and Himalayan patterns.

The study of the biology of evolution has been confined to laboratories and model organisms. However, controlled laboratory conditions are unlikely to model variations in environments that influence selection in wild populations. Thus, the study of "fitness" for survival and the genetics that influence this are best carried out in the field and in matching environments. Therefore, we studied highland populations in their native environments, to learn how they cope with ambient hypoxia. The Andeans, African highlanders and Himalayans have adapted differently to their hostile environment. Chronic mountain sickness (CMS), a loss of adaptation to altitude, is common in the Andes, occasionally found in the Himalayas; and absent from the East African altitude plateau. We compared molecular signatures (distinct patterns of gene expression) of hypoxia-related genes, in white blood cells (WBC) from Andeans with (n = 10), without CMS (n = 10) and sea-level controls from Lima (n = 20) with those obtained from CMS (n = 8) and controls (n = 5) Ladakhi subjects from the Tibetan altitude plateau. We further analyzed the expression of a subset of these genes in Ethiopian highlanders (n = 8). In all subjects, we performed the studies at their native altitude and after they were rendered normoxic. We identified a gene that predicted CMS in Andeans and Himalayans (PDP2). After achieving normoxia, WBC gene expression still distinguished Andean and Himalayan CMS subjects. Remarkably, analysis of the small subset of genes (n = 8) studied in all 3 highland populations showed normoxia induced gene expression changes in Andeans, but not in Ethiopians nor Himalayan controls. This is consistent with physiologic studies in which Ethiopians and Himalayans show a lack of responsiveness to hypoxia of the cerebral circulation and of the hypoxic ventilatory drive, and with the absence of CMS on the East African altitude plateau.

Autonomic regulation during orthostatic stress in highlanders: comparison with sea-level residents.

This report is a comparison of orthostatic tolerance and autonomic function in three groups of high-altitude dwellers: Andeans with and without chronic mountain sickness (CMS) and healthy Ethiopians. Results are compared with those from healthy sea-level residents. The aim was to determine whether different high-altitude populations adapted differently to the prevailing hypobaric hypoxia. Orthostatic tolerance was assessed using a test involving head-up tilt (HUT) and graded lower body suction. This was performed at the subjects' resident altitude. Blood pressure (Portapres) and R-R interval (ECG) were recorded during the test, and spectral and cross-spectral analyses of heart period and systolic blood pressure time series were performed using data obtained both while supine and during HUT. The transfer function gain in the low-frequency range (LF, approximately 0.1 Hz) at the point of maximal coherence was used as a measure of cardiac baroreflex sensitivity (BRS). As previously reported, Peruvians displayed an unusually good orthostatic tolerance, while Ethiopians showed an orthostatic tolerance comparable to that of healthy sea-level residents. There were no significant differences between groups in the supine values of the spectral analysis results. Head-up tilt induced the expected changes in Ethiopians (an increase in the LF components and a decrease in the respiratory components) but not in Andeans. Cross-spectral analysis showed abnormal results from all groups of high-altitude dwellers. These results indicate that Ethiopians, but not Peruvians, behave similarly to sea-level residents in terms of orthostatic tolerance and autonomic responses to orthostatic stress, as assessed from spectral analyses, and this indicates good adaptation to their environment. However, in all the high-altitude groups the results of cross-spectral analysis were atypical, suggesting some degree of impairment in baroreflex function.

Cerebral vasodilatation to exogenous NO is a measure of fitness for life at altitude.

BACKGROUND AND PURPOSE: Andean highlanders, unlike Ethiopians, develop chronic mountain sickness (CMS), a maladaptation to their native land. Ambient hypoxia induces NO-mediated vasodilatation. Fitness for life at altitude might be revealed by cerebrovascular responses to NO. METHODS: Nine altitude-native men were examined at 3622 and 794 m in Ethiopia and compared with 9 altitude-native Andean men tested at 4338 and 150 m in Peru. We assessed CMS scores, hematocrits, end-tidal pressure of carbon dioxide (P(ET)co2), oxygen saturations, and cerebral blood flow velocity (CBV). We evaluated fitness for life at altitude from the cerebrovascular response to an exogenous NO donor. RESULTS: At high altitude, CMS scores and hematocrits were higher in Andeans, and they had lower oxygen saturations. Ethiopians had higher P(ET)co2 at all study sites. At low altitude, saturations were similar in both groups. Responsiveness of the cerebral circulation to NO was minimal in Ethiopians at low altitude, whereas Andeans had a large response. In contrast, at high altitude, Ethiopians showed large responses, and Peruvians had minimal responses. CONCLUSIONS: By our measure, high altitude-native Peruvians were well-adapted lowlanders, whereas Ethiopian highlanders were well adapted to altitude life. Environmental pressures were sufficient for human adaptation to chronic hypoxia in Africa but not South America. The mechanisms underlying these differences are unknown, although studies of neurovascular diseases suggest that this may be related to a NO receptor polymorphism.