Acute Systemic Hypoxia Research Articles

Effects of Prolactin on Brain Neurons under Hypoxia.

The levels and potential role of prolactin (PRL) in the brain under conditions of acute systemic hypoxia were examined, focusing on the accumulation of PRL in cerebrospinal fluid (CSF) and its effects on neuronal activity and injury. The amount of PRL in the brain was investigated using brain tissues from forensic autopsy cases. We counted the number of neurites that formed in human primary neurons (HNs) after the addition of PRL. Furthermore, HNs supplemented with PRL or triiodothyronine (T3) were exposed to hypoxic conditions, and the dead cells were counted. The results showed correlations between brain PRL and CSF PRL levels. Additionally, PRL accumulation in the brain was observed in cases of asphyxia. In vitro experimental findings indicated increased neurite formation in the HNs treated with PRL. Moreover, both PRL and T3 demonstrated neuroprotective effects against hypoxia-induced neuronal cell death, with PRL showing stronger neuroprotective potential than T3. These results suggest that PRL accumulates in the brain during hypoxia, potentially influences neuronal activity, and exhibits neuroprotective properties against hypoxia-induced neuronal injury.

Mechanism of Traditional Tibetan Medicine Grubthobrildkr Alleviated Gastric Ulcer Induced by Acute Systemic Hypoxia in Rats.

Objective This study was aimed at investigating the potential mechanism of Grubthobrildkr (GTB) on systemic hypoxia-induced gastric ulcers in rats and at detecting the chemical profile of GTB. Methods Male Sprague-Dawley rats were separated into control, hypoxia, hypoxia+omeprazole, and hypoxia+GTBs (0.25, 0.5, and 1.0 g·kg−1·d−1) groups. Systemic hypoxia was created in a hypobaric chamber to simulate 5000 m high altitude by adjusting the inner pressure and oxygen content for 6 days. After that, the ulcer index, pH, and volume of gastric juice were assessed. The levels of endothelin-1 (ET-1), gastrin (GAS), motilin (MTL), phospholipase A2 (PLA2), and prostaglandin E2 (PGE2) were detected by ELISA. The expression level of hydrogen potassium ATPase (H+-K+-ATPase), cyclooxygenase-1 (COX-1), and cyclooxygenase-2 (COX-2) was tested by western blotting. Chemical profile of GTB was revealed by UHPLC-Q-exactive hybrid quadrupole-orbitrap mass (UHPLC-Q-Orbitrap MS). Results GTB decreased the ulcer index in rats under hypoxia for six days, which was related to increased pH and volume of gastric juice, enhanced MTL and PGE2 levels, and decreased ET-1 and PLA2 levels of gastric mucosa. Furthermore, GTB decreased the level of H+-K+-ATPase and COX-2 while increased COX-1 levels in gastric mucosal tissue. 44 constituents were identified by UHPLC-Q-Orbitrap MS in GTB. Conclusion GTB exerted a gastroprotective effect to alleviate gastric ulceration induced by acute systemic hypoxia in rats. The effect of GTB increasing the volume and pH of gastric juice in rats under acute systemic hypoxia could be regulated by gastrointestinal hormones, including MTL and ET-1. Mechanically, gastrointestinal protection of GTB was based on inhibition of the protons pumping H+-K+-ATPase and regulation of prostaglandin family in rats.

Acute performance and physiological responses to upper-limb multi-set exercise to failure: Effects of external resistance and systemic hypoxia

