Estrogen receptor (ESR1 and ESR2)-mediated activation of eNOS-NO-cGMP pathway facilitates high altitude acclimatization.

Higher levels of circulatory nitric oxide (NO) and NO metabolites reportedly facilitate high altitude acclimatization. But the underlying factors and molecular pathways promoting NO production at high altitude has been poorly characterized. Studying healthy lowlanders at sea level (C, lowlander) and high altitude (3500 m, after day 1, 4 and 7 of ascent), we report higher protein levels of eNOS and eNOSSer1177, higher plasma levels of BH4, NOx (nitrate and nitrites), cGMP and lower levels of endogenous eNOS inhibitor ADMA during healthy high altitude acclimatization. Our qRT-PCR-based gene expression studies identified higher levels of eNOS/NOS3 mRNA along with several other eNOS pathway genes like CALM1, SLC7A1 and DNM2. In addition, we observed higher mRNA levels of estrogen (E2) receptors ERα/ESR1 and ERß/ESR2 at high altitude that transcriptionally activates NOS3. We also observed higher mRNA level of membrane receptor ERBB2 that phosphorylates eNOS at Ser1177 and thus augments NO availability. Evaluating E2 biosynthesis at high altitude, we report higher plasma levels of CYP11A1, CYP19A1, E2, lower levels of testosterone (T) and T/E2 ratio as compared to sea level. Correlation studies revealed moderate positive correlation between E2 and NOx (R = 0.68, p = 0.02) after day 4 and cGMP (R = 0.69, p = 0.02) after day 7 at high altitude. These findings suggest a causative role of E2 and its receptors ESR1 and ESR2 in augmenting eNOS activity and NO availability during healthy high altitude ascent. These results will aid in better understanding of NO production during hypobaric hypoxia and help in designing better high altitude acclimatization protocols.

Plasma kallikrein-bradykinin pathway promotes circulatory nitric oxide metabolite availability during hypoxia.

Nitric oxide (NO) is an indispensible signalling molecule under hypoxic environment for both ethnic high altitude natives as well as lowland residents at high altitude. Several studies have reported higher levels of NO and bioactive NO products for both high altitude natives as well as healthy high altitude sojourners. But the metabolic pathways regulating the formation of NO and associated metabolites during hypoxia still remain elusive. In the present study, we profiled plasma proteomes of Ladakhi natives (3520 m) and lowland residents (post 1, 4 and 7 days stay) at the same altitude. This has resulted in the identification of 208 hypoxia responsive proteins (p < 0.05) and kininogen-plasma kallikrein-bradykinin as a major pathway regulating eNOS activity during hypoxia. In corroboration, we have also observed significant higher levels of plasma biomarkers for NO production (l-citrulline, nitrite, nitrate) for Ladakhi natives as compared to both lowland individuals healthy high altitude sojourners indicating higher NO availability. Since hypoxia-induced free radicals reduce NO availability, we also measured plasma levels of 8-isoprostanes, protein carbonyls and protein oxidation products in both Ladakhi natives and high altitude sojourners. Interestingly Ladakhi natives had significant lower levels of oxidative stress in comparison to high altitude sojourners but higher than lowland controls. These results suggest that plasma kallikrein-bradykinin-eNOS pathway along with moderate oxidative stress contributes to high altitude adaptation of Ladakhi natives.

Yoga Practice Improves Physiological and Biochemical Status at High Altitudes: A Prospective Case-control Study.

