High-altitude pulmonary edema is aggravated by risk loci and associated transcription factors in HIF-prolyl hydroxylases.

High-altitude (HA, >2500 m) hypoxic exposure evokes several physiological processes that may be abetted by differential genetic distribution in sojourners, who are susceptible to various HA disorders, such as high-altitude pulmonary edema (HAPE). The genetic variants in hypoxia-sensing genes influence the transcriptional output; however the functional role has not been investigated in HAPE. This study explored the two hypoxia-sensing genes, prolyl hydroxylase domain protein 2 (EGLN1) and factor inhibiting HIF-1α (HIF1AN) in HA adaptation and maladaptation in three well-characterized groups: highland natives, HAPE-free controls and HAPE-patients. The two genes were sequenced and subsequently validated through genotyping of significant single nucleotide polymorphisms (SNPs), haplotyping and multifactor dimensionality reduction. Three EGLN1 SNPs rs1538664, rs479200 and rs480902 and their haplotypes emerged significant in HAPE. Blood gene expression and protein levels also differed significantly (P < 0.05) and correlated with clinical parameters and respective alleles. The RegulomeDB annotation exercises of the loci corroborated regulatory role. Allele-specific differential expression was evidenced by luciferase assay followed by electrophoretic mobility shift assay, liquid chromatography with tandem mass spectrometry and supershift assays, which confirmed allele-specific transcription factor (TF) binding of FUS RNA-binding protein (FUS) with rs1538664A, Rho GDP dissociation inhibitor 1 (ARHDGIA) with rs479200T and hypoxia upregulated protein 1 (HYOU1) with rs480902C. Docking simulation studies were in sync for the DNA-TF structural variations. There was strong networking among the TFs that revealed physiological consequences through relevant pathways. The two hydroxylases appear crucial in the regulation of hypoxia-inducible responses.

Beneficial Role of Erythrocyte Adenosine A2B Receptor-Mediated AMP-Activated Protein Kinase Activation in High-Altitude Hypoxia.

BACKGROUND: High altitude is a challenging condition caused by insufficient oxygen supply. Inability to adjust to hypoxia may lead to pulmonary edema, stroke, cardiovascular dysfunction, and even death. Thus, understanding the molecular basis of adaptation to high altitude may reveal novel therapeutics to counteract the detrimental consequences of hypoxia. METHODS: Using high-throughput, unbiased metabolomic profiling, we report that the metabolic pathway responsible for production of erythrocyte 2,3-bisphosphoglycerate (2,3-BPG), a negative allosteric regulator of hemoglobin-O2 binding affinity, was significantly induced in 21 healthy humans within 2 hours of arrival at 5260 m and further increased after 16 days at 5260 m. RESULTS: This finding led us to discover that plasma adenosine concentrations and soluble CD73 activity rapidly increased at high altitude and were associated with elevated erythrocyte 2,3-BPG levels and O2 releasing capacity. Mouse genetic studies demonstrated that elevated CD73 contributed to hypoxia-induced adenosine accumulation and that elevated adenosine-mediated erythrocyte A2B adenosine receptor activation was beneficial by inducing 2,3-BPG production and triggering O2 release to prevent multiple tissue hypoxia, inflammation, and pulmonary vascular leakage. Mechanistically, we demonstrated that erythrocyte AMP-activated protein kinase was activated in humans at high altitude and that AMP-activated protein kinase is a key protein functioning downstream of the A2B adenosine receptor, phosphorylating and activating BPG mutase and thus inducing 2,3-BPG production and O2 release from erythrocytes. Significantly, preclinical studies demonstrated that activation of AMP-activated protein kinase enhanced BPG mutase activation, 2,3-BPG production, and O2 release capacity in CD73-deficient mice, in erythrocyte-specific A2B adenosine receptor knockouts, and in wild-type mice and in turn reduced tissue hypoxia and inflammation. CONCLUSIONS: Together, human and mouse studies reveal novel mechanisms of hypoxia adaptation and potential therapeutic approaches for counteracting hypoxia-induced tissue damage.

Heme oxygenase-1 (HO-1) is constitutively up-regulated in top alpinists.