ABSTRACT This study quantified performance and physiological responses during multi-set resistance exercise to failure at light versus moderate loads in normoxia and systemic hypoxia. On separate visits, fifteen resistance-trained adults performed barbell biceps curl exercise trials (6 sets to failure, 2 min rest between sets) in four separate randomised conditions; i.e. in normoxia at 380 m above sea level or systemic hypoxia at ∼3800 m simulated altitude (inspired oxygen fraction = 20.9% and 12.9%, respectively) combined with two different intensity levels (30% and 70% of 1 repetition maximal or 1RM). Muscle activation (root mean square value calculated from surface electromyography) and oxygenation (integrated-tissue saturation index derived from near-infrared spectroscopy) were monitored for the biceps brachii muscle. The total number of repetitions before failure at 30% 1RM (122 ± 5 vs. 131 ± 5; P = 0.021), but not 70% 1RM (39 ± 1 vs. 41 ± 2; P = 0.313), was lower in hypoxia compared to normoxia. Root mean square activity of the biceps brachii muscle was higher for 70% 1RM compared to 30% 1RM (P < 0.001), while the increase in muscle activation from the first to the last set (P < 0.001) occurred independently of altitude (P > 0.158). Deoxygenation and reoxygenation responses were higher under hypoxic versus normoxic conditions at 70% 1 RM (P = 0.013 and P = 0.015) but not 30% 1RM (P = 0.528 and P = 0.384). During upper-limb multi-set resistance exercise to failure, exposure to acute normobaric hypoxia negatively impacts performance at light, but not moderate, loads. Overall, external resistance has more profound effects on physiological strain than hypoxic exposure per se. Highlights The addition of acute systemic hypoxia negatively affects work performed at low, but not moderate, loads during upper-limb resistance exercise to failure. Hypoxic exposure, however, does not fundamentally alter muscle activation and oxygenation patterns. Muscle activation and oxygenation responses in turn are more largely influenced by load lifted.

Nitric oxide and interval hypoxic training in COVID-19 rehabilitation— new research direction

COVID-19, a disease caused by the novel coronavirus SARS-CoV-2, primarily affects lung tissue and disrupts gas exchange, leading to acute respiratory distress syndrome, systemic hypoxia, and lung damage. The search for methods of prevention and rehabilitation, especially after suffering from pneumonia caused by COVID-19, is on the agenda. This article discusses the possibilities of the interval hypoxic training (IHT) method for preventing infections by initiating nitric oxide production in the body. One of the main effects of IHT is the balanced stimulation of nitric oxide (NO) secretion. Over the past two decades, there has been an increasing interest in the function of nitric oxide (NO) in the human body. Nitric oxide plays a key role in maintaining normal vascular function and regulating inflammatory processes, including those leading to lung damage and the development of acute respiratory distress syndrome (ARDS). Our immune system destroys bacteria and viruses by oxidative burst, i.e. when oxygen accumulates inside the cell. This process also involves nitric oxide, a signaling molecule that has an antibacterial and antiviral effect, as well as regulates vascular tone and affects the permeability of the cell wall. Interval hypoxytherapy enhances endogenous oxidative protection and increases the amount of nitric oxide, thus allowing the body’s cells to resist infection more effectively. Mitochondrial NOS induction and mitochondrial NO synthesis increase under the action of pathogenic factors on the cell. By modulating the activity of mtNOS and the synthesis of mitochondrial NO, it is possible to increase the resistance to hypoxic effects. Interval hypo-hyperoxic training as an effective non-specific method of increasing the body’s defenses is indispensable not only in the prevention of viral infection, but also in rehabilitation after viral pneumonia, as well as as a method that reduces the severity of viral infection in the event of infection.

Morphological and biochemical changes in the pancreas associated with acute systemic hypoxia

This study aimed to investigate the changes associated with acute systemic hypoxia in the endocrine system, particularly in pancreatic tissues. The investigation was based on macroscopic, pathohistological, biochemical, and molecular biological findings in cell lines and human cadavers. The results showed that cases of death due to asphyxia more frequently showed severe subcapsular/interstitial hemorrhage versus the other causes of death. Histological examination showed that asphyxia cases were associated with severe morphological changes. Although measured insulin levels in the asphyxia were higher compared to other causes of death, no differences were noted for the glucagon and amylase levels with regard to the cause of death. Increased blood insulin levels were not associated with macro- and micromorphological changes, and did not show any association with glucose or cortisol levels. The experiment conducted under hypoxic conditions in cultured cells demonstrated that insulin mRNA expression and insulin protein levels peaked at 10 min after hypoxia exposure. However, there were no changes in either the amylase mRNA or protein levels. Corticosterone level peaked at 120 min after exposure to hypoxic conditions. Overall, acute systemic hypoxic conditions can directly affect the mechanisms involved in pancreatic insulin secretion.

