Simulated High Altitude Research Articles

Iptakalim protects against hypoxic brain injury through multiple pathways associated with ATP-sensitive potassium channels

The rapid and irreversible brain injury produced by anoxia when stroke occurs is well known. Cumulative evidence suggests that the activation of neuronal ATP-sensitive potassium (K ATP) channels may have inherent protective effects during cerebral hypoxia, yet little information regarding the therapeutic effects of K ATP channel openers is available. We hypothesized that pretreatment with a K ATP channel opener might protect against brain injury induced by cerebral hypoxia. In this study, adult Wistar rats were treated with iptakalim, a new K ATP channel opener, which is selective for SUR2 type K ATP channels, by intragastric administration at doses of 2, 4, or 8 mg/kg/day for 7 days before being exposed to simulated high altitude equivalent to 8000 m in a decompression chamber for 8 h leading to hypoxic brain injury. By light and electron microscopic images, we observed that hypobaric hypoxia-induced brain injury could be prevented by pretreatment with iptakalim. It was also observed that the permeability of the blood–brain barrier, water content, Na + and Ca 2+ concentration, and activities of Na +,K +-ATPase, Ca 2+-ATPase and Mg 2+-ATPase in rat cerebral cortex were increased and the gene expression of the occludin or aquaporin-4 was down- or upregulated respectively, which could also be prevented by the pretreatment with iptakalim at doses of 2, 4, or 8 mg/kg in a dose-dependent manner. Furthermore, we found that in an oxygen-and-glucose-deprived model in ECV304 cells and rat cortical astrocytes, pretreatment with iptakalim significantly increased survived cell rates and decreased lactate dehydrogenate release, which were significantly antagonized by glibenclamide, a K ATP channel blocker. We conclude that iptakalim is a promising drug that may protect against brain injury induced by acute hypobaric hypoxia through multiple pathways associated with SUR2-type K ATP channels, suggesting a new therapeutic strategy for stroke treatment.

High altitude memory impairment is due to neuronal apoptosis in hippocampus, cortex and striatum

Cognitive and neuropsychological functions have been impaired at high altitude and the effects depend on altitude and duration of stay. However, the neurobiological mechanism of this impairment is poorly understood especially exposure to different duration. Aim of the present study was to investigate the changes of behavior, biochemistry and morphology after exposure to different duration of hypobaric hypoxia. The rats were exposed continuously to a simulated high altitude of 6100 m for 3, 7, 14 and 21 days in an animal decompression chamber. Spatial reference memory was tested by Morris water maze. The oxidative stress markers like free radicals, NO, lipid peroxidation, LDH activity and antioxidant systems like GSH, GSSG, GPx, GR, SOD were estimated from cortex, hippocampus and striatum. The morphological changes, neurodegeneration, DNA fragmentation and mode of cell death have also been studied. It was observed that the spatial reference memory was significantly affected after exposure to hypobaric hypoxia. Increased oxidative stress markers along with decreased effectiveness of antioxidant system were also observed in hypoxia-exposed animals. Further pyknotic, shrunken, tangle-like neurons were observed in all these regions after hypoxia and neurodegeneration, DNA fragmentation and apoptosis were also observed in all the three regions. But after 21 days of exposure, the spatial memory was improved along with improvement of antioxidant activities. Our result suggests that the apoptotic death may be involved in HA-induced memory impairment and after 7 days of exposure the effect was more pronounced but after 21 days of exposure recovery was observed.

Time course of regression of the protection conferred by simulated high altitude to rat myocardium: correlation with mtNOS