Alpinists who challenge Mt. Everest need adaptation to hypoxia before the attack of Mt. Everest. Although this adaptation is important for the success of climbing Mt. Everest, the molecular mechanism on the adaptation to hypoxia is not well understood. In order to clarify this mechanism, we investigated hypoxia-induced gene expressions specific for top alpinists using microarray analyses. We report here that heme oxygenase-1 (HO-1) is significantly higher in the blood of top alpinist compared with non-alpinists. Although HO-1 expression of non-alpinists is also up-regulated in response to hypoxia, HO-1 level of the top alpinists are constitutively higher than that of non-alpinists. Serial examinations of HO-1 in one top alpinist revealed that the higher expression of HO-1 is maintained in high-level several months after the attack of top mountains. Taken together with the biochemical function of HO-1 that catalyzes heme into CO and bilirubin, HO-1 expression may improve the circulation and compensate with oxidative tissue damages induced by hypoxia. These data also suggest that peripheral blood has the memory on hypoxia independent of antigens by maintaining the high-level of HO-1 expression in top alpinists, which merits the rapid adaptation to hypoxia for 8000m climbing.

Association of endothelial nitric oxide synthase (eNOS) G894T polymorphism with high altitude pulmonary edema susceptibility: a meta-analysis.

BACKGROUND: High altitude pulmonary edema (HAPE) is a potentially deadly disease associated with exposure to altitudes greater than 3000 m. Individuals who have previously experienced HAPE are at a significantly higher risk of recurrence, suggesting an underlying genetic component to HAPE pathogenesis. In a previous nuclear genomic study of individual variation in susceptibility to HAPE, the endothelial nitric oxide synthase (eNOS) gene G894T polymorphism was identified as being associated with HAPE. However, another study found no association. Because of the low incidence of HAPE, sample sizes in current reports have been relatively limited. In this study, the association between the eNOS G894T polymorphism and HAPE was assessed through a meta-analysis of published data. METHODS: The literature was searched in PubMed, Web of Science, and Embase for papers published before July 15, 2011. A fixed-effects model and a random-effects model were applied (Revman 5.0) on the basis of heterogeneity, and study quality was assessed in duplicate. RESULTS: Five studies with 360 HAPE patients and 469 control subjects were analyzed. There were no significant differences between carriers of the eNOS 894G and 894T polymorphism alleles in terms of the risk of developing HAPE. CONCLUSIONS: The eNOS 894G and 894T polymorphism alleles are not associated with HAPE incidence.

B-type natriuretic peptide, vascular endothelial growth factor, endothelin-1, and nitric oxide synthase in chronic mountain sickness.

The pathogenesis of chronic mountain sickness (CMS) may involve vasoactive peptides. The aim of this study was to investigate associations between CMS and levels of B-type natriuretic peptide (BNP), vascular endothelial growth factor (VEGF), endothelin-1 (ET-1), and endothelial nitric oxide synthase (eNOS). A total of 24 patients with CMS and 50 control subjects residing at 4,300 m participated in this study. Mean pulmonary arterial pressure (mPAP) was measured by echocardiography. Serum BNP, VEGF, ET-1, and eNOS were measured. Receiver operator characteristic curves to assess the balance of sensitivity and specificity for CMS were constructed. As a result, patients with CMS had significantly greater mPAP compared with controls and had lower arterial O(2) saturation (Sa(O(2))). Both BNP and ET-1 correlated positively with mPAP and negatively with Sa(O(2)), whereas serum VEGF levels were inversely correlated with Sa(O(2)); eNOS correlated negatively with mPAP and positively with Sa(O(2)). Median concentrations of BNP were greater in patients with CMS compared with those without CMS: 369 pg/ml [interquartile range (IQR) = 336-431] vs. 243 pg/ml (IQR = 216-279); P < 0.001. Similarly, concentrations of VEGF [543 pg/ml (IQR = 446-546) vs. 243 pg/ml (IQR = 216-279); P < 0.001] and ET-1 [14.7 pg/ml (IQR = 12.5-17.9) vs. 11.1 pg/ml (IQR = 8.7-13.9); P = 0.05] were higher in those with CMS compared with those without, whereas eNOS levels were lower in those with CMS [8.90 pg/ml (IQR 7.59-10.8) vs. 11.2 pg/ml (9.13-13.1); P < 0.001]. The areas under the receiver operator characteristic curves for diagnosis of CMS were 0.91, 0.93, 0.77, and 0.74 for BNP, VEGF, ET-1, and eNOS, respectively. In age- and biomarker-adjusted logistic regression, BNP and VEGF were positively predictive of CMS, whereas eNOS was inversely predictive. In conclusion, severe chronic hypoxemia and consequent pulmonary hypertension in patients with CMS may stimulate release of natriuretic peptides and angiogenic cytokines. These vasoactive peptides may play an important role in the pathogenesis and clinical expression of CMS and may indicate potential prognostic factors in CMS that could serve as targets for therapeutic trials or clinical decision making.