Prone Position Impairs Oxygen Supply-Demand Balance During Systemic Hypoxia in Rabbits

Ventilation in the prone position improves the prognosis of patients with severe acute respiratory distress syndrome (ARDS). Contraindications to ventilation in this position include unstable systemic circulation. Only a few reports exist on the effects of prone ventilation in respiratory failure on systemic circulation. This animal study compared systemic hemodynamic changes between supine and prone positions in anesthetized rabbits under acute systemic hypoxia (breathing 15% O2). Cardiac output and the systemic O2 extraction ratio increased under the hypoxia, but only in the supine group. Besides, the rate pressure product was higher in the prone group than in the supine group. This study showed that prone ventilation increases myocardial O2 consumption and suppresses compensatory mechanisms to maintain aerobic metabolism during systemic hypoxia. First of all, it will be necessary to examine the effect of prone ventilation on the O2 supply-demand balance in the ARDS model.

Pathogenetic justification of the use of hypohyperoxic training in the treatment and prevention of complications of the COVID-19 coronavirus infection

The 2019 coronavirus pandemic primarily affects lung tissue and disrupts gas exchange, leading to acute respiratory distress syndrome, systemic hypoxia, and lung damage. The search for methods of prevention and rehabilitation, especially after suffering from pneumonia caused by COVID-19, is on the agenda. Currently, it is known that the COVID-19 virus needs certain conditions from the cell membranes to enter the lung or intestinal cells: the presence of structures that allow the virus to «catch» on the cell (ACE2 receptor), the TMPRSS2 protein structure. Coronaviruses such as SARS-CoV and SARS-CoV-2 are activated by the TMPRSS2 enzyme and, therefore, inhibitors of this enzyme can block the virus. The virus uses APF2 as a receptor to enter the cell, and TMPRSS2 is required for activation of the viral S-protein. Without these structures, the COVID-19 virus cannot enter the cell. It was found that activation of the HIF-1 α-signaling pathway under moderate hypoxia would reduce ACE2 and TMPRSS2 and increase levels of ADAM17 on the alveolocyte surface and, consequently, reduce the invasiveness of SARS-CoV-2. As a result of numerous studies, the possibility of using a new technique, normobaric interval hypo-hyperoxic training, was justified. It was proved that ROS formed during hypoxia-normoxia participate in the initial stages of intracellular redox signaling, which triggers signal transmission to the cell nucleus. As a result, redox signaling leads to saturation of the cell with molecules that increase its protection from damaging effects. It is on these principles that the main provisions for creating a new technique and a new generation of hypoxicator that gives not only hypoxic, but also hyperoxic mixtures were formulated. Interval hypo-hyperoxic training as an effective non-specific method of increasing the body’s defenses is indispensable not only in the prevention of viral infection, but also in rehabilitation after viral pneumonia, as well as as a method that reduces the severity of viral infection in the event of infection.

Hypoxia, HIF-1α, and COVID-19: from pathogenic factors to potential therapeutic targets.

The pandemic of coronavirus disease 2019 (COVID-19) and its pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have become the greatest current threat to global public health. The highly infectious SARS-CoV-2 virus primarily attacks pulmonary tissues and impairs gas exchange leading to acute respiratory distress syndrome (ARDS) and systemic hypoxia. The current pharmacotherapies for COVID-19 largely rely on supportive and anti-thrombi treatment and the repurposing of antimalarial and antiviral drugs such as hydroxychloroquine and remdesivir. For a better mechanistic understanding of COVID-19, our present review focuses on its primary pathophysiologic features: hypoxia and cytokine storm, which are a prelude to multiple organ failure and lethality. We discussed a possible link between the activation of hypoxia inducible factor 1α (HIF-1α) and cell entry of SARS-CoV-2, since HIF-1α is shown to suppress the angiotensin-converting enzyme 2 (ACE2) receptor and transmembrane protease serine 2 (TMPRSS2) and upregulate disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). In addition, the protein targets of HIF-1α are involved with the activation of pro-inflammatory cytokine expression and the subsequent inflammatory process. Furthermore, we hypothesized a potential utility of so-called “hypoxic conditioning” to activate HIF-1α-induced cytoprotective signaling for reduction of illness severity and improvement of vital organ function in patients with COVID-19. Taken together, we would propose further investigations into the hypoxia-related molecular mechanisms, from which novel targeted therapies can be developed for the improved management of COVID-19.