During acclimatization to sustained hypobaric hypoxia, retardation of age-associated decline in left ventricle mechanical activity and improved posthypoxic recovery were accompanied by upregulation of mitochondrial nitric oxide synthase (mtNOS). To evaluate the time course of regression of these effects on deacclimatization, rats exposed to 53.8 kPa in a hypopressure chamber for 5 mo were returned to 101.3 kPa, whereas controls remained at 101.3 kPa throughout the study. At three time points, contractile function in response to calcium and to hypoxia-reoxygenation (H/R) were determined in papillary muscle, and NOS activity and expression were determined in mitochondria isolated from left ventricle. Developed tension was, before H/R, 65, 58, and 40%, and, after H/R, 129, 107, and 71% higher than in controls at 0.4, 2, and 5 mo of normoxia, respectively. Maximal rates of contraction and relaxation followed a similar pattern. All three parameters showed a linear decline during deacclimatization, with mean half-time (t(1/2)) of 5.9 mo for basal mechanical activity and 5.3 mo for posthypoxic recovery. Left ventricle mtNOS activity was 42, 27, and 20% higher than in controls at 0.4, 2, and 5 mo, respectively (t(1/2) = 5.0 mo). The expression of mtNOS showed similar behavior. The correlation of mtNOS activity with muscle contractility sustained a biphasic modulation, suggesting an optimal mtNOS activity. This experimental model would provide the most persistent effect known at present on preservation of myocardial mechanical activity and improved tolerance to O(2) deprivation. Results support the putative role of mtNOS in the mechanism involved.

Inhalation of Dry, Normobaric Hypoxic Air Impairs Thermal Conditioning of Nasal Air in Humans: Potential Role of Nitric Oxide

Hypoxic, dry, cold air is a stress to nasal air temperature conditioning (NATC) at high altitude, where humans often complain of nasal irritation. The vasodilator nitric oxide (NO) may modulate NATC (J Appl Physiol 87:1260, 1999). Hypoxic, dry (but not cold) air also reduces NO release into nasal air (Resp Physiol 114:285, 1998). Thus, we asked if simulated high altitude (normobaric hypoxic, dry air) would impair NATC. We infused (12 L/min) normobaric, hypoxic (100% N2), dry (0% humidity) air (21° C) or dry air (21° C, 21% O2, balance N2) into the nasal passages of seven adult humans. During breath holding, air entered the nose, passed around the soft palate, exited from the mouth and was collected for analysis of nasal NO release by chemiluminescence. NO output (nL/min) was calculated as the product of NO concentration and flow rate (timed collection measured in a Tissot gasometer). Nasal air temperatures were measured at one cm intervals from the nasal verge to a depth of 7 cm by thermocouples. Exponential curve fitting generated a half‐point value—the depth where nasal air reached half the difference between ambient and maximum cavity temperature. Half point depth increased during normobaric hypoxic, dry air infusion compared with dry air indicating impediment of NATC (see table). Nitric oxide release decreased during normobaric hypoxic, dry air infusion compared with compressed air. We confirm that nasal NO release is impaired by hypoxic, dry air and further suggest that, hypoxic air impedes NATC. Our findings are consistent with a role of NO in NATC and may help explain nasal irritation in humans at high altitude.NO output (nL/min)Half‐point (cm)(Supported by the Murdock Foundation).

Reticulocytes in Sports Medicine

Reticulocytes are the transitional cells from erythroblasts to mature erythrocytes. Reticulocytes are present in blood for a period of 1-4 days and can be recognized by staining with supravital dyes, such as new methylene blue, or fluorescent markers, which couple residual nucleic acid molecules, a hallmark of the immature forms of erythrocytes. Although reticulocytes could be counted through a microscope (there is a standard of International Committee for Standardisation in Haematology for manual counting), this method is reported to be time consuming, inaccurate and imprecise. The integration of the reticulocyte count in automated haematology systems allowed the widespread use of these parameters, although the lack of calibration material and different markers, technologies and software used in automated systems could engender discrepancies among data obtained from different analytical systems.The importance of reticulocytes in sports medicine derives from their sensitivity, the highest among haematology parameters, in identifying the bone marrow stimulation, especially when recombinant human erythropoietin is fraudulently used. Automated systems are also able to supply information on volume, density and the haemoglobin content of reticulocytes. Some of the related parameters are also used in algorithms for identifying abnormal stimulation of bone marrow as reticulocytes haematocrit. The pre-analytical variability of reticulocytes (transportation, storage, biological variability) should be taken into account in sports medicine also. Reticulocytes remain stable for almost 24 hours at 4 degrees C from blood drawing, they are affected by transportation, and biological variability is not high in general. It could be remarked, however, that the intra-individual variability is high when compared with other haematological parameters such as haemoglobin and haematocrit. The intervals of data reported in athletes are very similar to reference intervals characterizing the general population.The reticulocyte count shows some modifications after training and during the competition season. The variability induced by exercise cannot be overlooked since the so-called haematological passport, a personal athlete's document in which haemoglobin and other parameters are registered, may be introduced by sports federations. Exposure to naturally high altitude and 'living high-training low' programmes determined contentious results on reticulocytes. Simulated high altitude induced by intermittent hypobaric hypoxia does not modify reticulocytes, despite an increase in erythropoietin serum concentration. The variability among athletes competing in different sport disciplines is apparently limited. The knowledge of the behaviour of reticulocytes in training and competitions is crucial for defining their role in an antidoping control context. It is important for sport physicians and clinical pathologists to know the reticulocyte variability in the general population and in athletes, the pre-analytical warnings, the different methodologies for counting reticulocytes and the derived parameters automatically available, and, finally, the possible influence of training, competitions, type of sport and altitude.