Possible role of cholinesterase inhibitors on memory consolidation following hypobaric hypoxia of rats.

High altitude (HA) generates a deleterious effect known as hypobaric hypoxia (HBH). This causes severe physiological and psychological changes such as acute mountain sickness (AMS) and cognitive functions in terms of learning and memory. The present study has evaluated the effect of cholinesterase inhibitors on memory consolidation following HBH. Adult male Sprague Dawley rats (80-90 days old) with an average body weight of 250 ± 25 g were used. Rats were assessed memory consolidation by using Morris water maze (MWM) for 8 days. After assessment of memory consolidation, rats were then exposed to HBH in stimulated chamber for 7 days at 6,100 m. After exposure to HBH, the memory consolidation of rats has been assessed in MWM. The results showed that there was memory consolidation impairment in HBH-exposed rats as compared to normoxic rats in terms of time spent in quaradents, rings, and counters. The rats which have been treated with physostigmine (PHY) and galantamine (GAL) showed better time spent in quaradents, rings, and counters as compared with hypoxic rats. In conclusion, the cholinesterase inhibitors could ameliorate the impairment of memory consolidation following HBH.

Effects of chronic hypoxia on soluble guanylate cyclase activity in fetal and adult ovine cerebral arteries.

A broad variety of evidence obtained largely in pulmonary vasculature suggests that chronic hypoxia modulates vasoreactivity to nitric oxide (NO). The present study explores the general hypothesis that chronic hypoxia also modulates cerebrovascular reactivity to NO, and does so by modulating the activity of soluble guanylate cyclase (sGC), the primary target for NO in vascular smooth muscle. Pregnant and nonpregnant ewes were maintained at either sea level or at 3,820 m for the final 110 days of gestation, at which time middle cerebral arteries from term fetal lambs and nonpregnant adults were harvested. In both fetal and adult arteries, NO-induced vasodilatation was attenuated by chronic hypoxia and completely inhibited by 10 microM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a selective inhibitor of sGC. sGC abundance (in ng sGC/mg protein) measured via Western immunoblots was approximately 10-fold greater in fetal (17.6 +/- 1.6) than adult (1.7 +/- 0.3) arteries but was not affected by chronic hypoxia. The specific activity of sGC (in pmol cGMP.microg sGC(-1).min(-1)) was similar in fetal (255 +/- 64) and adult (280 +/- 75) arteries and was inhibited by chronic hypoxia in both fetal (120 +/- 10) and adult (132 +/- 26) arteries. Rates of cGMP degradation (in pmol cGMP.mg protein(-1).min(-1)) were similar in fetal (159 +/- 59) and adult (134 +/- 36) arteries but were not significantly depressed by chronic hypoxia in either fetal (115 +/- 25) or adult (108 +/- 25) arteries. The cGMP analog 8-(p-chlorophenylthio)-cGMP was a more potent vasorelaxant in fetal (pD(2) = 4.7 +/- 0.1) than adult (pD(2) = 4.3 +/- 0.1) arteries, but its ability to promote vasodilatation was not affected by chronic hypoxia in either age group. Together, these results reveal that hypoxic inhibition of NO-induced vasodilatation is attributable largely to attenuation of the specific activity of sGC and does not involve significant changes in sGC abundance, cGMP-phosphodiesterase activity, or the vasorelaxant activity of protein kinase G.

The effect of angiotensin-converting enzyme genotype on acute mountain sickness and summit success in trekkers attempting the summit of Mt. Kilimanjaro (5,895 m).