UNLABELLED: Context • High altitude (HA) is a psychophysiological stressor for natives of lower altitudes. Reducing the morbidity and optimizing the performance of individuals deployed in an HA region has been attempted and reported with varied results. Objective • The present study intended to explore the effects of comprehensive yogic practices on the health and performance of Indian soldiers deployed at HAs. Design • The research team designed a prospective, randomized, case-control study. SETTING: The study was done at Karu, Leh, India, at an altitude of 3445 m. Participants • Fully acclimatized soldiers in the Indian army were randomly selected from those posted to HA regions (ie, altitudes >3000 m). Intervention • The soldiers were divided into 2 groups of equal size. The first group, the control group, carried out the routine activities for physical training in the Indian army. The second group, the intervention group practiced a comprehensive yoga package, including physical asanas, pranayama, and meditation, and did not perform the physical training that the first group did. Both groups were monitored during their activities. Outcome Measures • A wide and comprehensive range of anthropometrical, physiological, biochemical, and psychological parameters were measured: (1) height and weight; (2) body fat percentage (BFP); (3) heart rate (HR); (4) respiratory rate (RR); (5) systolic and diastolic blood pressure (DPB); (6) peripheral saturation of oxygen; (7) end tidal CO2 (EtCO2); (8) chest expansion; (9) pulmonary function; (10) physical work capacity (VO2Max); (11) hematological variables; (12) lipid profile; (13) serum urea; (14) creatinine; (15) liver enzymes; (16) blood glucose; and (17) anxiety scores. Measurements were made at baseline and postintervention. Results • Two-hundred soldiers took part in the study. The yoga group showed a significant improvement in health indices and performance as compared with the control group. They had lower weights, BFPs, RRs, DBPs, and anxiety scores. They also had a significantly higher EtCO2, forced vital capacity, forced expiratory volume in the first second (FEV1), and VO2Max. Also, the yoga group showed a significant reduction in serum cholesterol, low-density lipoprotein, triglycerides, and blood urea as compared with their preyoga levels and with the exercise group. Conclusions • Practice of yoga facilitates improvements in health and performance at HAs and is superior to routine training with physical exercises. Comprehensive yogic practices are an effective modality for improving health and performance at HAs.

Sleep and performance--recent trends.

Sleep and sleep deprivation are intimately related to performance. Sleep management of people working in different sectors of the society like multi shift workers, nurses, doctors, students in professional schools and the armed forces has a great bearing on performance, health and safety of the subject population. The detrimental effects of sleep deprivation on psychological performance are indicated as increased lapsing, cognitive slowing, memory impairment, decrease in vigilance and sustained attention and shift in optimum response capability. Its effects on physical performance are manifested as decline in ability to perform maximal exercise, self-selected walking pace and increase in perceived exertion. Sleep deprivation appears to have no effect in respect of muscle contractile properties and maximum anaerobic power. At high altitude (HA), there is a reduction in NREM sleep with frequent awakening due to hypoxia as a physiological adaptive measure to prevent accentuation of hypoxemia due to sleep-hypoventilation. Total sleep deprivation for 48 hours at high altitude can affect the acclimatization status, thermoregulation efficiency and cognitive functions. The concept of 'sleepiness' has also been studied, as it is an emerging concept for better understanding of the effects of sleep deprivation and its effects on performance. A special mention of sustained operations in the armed forces has been made keeping in mind its uniqueness in challenging the normal sleep-work schedule and its deployment in extreme environment and operational condition. This article reviews in detail the functions of sleep, its requirement and the effects of sleep deprivation on human performance.

Polymorphisms of renin--angiotensin system genes as a risk factor for high-altitude pulmonary oedema.

The genes of the renin--angiotensin system (RAS) play an important role in the regulation of pulmonary vascular tone. Although studies on individual genes polymorphisms have reported association with high-altitude pulmonary oedema (HAPE), studies on multiple genes or epistasis are lacking. We therefore investigated the association of the RAS polymorphisms with HAPE. In a case-control design, we screened 163 HAPE-resistant/controls (HAPE-r) and 160 HAPEpatients (HAPE-p) of Indian origin for eight polymorphisms of four RAS genes, ACE, AGT, AGTR1 and AGTR2. Significant difference in genotype and allele frequencies of the ACE I/D and AGT M235T polymorphisms was observed between HAPE-p and HAPE-r (p < 0.05). In three-locus haplotype analysis of AGT the haplotype GTM was significantly higher in HAPE-p (29%) and haplotype GTT in HAPE-r (27%) after Bonferroni correction (p < 0.006). The differences were insignificant for polymorphisms from AGTR1 and AGTR2. The MDR (multifactor dimensional reduction) approach for gene--gene interaction depicted individual polymorphism M235T as the best disease predicting model (cross validation consistency, CVC = 10/10). We found a significant association of D allele of ACE and M allele of AGT with HAPE. The findings are supported at the haplotypic level as well as through nested genetic interaction between the RAS gene polymorphisms using the MDR approach.