Divergent Selection for Ascites Incidence in Chickens

Chicken lines that were either resistant or susceptible to ascites syndrome were developed by using a hypobaric chamber to induce the disease. Birds were reared in a hypobaric chamber that simulated high altitude by operating under a partial vacuum, which thereby lowered the partial pressure of oxygen. Ascites mortality data from birds reared under hypobaric chamber conditions were used to select siblings to be used for breeding. The response to selection for the susceptible (SUS) and resistant (RES) lines of chickens was very rapid from the base population, which exhibited an incidence of ascites of 75.3%. Extremes in the incidence of ascites were observed in generation 8, with line SUS exhibited an average incidence of ascites of 95.1%, and in generation 9, with line RES exhibited an average incidence of ascites of 7.1%. The incidence of ascites in the relaxed line remained relatively stable and currently has a general incidence of ascites of 60%. The heritability estimates ± SE for ascites were estimated to be 0.30 ± 0.05 and 0.55 ± 0.05 for lines SUS and RES, respectively. Changes in the incidence of ascites appeared to be associated with livability. By generation 10, selection for ascites in line RES increased livability by 11.5 d, whereas in line SUS, livability was decreased by 8 d. Although divergent selection for ascites resulted in a reduction in d 42 BW for both the SUS and RES lines, the SUS line was approximately 163 g heavier than the RES line. Negative genetic correlations between ascites and the right ventricle:total ventricle (RV:TV) ratio were observed in both the SUS and RES lines; however, no significant change in the RV:TV ratio was observed for birds reared under normal conditions in either line. The current data raise questions about the validity of using the RV:TV ratio as an indicator trait in a selection program designed to reduce the incidence of ascites. Overall, direct selection for resistance to ascites by using sire family performance appeared to be an effective means of reducing the incidence of ascites. However, simultaneous selection for BW should be applied to counterbalance the losses in correlated BW.

Venous but not skeletal muscle interstitial nitric oxide is increased during hypobaric hypoxia

Systemic hypoxia leads to peripheral vasodilation that serves to counteract the decrease in peripheral oxygen (O(2)) delivery. Skeletal muscle vasodilation associated with hypoxia is due to release of vasodilator substances such as adenosine and/or nitric oxide (NO). We hypothesized that skeletal muscle may act as a source of NO during exposure to hypoxia. Therefore, we measured NO in forearm venous plasma and in skeletal muscle interstitial dialysate in seven healthy young men during exposure to simulated altitude of 2,438 and 4,877 m (20 min at each level) in a hypobaric chamber. O(2) saturation (mean +/- SEM) fell from 98.0 +/- 0.2% at ambient conditions to 91.0 +/- 0.4% at 2,438 m and to 73.2 +/- 4.4% at 4,877 m (P < 0.05). While blood pressure remained unchanged, heart rate increased in a graded fashion (P < 0.05). Plasma NO (chemiluminescence method) rose from 11.6 +/- 1.3 to 16.9 +/- 2.9 microM at 2,438 m (P < 0.05) but remained similar at 16.4 +/- 2.3 microM at 4,877 m (NS). In contrast, skeletal muscle microdialysate NO levels were lower than plasma NO (P < 0.01) and did not change during simulated altitude. Thus, hypoxia produced by simulated high altitude exposure leads to an increase in plasma but not skeletal muscle interstitial NO. These data support an important role of NO in the peripheral vascular responses to hypoxia. The differential responses of plasma vs. interstitial NO during hypoxia suggest an endothelial or intravascular source of NO.