The I-allele rather than the D-allele of the human angiotensin converting enzyme (ACE) gene has been associated with high-altitude mountaineering success. We investigated whether the I-allele was associated with summit success, and also with AMS development, in altitude-naïve trekkers. Subjects ascended from 1,860 m to the summit over 4 days (n = 34, 'direct-profile') or 5 days (n = 82, 'slower-profile'). Proportionally more II direct-profile subjects were successful than ID or DD, although the difference was not significant (100% of II subjects, 52% ID and 43% DD, P = 0.09). There was no difference in success amongst subjects on the slower-profile (50% II, 45% ID and 58% DD, P = 0.54). There was a non-significant trend for increasing AMS scores in ID/DD subjects. Amongst tourist trekkers on Mt. Kilimanjaro the I-allele is not associated with summit success. No evidence is found to support an association between ACE genotype and AMS development.

Endothelial nitric oxide synthase polymorphisms do not influence pulmonary artery systolic pressure at altitude.

Previous genetic association studies in high-risk subjects have suggested that polymorphisms in the gene encoding endothelial nitric oxide synthase (eNOS) may be associated with susceptibility to high altitude pulmonary edema (HAPE). We aimed to determine whether eNOS polymorphisms influence systolic pulmonary artery pressure measurements (PASP) in healthy trekkers ascending to high altitude. We examined two polymorphisms of the eNOS gene in Caucasian volunteers: Glu298Asp variant and 27-base pair (bp) variable number of tandem repeats polymorphism (27-bp VNTR). In 33 subjects, the relationships between polymorphisms and absolute pulmonary artery systolic pressure measurements (PASP), determined by echocardiography, were assessed at sea level and 1, 3, and 7 days after acute ascent by vehicle transport to 5200 m. As expected, there was a significant rise in pulmonary artery pressure on ascent to high altitude. By contrast, at sea level and at each time point at high altitude, no difference was found in mean PASP according to eNOS polymorphism. We found no association of Glu298Asp and 27-bp VNTR polymorphisms in the eNOS gene with PASP in a population of healthy trekkers at low or high altitude.

Neuronal NADPH-d/NOS expression in the nodose ganglion of severe hypoxic rats with or without mild hypoxic preconditioning.

This study aimed to test the hypothesis that mild hypoxic preconditioning (MHPC)-induced NOS expression would attenuate the neuropathological changes in the nodose ganglion (NG) of severe hypoxic exposure (SHE) rats. Thus, the young adult rats were caged in the altitude chamber for 4 weeks prior to SHE for 4 h to gain hypoxic preconditioning. The altitude chamber was used to set the height at the level from 5500 m (0.50 atm; pO2=79 Torr) to 10,000 m (0.27 atm; pO2=43 Torr) for MHPC and SHE, respectively. The experimental animals were allowed to survive for 0, 7, 14, 30 and 60 successive days, respectively. Nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry and neuronal nitric oxide synthase (nNOS) immunohistochemistry were used to detect NADPH-d/nNOS reactivity in the NG at various time points following hypoxic exposure. The present results showed that about 38% of the neurons in the NG displayed NADPH-d/nNOS positive [NADPH-d/nNOS(+)] in normoxic rats. In SHE rats, a peak in the percentage (71%) and staining intensity (230%) of NADPH-d/nNOS(+) nodose neurons at 0 day, which then gradually decreased at 7-60 days. About 25% of the nodose neurons died 60 days after SHE. However, in MHPC rats subjected to SHE, NADPH-d/nNOS(+) neurons peaked in the percentage (51%) and staining intensity (171%) at 0 day, which then decreased at 7-60 days. In addition, neuronal survival was markedly increased by MHPC. These results suggested that MHPC might have a neuroprotective effect that reduces the susceptibility of the nodose neurons to NOS mediated neuropathy subsequent to SHE.

Developmental changes of erythrocyte catalase activity in rats exposed to acute hypoxia.