Persistence of baroreceptor control of cerebral blood flow velocity at a simulated altitude of 5000 m

To assess the effects of acute exposure to simulated high altitude on baroreflex control of mean cerebral blood flow velocity (MCFV). We compared beat-to-beat changes in RR interval, arterial blood pressure, mean MCFV (by transcranial Doppler velocimetry in the middle cerebral artery), end-tidal CO2, oxygen saturation and respiration in 19 healthy subjects at baseline (Albuquerque, 1779 m), after acute exposure to simulated high altitude in a hypobaric chamber (barometric pressure as at 5000 m) and during oxygen administration (to achieve 100% oxygen saturation) at the same barometric pressure (HOX). Baroreflex control on each signal was assessed by univariate and bivariate power spectral analysis performed on time series obtained during controlled (15 breaths/min) breathing, before and during baroreflex modulation induced by 0.1-Hz sinusoidal neck suction. At baseline, neck suction was able to induce a clear increase in low-frequency power in MCFV (P<0.001) as well as in RR and blood pressure. At high altitude, MCFV, as well as RR and blood pressure, was still able to respond to neck suction (all P<0.001), compared to controlled breathing alone, despite marked decreases in end-tidal CO2 and oxygen saturation at high altitude. A similar response was obtained at HOX. Phase delay analysis excluded a passive transmission of low-frequency oscillations from arterial pressure to cerebral circulation. During acute exposure to high altitude, cerebral blood flow is still modulated by the autonomic nervous system through the baroreflex, whose sensitivity is not affected by changes in CO2 and oxygen saturation levels.

The magic mountain or death in Venice: chronic hypoxia may alleviate oxidative stress in the kidney

Chronic hypoxia, as induced by simulated high altitude at 5500 m, seems to have astonishing beneficial effects when it comes to oxidative stress. In this issue of The Journal of Physiology, Yang et al. (2007) induced lipopolysaccharide-induced oxidative stress (LPS-OS) in rats maintained at sea level and in rats being kept for 15 days in an altitude chamber. This is an original way of preconditioning the kidney. Renal preconditioning is an area of increasing interest. It refers to the prospect of rendering the kidney resistant to subsequent injury by a prior insult manoeuvre. Ischaemic preconditioning of the kidney has been commonly used and provides protection against a subsequent ischaemic attack. Several candidates that could potentially serve as mediators of preconditioning have been identified. Yang et al. (2007) focus on the formation of superoxide by two major oxidative enzymes, NAD(P)H oxidase and xanthine oxidase, and the authors examine two antioxidative superoxide dismutase isoforms, Cu/ZnSOD and MnSOD. The impact of chronic hypoxia on the outcome of LPS-OS on renal haemodynamics and excretory functions was remarkably clear. Non-preconditioned rats (sea level) responded to LPS-OS with pronounced reduction of renal blood flow (RBF) and glomerular filtration rate (GFR). In contrast, RBF and GFR in preconditioned rats (altitude chamber) were far less impaired. Moreover, urine and sodium excretion were significantly reduced in the rats kept at sea level, whereas this drop was not found in the rats housed in high altitude chambers. The reasons for the differences may be of pre-renal origin, since mean arterial blood pressure drops by roughly 30 mmHg in the sea level group, whereas the pressure drop in the preconditioned animals was only roughly 10 mmHg. Autoregulation of RBF and GFR may not be as pronounced as normal (Flemming et al. 2001) in this setting, and therefore these measures may drop in response to decreases in perfusion pressure. Moreover, diuresis as well as natriuresis are extremely pressure dependent (Seeliger et al. 2001). A pre-renal origin of LPS-OS has been suggested before. Cohen et al. (2001) showed that haemodynamic changes after LPS-OS are only found in vivo, not in the isolated perfused kidney. However, in the highlighted study by Yang et al. evidence is provided for additional intrarenal effects of LPS-OS. It seems that lipopolysaccharides cause cytokine release via Toll-like receptor 4 (TLR4) (Cunningham et al. 2004), a receptor exclusively located in the kidney. Not only is TLR4 restricted to the kidney, it is also known to stimulate tumour necrosis factor-α, and interleukin-β production, resulting in NAD(P)H-oxidase generated superoxide (Li et al. 2002). Indeed, Yang et al. could demonstrate increased renal superoxide formation by LPS-OS along with augmented tumour necrosis factor-α, and interleukin-β levels. Maintenance of rats under hypoxic conditions for 15 days prior to the LPS-OS challenge effectively blunted the changes in this chain of effects. Moreover increases in antioxidative enzymes, such as Cu/ZnSOD, MnSOD and catalase, may further contribute to the beneficial effects of high altitude, as shown in the study reviewed. Taken together, the findings of Yang et al. provide a detailed picture of how chronic hypoxia may precondition the kidney to better cope with LPS-OS. When considering that hypoxia also stimulates erythropoietin synthesis, more possible routes of renal preconditioning appear likely. Erythropoietin is well known as a potent mediator of preconditioning in the brain and heart (Dawson, 2002; Baker, 2005). Lately it has been suggested that erythropoietin is also involved in the preconditioning of the kidney (Sharples & Yaqoob, 2006).

Leukotriene Receptor Blockade Does Not Prevent Acute Mountain Sickness Induced by Normobaric Hypoxia

Previous research has demonstrated that blood and urine concentrations of various leukotrienes are elevated with acute hypoxic exposure. Some of these studies have suggested that leukotrienes may be mediators in the pathogenesis of acute mountain sickness (AMS). We conducted a randomized, double-blind study to determine if AMS symptoms correlated with the increase in leukotriene synthesis and if prophylactic leukotriene receptor blockade would prevent the development of AMS in a simulated high altitude exposure. Three male and five female subjects completed two normobaric hypoxia chamber exposures (average F(IO2) 12.4 +/- 0.09%), receiving montelukast 10 mg daily for 4 days prior to one session and placebo for 4 days prior to the other session. There were no differences in Lake Louise AMS scores, time spent in the chamber, average oxygen saturation, and average heart rate during the montelukast and placebo sessions. Headache scores were higher during treatment with montelukast than during treatment with placebo. Compared to preexposure values, urinary leukotriene E4 concentrations were unchanged during the hypoxic chamber exposure following treatment with placebo or montelukast. Urinary leukotriene E4 excretion during the hypoxic exposure did not differ between the two sessions. A 4-day course of leukotriene receptor blockade does not prevent symptoms of AMS. These results suggest that leukotrienes do not play a causal role in the pathophysiology of AMS.

Intermittent Hypoxia does not Increase Exercise Ventilation at Simulated Moderate Altitude

Recent human studies have shown that resting hypoxic ventilatory response (HVR), which is an index of ventilatory chemosensitivity to hypoxia, increased after short-term intermittent hypoxia at rest. In addition, intermittent hypoxia leads to increases in ventilation and arterial oxygen saturation (SaO (2)) during exercise at simulated high altitude, with the increase in ventilation correlated to the change in HVR. However, no study has been made to clarify the relationship between ventilatory chemosensitivity and the exercise ventilation at moderate altitude following intermittent hypoxia during a resting state. The purpose of the present study, therefore, was to elucidate whether intermittent hypoxia at rest induces the increase in ventilation during exercise at moderate altitude that is accompanied by an increase in hypoxic chemosensitivity. Eighteen trained male runners were assigned to three groups, i.e., the first hypoxic group (H-1 group, n = 6), the second hypoxic group (H-2 group, n = 6), and a control group (C group, n = 6). The hypoxic tent system was utilized for intermittent hypoxia, and the oxygen levels in the tent were maintained at 15.5 +/- 0.1 % (simulated 2500 m altitude) for the H-1 group and 12.3 +/- 0.2 % (simulated 4300 m altitude) for the H-2 group. The H-1 and H-2 groups spent 1 hour per day in the hypoxic tent for 1 week. Maximal and submaximal exercise tests while breathing 15.5 +/- 0.01 % O (2) (simulated altitude of 2500 m) were performed before and after intermittent hypoxia. Resting HVR was also determined in each subject using a progressive isocapnic hypoxic method. In the H-2 group, HVR increased significantly (p < 0.05) following intermittent hypoxia, while no change in HVR was found in the H-1 or C group. Neither ventilation nor SaO (2) during maximal and submaximal exercise at a simulated altitude of 2500 m were changed in either group after 1 hour per day for 1 week of intermittent hypoxia. These results suggest that the change in resting hypoxic chemosensitivity after short-term intermittent hypoxia does not affect ventilation during exercise at moderate altitude.