The erythrocytes represent an important source of antioxidant capacity of the blood. Catalase (EC 1.11.1.6.) is one of the enzymatic components of their antioxidant defense system. The objective of this study was to follow erythrocyte catalase (CAT) in 7-, 15-, 21-, 35-, 60- and 90-day-old Wistar rats of both sexes in normoxia and after exposure to intensive acute hypobaric hypoxia. During the development CAT activity increases in both sexes, but the rise was usually higher in females. Hypobaric hypoxia increased CAT activity in all studied age groups of both sexes. However, higher CAT activity in females was less affected by hypoxia than the lower activity in males. This was true for nearly all age groups studied. It can be concluded that both ontogenetic aspects and sex differences play a major role in establishing the activity of CAT, which is an important part of the antioxidant defense of the organism.

High altitude increases the expression of hypoxia-inducible factor 1α and inducible nitric oxide synthase with intest-inal mucosal barrier failure in rats.

BACKGROUND: The failure of intestinal mucosal barrier may induce multiple organ dysfunction and systemic inflammatory response syndrome, but little work has been done on whether hypobaric hypoxia related to the failure of intestinal mucosal barrier. AIMS: To study the expression of hypoxia-inducible factor 1α (HIF-1α), inducible nitric oxide synthase (iNOS) and morphological changes of intestinal mucosa in albino rats at different altitude. METHODS: 30 male Wistar rats raised in plain for one month were randomly divided into 3 groups: Plain 500 m group (n=10), High-altitude (HA) 3842 m group (n=10) and HA4767 m group (n=10). Each group was delivered to different altitude area at the same shipping time and executed after 3 days' exposure to different altitude. Intestinal segments with the same location of all rats were removed for morphological analyses. Morphologic parameters (villous height, crypt depth, mucosal wall thickness and villous surface area) were measured by optical and scanning electron microscope. The expression of iNOS and HIF-1α were detected by immunohistochemistry. RESULTS: Morphological indexes in higher altitude groups were exacerbated obviously compared with those of lower altitude groups. While the expression of iNOS and HIF-1α in higher altitude groups were significantly increased than those of lower altitude groups. Linear correlation analysis showed that the expression of iNOS was positively correlated with that of HIF-1α. CONCLUSIONS: Hypobaric hypoxia increases the expression of HIF-1α and iNOS in intestinal mucosa, however exacerbates the mucous morphologic parameters with altitude increasing. HIF-1α may regulate the expression of iNOS and be involved in the damage of intestinal mucosa.

Statin use and the development of acute mountain sickness.

INTRODUCTION: Our prior publication suggested that elevated serum concentrations of low-density lipoprotein (LDL) was protective against the development of acute mountain sickness (AMS) while an inflammatory response was contributory to its development. The use of 3-hydroxy-3-methylglutaryl-coenzyme-A-reductase inhibitors ("statins") may be of interest to those traveling to altitude-these medications will lower serum LDL concentrations, but are also reported to have anti-inflammatory properties. METHODS: Prior to flying from sea level to the South Pole (∼10,498.7 ft or 3200 m) during the austral summer months of 2005-2006 and 2006-2007, the 248 subjects provided informed consent. Questionnaires related to AMS symptoms, acetazolamide use, personal history, and anthropometrics were paired with results from blood samples. Statin use was reported by six subjects who were matched for age, sex, altitude of residence, and acetazolamide use with seven subjects not using a statin. RESULTS: No significant differences were identified in any of the matched variables between the groups. No statin users reported symptoms of AMS while 57% of participants not using a statin did report AMS symptoms (P = 0.03). No significant difference was noted between LDL levels in the statin group (108.3 ± 61.0) as compared to the group not taking statins (104.6 ± 22.1) (P = 0.88). DISCUSSION: Our previous results suggested that elevated LDL was protective while an inflammatory response was contributory with respect to AMS development. The present results suggest that statin use may provide protection against AMS symptoms, possibly through an anti-inflammatory property, despite its lipid-lowering capacity. Harrison MF, Johnson BD. Statin use and the development of acute mountain sickness.

Acral paresthesias in the Andes and neurology at sea level.