Cardiac adaptation to chronic high-altitude hypoxia: Beneficial and adverse effects

This review deals with the capability of the heart to adapt to chronic hypoxia in animals exposed to either natural or simulated high altitude. From the broad spectrum of related issues, we focused on the development and reversibility of both beneficial and adverse adaptive myocardial changes. Particular attention was paid to cardioprotective effects of adaptation to chronic high-altitude hypoxia and their molecular mechanisms. Moreover, interspecies and age differences in the cardiac sensitivity to hypoxia-induced effects in various experimental models were emphasized.

Dehydroepiandrosterone upregulates soluble guanylate cyclase and inhibits hypoxic pulmonary hypertension

It has been reported that dehydroepiandrosterone is a pulmonary vasodilator and inhibits chronic hypoxia-induced pulmonary hypertension. Additionally, dehydroepiandrosterone has been shown to improve systemic vascular endothelial function. Thus, we hypothesized that chronic treatment with dehydroepiandrosterone would attenuate hypoxic pulmonary hypertension by enhancing pulmonary artery endothelial function. Rats were randomly assigned to five groups. Three groups received food containing 0, 0.3, or 1% dehydroepiandrosterone during a 3-wk-exposure to simulated high altitude (HA). The other 2 groups were kept at Denver's low altitude (LA) and received food containing 0 or 1% dehydroepiandrosterone. Dehydroepiandrosterone dose-dependently inhibited hypoxic pulmonary hypertension (mean pulmonary artery pressures after treatment with 0, 0.3, and 1% dehydroepiandrosterone=45+/-5, 33+/-2*, and 25+/-1*# mmHg, respectively. *P<0.05 vs. 0% and # vs. 0.3%). Dehydroepiandrosterone (1%, 3 wks) treatment started after rats had been exposed to 3-wk hypoxia also effectively reversed established hypoxic pulmonary hypertension. Pulmonary artery rings isolated from both LA and HA rats treated with 1% dehydroepiandrosterone showed enhanced relaxations to acetylcholine and sodium nitroprusside, but not to 8-bromo-cGMP. In the pulmonary artery tissue from dehydroepiandrosterone-treated LA and HA rats, soluble guanylate cyclase, but not endothelial nitric oxide synthase, protein levels were increased. These results indicate that the protective effect of dehydroepiandrosterone against hypoxic pulmonary hypertension may involve upregulation of pulmonary artery soluble guanylate cyclase protein expression and augmented pulmonary artery vasodilator responsiveness to nitric oxide.

Increased inosine 5-monophosphate accumulation despite no sign of increased glycolytic rate during one-legged exercise at simulated high altitude

Muscle metabolism during one-legged submaximal exercise executed in a hypobaric chamber (corresponding to 2300 m above sea level) was studied by percutaneous muscle biopsies from the vastus lateralis and compared with corresponding data from the other leg, exercising at the same absolute load under normobaric conditions on another Occasion. After 15 min of exercise, the adenosine triphosphate/adenosine diphosphate ratio was lower and inosine 5-monophosphate higher in the hypobaric than in the normobaric leg. The possibility is suggested that this metabolic alteration stimulates increased expression of oxidation-related mitochondrial enzymes. Despite this sign of energy depletion, there was no indication of increased glycolysis. A tendency to increased citrate concentration in the hypobaric leg could suggest an increased mobilization and utilization of fat, which auld have counteracted any stimulating effect on the glycolytic rate.