BACKGROUND: Thirty-nine percent of permanent altitude dwellers in the Andes experience acral paresthesias. METHODS: Clinical examinations, sural nerve biopsies, and electrodiagnostic studies on peripheral nerves were performed on 15 men. Ten Cerro de Pasco (CP) natives living at 4,338 meters were biopsied. Three of these subjects had no burning feet/burning hands (BF/BH); three had BF/BH; and four had chronic mountain sickness (CMS), a maladaptation syndrome resulting from living in the Andes, all with BF/BH. Three patients with CMS were biopsied in Lima within hours after leaving CP. Two normal Lima natives were biopsied in Lima. Symptom scores for BF/BH and CMS score ratings were used. The nerves were assayed for Na+, K+ adenosine triphosphatase (ATPase), cytochrome oxidase (CO), substance P (SP), and endothelin (ET). RESULTS: Low ATPase was inversely related to symptom scores and CMS scores (p < 0.001). Patients with CMS biopsied in normoxia (Lima) had ATPase levels similar to those of controls. Nerve motor conduction velocities and sensory action potentials were normal. CO was inversely related to age (p < 0.03) and no relation of SP to any variable was found. ET levels were lower in sea level natives (p = 0.04). CONCLUSIONS: Acral paresthesias are associated with low ATPase in peripheral nerves. Lower ET levels of sea level natives likely reflect lowered release from vasa nervorum.

Hypobaric hypoxia induces fos and neuronal nitric oxide synthase expression in the paraventricular and supraoptic nucleus in rats.

This study examined the effects of high altitude exposure on neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus in adult and neonatal rats. In adult control rats, occasional Fos-like immunoreactive neurons were localized in both the hypothalamic nuclei. A marked increase in Fos positive cells was induced at 1-4 h following altitude exposure but it was reduced to levels comparable to the controls at 24 h. The expression of neuronal nitric oxide synthase (nNOS) immunoreactivity in the PVN and SON followed a similar temporal pattern. The nNOS immunoreactivity, which was constitutively expressed in the hypothalamic neurons in the control rats, was noticeably augmented at 1-4 h, but it was comparable to the controls at 24 h following altitude exposure. In postnatal rats, Fos expression was not detected in the hypothalamic neurons of the controls. Induction of Fos expression was observed in some neurons at 1-4 h following altitude exposure but it was diminished at 24 h. There was no noticeable change in nNOS expression in both the control and altitude exposed postnatal rats; in both instances, it was barely detectable. It is concluded that both the PVN and SON of the adult rats are activated at high altitude exposure and that they may be involved in the regulation of neuroendocrine, cardiovascular and respiratory functions in hypobaric hypoxia. This study has also shown the differential response of the hypothalamus neurons between the two age groups to the hypoxic insult. Our results suggest that the adult neurons are probably more sensitive to the reduced oxygen levels in hypobaric hypoxia, as reflected by the upregulated NOS expression in this age group but not in the postnatal rats.

Changes in the serum LDH isoenzymes in monkey during chronic exposure to simulated high altitude.

When the monkey was exposed to a simulated high altitude of 18,000 ft (5,486 m) for 30 d, the serum LDH activity was increased to its maximum in 1 week. After the monkey returned to sea level, the enzyme activity showed a rapid recovery. On the basis of electrophoretic analysis of LDH isoenzymes, the percentages of LDH-1 and LDH-2 were decreased during the first 2-3 weeks of hypoxic exposure whereas those of LDH-3, LDH-4 and LDH-5 were increased. After 2 or 3 weeks of hypoxic exposure, LDH-3, LDH-4, and LDH-5 become predominant, indicating that the isoenzyme pattern shifted to an anaerobic form from an aerobic form. These results clearly showed that relative proportions of the five isoenzymes were significantly altered by chronic hypoxia of high altitude and that the elevation of total serum LDH activity induced by hypoxia came predominantly from rapid accumulation of M type LDH isoenzymes in serum.

Effect of time exposure to high altitude on zinc and copper concentrations in human plasma.

BACKGROUND: Research has focused mainly on the relationship of zinc and copper contents and physical stresses like running, cycling, etc. It has also been reported that other forms of stresses change the concentration of these trace elements in humans. However,there are no reports on the effects of high altitude induced hypoxic stress on the plasma levels of these metals. Since hypoxia is one of the important stresses, we considered it appropriate to observe the changes in the levels of zinc and copper concentrations and in certain related zinc and copper enzymes and hormones in the plasma of human volunteers on acute induction to high altitude. From these findings, we intended to ascertain whether supplementation of these trace elements would be required for optimal health under such conditions. HYPOTHESIS: On acute induction to hypoxia, contents of these trace elements may change as the requirements of stressed organs and tissue may increase. Hence, further supplementation may be beneficial under hypoxic stress for better adaptability. METHOD: Volunteers were divided into two groups: with and without zinc and copper salt supplementation. Blood samples were collected at sea level and on induction to acute hypoxia on days 3 and 10. Trace mineral contents and their related enzyme (alkaline phosphatase) and hormone (ceruloplasmin) levels were determined in plasma samples. RESULTS: Plasma zinc contents were significantly reduced upon induction to high altitude in the non-supplemented group, but not in the zinc-supplemented group. Alkaline phosphatase activity increased significantly upon induction to the high altitude stress. The enzyme activity remained elevated up to day 10 of the stress. Plasma copper contents and ceruloplasmin activity did not change upon induction to high altitude. CONCLUSION: Under hypoxic stress, circulating levels of zinc and alkaline phosphatase in plasma changed appreciably as plasma zinc was transported into the organs and tissues. However, circulating levels of copper and ceruloplasmin in plasma did not change, indicating no extra supplementation of copper is required under hypoxic stress.

[Pharmacological correction of lipid peroxidation during hypoxia and possibility to enhance human resistance to high altitude by using preparations of the metabolic type of action]. / Farmakologicheskaia korrektsiia protsessa lipoperoksidatsii pri gipoksii i vozmozhnost' povysheniia vysotnoi ustoichivosti cheloveka s pomoshch'iu preparatov metabolicheskogo tipa deistviia.

In simulating acute hypoxic hypoxia with the participation of male volunteers, the authors investigated the antihypoxic and antioxidative activity of metabolic drugs (jakton, amtizole succinate, nootropil, probucol, and a mixture which consists of jakton, amtizole succinate, and probucol). The pharmaceuticals were shown to have heterodirectional effects on lipid peroxidative processes. Drugs having a pronounced antioxidative activity (such as probucol and the mixture) promotes oxygen utilization during hypoxia and posthypoxic reoxygenation chiefly by the oxygenase pathway. This rearrangement of oxygen utilization processes caused an increase in human high-altitude resistance. The use of the above drugs is a promising trend in the development of an adaptative response to hypoxia in persons engaged in hazardous jobs.

[Cerebral lactate dehydrogenase isoenzymes in different hypoxic conditions]. / Izofermenty laktatdegidrogenazy mozga v raznykh usloviiakh kislorodnogo golodaniia.

Spectrum of LDH isozymes and their activity were compared in animal brain tissue under circulatory and hypoxic forms of hypoxia. Dynamics and manifestation of alterations observed correlated primarily with the type of oxygen deficiency as well as with its severity and length of action. Development of oxygen deficiency in brain tissue was accompanied by increase in total LDH activity and by elevation in content of M-subunits, typical for "anaerobic" spectrum of LDH isozymes, with simultaneous decrease in amount of H-subunits.

The activity, protein, and mRNA expression of CYP2E1 and CYP3A1 in rats after exposure to acute and chronic high altitude hypoxia.

The effects of exposure to acute and chronic high altitude hypoxia on the activity and expression of CYP2E1 and CYP3A1 were examined in rats. Rats were divided into low altitude (LA, 400 m), acute moderate altitude hypoxia (AMH, 2800 m), chronic moderate altitude hypoxia (CMH, 2800 m), acute high altitude hypoxia (AHH, 4300 m), and chronic high altitude hypoxia groups (CHH, 4300 m). Probe drugs were administrated orally to all five groups. Then the serum concentration of probe drug and its metabolite was determined by RP-HPLC. The activity of CYP2E1 and CYP3A1 was evaluated using the ratio of the metabolite to chlorzoxazone and testosterone, respectively. ELISA and real-time PCR were used to analyze the protein and mRNA expression of CYP2E1 and CYP3A1 in liver microsomes, respectively. Chronic high altitude hypoxia caused significant decreases in the activity and protein and mRNA expression of rat CYP2E1 and CYP3A1 in vivo. Acute high altitude hypoxia was not found to change the activity, protein or mRNA expression of rat CYP2E1 or CYP3A1. This study showed significant changes in the activity and protein and mRNA expression of CYP2E1 or CYP3A1 in rats after exposure to chronic high altitude hypoxia.