Mitochondrial contribution to the molecular mechanism of heart acclimatization to chronic hypoxia: role of nitric oxide

A remarkable number of adaptive responses; including changes in the cardiovascular, respiratory and hematologic systems; takes place during acclimatization to natural or simulated high altitude. This adaptation to chronic hypoxia confers the heart an improved tolerance to all major deleterious consequences of acute O2 deprivation, not only reducing infarct size but also alleviating post-ischemic contractile dysfunction and ventricular arrhythmias. There is growing evidence about the involvement of mitochondria and NO in the establishment of cardioprotection. This review focuses on evidence about the putative role of different effectors of heart acclimatization to chronic hypoxia. Along with classical parameters, we consider NO, specially that generated by mtNOS, mitochondrial respiratory chain, mitoK(ATP) channels, reactive oxygen species and control of gene expression by HIF-1.

The effect of 18 h of simulated high altitude on left ventricular function

High altitude produces increased pulmonary capillary pressure by hypoxia induced pulmonary vasoconstriction. It is also possible that hypoxia results in mildly elevated left ventricular (LV) filling pressures that may contribute to the elevated capillary pressures. This study investigates the impact of simulated high altitude on global and regional echocardiographic measures of LV performance and filling pressure. Seventeen healthy individuals underwent transthoracic echocardiography, including tissue Doppler of the septal mitral annulus and basal segments before and after an 18-h overnight stay in a high altitude simulation tent with a FiO(2) of 12%, simulating an altitude of approximately 4,000 m above sea level. In simulated high altitude, the ratio of early transmitral flow velocity to early myocardial relaxation velocity increased 22%, P < 0.001, and the Index of Myocardial Performance increased 30%, P < 0.01 due to an 58% increase in the isovolumic relaxation time (IVRT), P < 0.001. Simulated high altitude leads to a reduction in LV performance with an accompanying increase in markers of LV filling pressure. The significant changes in filling pattern and IVRT in the setting of normal and unchanged systolic function, indicates that hypoxia induces mild diastolic dysfunction in young healthy individuals.

Hypobaric hypoxia induces oxidative stress in rat brain

High altitude exposure results in decreased partial pressure of oxygen and an increased formation of reactive oxygen and nitrogen species (RONS), which causes oxidative damage to lipids, proteins and DNA. Exposure to high altitude appears to decrease the activity and effectiveness of antioxidant enzyme system. The antioxidant system is very less in brain tissue and is very much susceptible to hypoxic stress. The aim of the present study was to investigate the time dependent and region specific changes in cortex, hippocampus and striatum on oxidative stress markers on chronic exposure to hypobaric hypoxia. The rats were exposed to simulated high altitude equivalent to 6100 m in animal decompression chamber for 3 and 7 days. Results indicate an increase in oxidative stress as seen by increase in free radical production, nitric oxide level, lipid peroxidation and lactate dehydrogenase levels. The magnitude of increase in oxidative stress was more in 7 days exposure group as compared to 3 days exposure group. The antioxidant defence system such as reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD) and reduced/oxidized glutathione (GSH/GSSG) levels were significantly decreased in all the three regions. The observation suggests that the hippocampus is more susceptible to hypoxia than the cortex and striatum. It may be concluded that hypoxia differentially affects the antioxidant status in the cortex, hippocampus and striatum.

Sildenafil improves cardiac output and exercise performance during acute hypoxia, but not normoxia

Sildenafil causes pulmonary vasodilation, thus potentially reducing impairments of hypoxia-induced pulmonary hypertension on exercise performance at altitude. The purpose of this study was to determine the effects of sildenafil during normoxic and hypoxic exercise. We hypothesized that 1) sildenafil would have no significant effects on normoxic exercise, and 2) sildenafil would improve cardiac output, arterial oxygen saturation (SaO2), and performance during hypoxic exercise. Ten trained men performed one practice and three experimental trials at sea level (SL) and simulated high altitude (HA) of 3,874 m. Each cycling test consisted of a set-work-rate portion (55% work capacity: 1 h SL, 30 min HA) followed immediately by a time trial (10 km SL, 6 km HA). Double-blinded capsules (placebo, 50, or 100 mg) were taken 1 h before exercise in a randomly counterbalanced order. For HA, subjects also began breathing hypoxic gas (12.8% oxygen) 1 h before exercise. At SL, sildenafil had no effects on any cardiovascular or performance measures. At HA, sildenafil increased stroke volume (measured by impedance cardiography), cardiac output, and SaO2 during set-work-rate exercise. Sildenafil lowered 6-km time-trial time by 15% (P<0.05). SaO2 was also higher during the time trial (P<0.05) in response to sildenafil, despite higher work rates. Post hoc analyses revealed two subject groups, sildenafil responders and nonresponders, who improved time-trial performance by 39% (P<0.05) and 1.0%, respectively. No dose-response effects were observed. During cycling exercise in acute hypoxia, sildenafil can greatly improve cardiovascular function, SaO2, and performance for certain individuals.

Neutral Endopeptidase Null Mice Are Less Susceptible to High Altitude-Induced Pulmonary Vascular Leak

Hypoxia increases pulmonary vascular leak, which is regulated in part by neutral endopeptidase (NEP). NEP is a cell-surface metalloprotease that degrades several vasoactive peptides, including endothelin-1 (ET-1) and atrial natriuretic peptide (ANP). We therefore hypothesized that NEP attenuates high altitude-induced pulmonary vascular leak. Wild-type and NEP null mice were exposed to a simulated high altitude (HA) of 6,728 m (22,000 ft; P(B) = 328 mmHg) or remained at the relatively low altitude (LA) of 1,500 m (4,920 ft; P(B) = 640 mmHg) for 24 h. Plasma ANP and ET-1 concentrations, right ventricular pressure (P(RV)), and indexes of lung injury were recorded. At HA, lung wet weight-to-body weight increased in all animals, but was greatest in the NEP wild-type mice. Vascular leak, as measured by Evans blue dye, increased only in the NEP wild-type mice at HA. P(RV) increased in both genotypes at HA. Plasma ANP concentrations increased at HA in both genotypes, but plasma ET-1 concentrations were elevated only in the NEP null mice at HA. Correlations between lung wet weight-to-body weight versus P(RV) (r = 0.56; p = 0.0136) and ANP versus P(RV) (r = -0.54; p = 0.02) were noted. We conclude that NEP null mice exposed to HA have a greater rise in ANP versus ET-1 plasma concentration, decreased pulmonary vascular pressure, and reduced high altitude-induced pulmonary vascular leak.

Simulated high altitude selectively decreases protein intake and lean mass gain in rats

The aim of this study was to find out whether high altitude (HA)-induced hypophagia was macronutrient-specific using a self-selection procedure. Body composition was assessed by dual X-ray absorptiometry before and after exposure and by dissection at the end of the experiment. Energy intake, macronutrient selection, body composition, plasma insulin and leptin concentrations were measured in rats (FHx) exposed 16 h daily for 10 days to hypobaric hypoxia (HH) simulating an altitude of 5500 m. Rats were fasted during the exposure to HH and had access to food only during the 8 h of normoxia in their active period. This group was compared to control group (C) with ad libitum access to food and a group of rats submitted only to the 16-h fast (FNx). Results showed that sustained hypophagia was specific to protein (55 ± 5% of C, P < .05), whereas after a decline, carbohydrate intake reached its basal level on the 5th day. HH dramatically reduced fat-free mass gain ( P < .05 and P < .0001 compared to C and FNx, respectively). Plasma leptin concentrations at the onset of the period of access to food were not significantly different from those of controls. Across groups, leptin was positively correlated with fat mass ( r = .71, P < .001) and negatively with energy intake ( r = − .52, P < .05), more specifically with protein intake ( r = − .57, P < .05). These results suggest that HA leads to a reduced preference for protein impairing fat-free mass gain and that leptin may contribute to this hypophagia.