Systemic hypoxia potentiates anti-tumor effects of metformin in hepatocellular carcinoma in mice.

Local hypoxia is a universal phenomenon in most solid tumors. The role of local hypoxia in the tumor microenvironment and cancer growth and metastasis has been well established. However, the effect of acute systemic hypoxia (exposing the whole body to 10% O2 environment) on cancer has not yet been investigated. In this study, we investigated the potential effects of acute systemic hypoxia itself and in combination with metformin on hepatocellular carcinoma (HCC) growth and metastasis in a mouse model of HCC. Acute systemic hypoxia significantly decreased tumor volume and weight in H22 tumor-bearing mice. Interestingly, the combined treatment of acute systemic hypoxia and metformin showed a more pronounced effect in reducing tumor volume and weight. Moreover, acute systemic hypoxia and metformin in combination had a potent inhibitory effect on tumor progression. More importantly, the expressions of hypoxia response genes including hypoxia-inducible factor-1 α, vascular endothelial growth factor, and matrix metalloproteinase 2 were significantly decreased in the tumor tissues with combination treatment. Our study demonstrated that acute systemic hypoxia repressed tumor progression of the HCC and potentiated the anti-tumor activities of metformin. This study supports that combination of systemic hypoxia and metformin treatment may represent a novel strategy for HCC.

Detection and response to acute systemic hypoxia

Detection and response to acute systemic hypoxia

P3486Experimental model for heart failure in rats: apelin-13/apj and bnp-45 gene expression analysis

Abstract Background Apelin, an adipokine peptide and its receptor has recently emerged as a key signaling pathway in maintaining cardiac performance at chronic pressure loads. Apelin has been linked to ventricular dysfunction and therefore maybe of pathophysiologic relevance as a candidate biomarker in HF patients. Purpose This study aims to investigate Apelin-13 gene expression and level, and Apelin receptor (APJ) level in a rat model of heart failure induced by chronic systemic hypoxia and their correlation to BNP-45 gene expression and level, the current gold standard biomarker for heart failure, and to cardiac histopathologic changes. The effect of chronic systemic hypoxia on cardiac hypertrophy, remodeling and heart failure parameters is also of interest. Methods Twenty-eight male Sprague-Dawley rats (8–12 weeks of age) were placed in special hypoxic chambers divided into 7 groups – a control group provided with normoxia (atmospheric O2 levels) and 6 exposure groups exposed to hypoxia (8% O2) for 6 hours, 1, 3, 5, 7 and 14 days respectively prior to measurement. Changes in the expression of Apelin and BNP-45 were measured using quantitative real-time PCR, whereas changes in Apelin-13, APJ and BNP-45 levels were measured using ELISA. Histopathology staining using Hematoxylin and Eosin was performed on cardiac tissues post-termination. Results Compared to control, BNP-45 mRNA expression in the hypoxic heart was only significantly different in day 14, whereas, Apelin mRNA expression had showed significantly higher values starting from day 7 onward. This is in line with the evidence of cardiac hypertrophy based on histopathologic examination present from day 7 onwards. BNP-45 and Apelin-13 levels were significantly higher compared to control from day 5 onwards with a peak on day 7. Although significantly higher than control, Apelin-13 and BNP-45 level decreases in day 14 as compared to day 7. Mean APJ levels showed a similar profile with Apelin-13 and BNP-45 levels with a peak in day 7 (4.619 ng/mL). The cardiac Apelin-13 level shows strong significant correlation with BNP-45 levels (r 0.823, p-value 0.0001). There was also a strong significant correlation between APJ receptor levels with Apelin-13 (r 0.9029, p-value 0.001) and BNP-45 (r 0.9062, p-value 0.0009) levels. Apelin-13, APJ and BNP-45 levels also showed strong significant positive correlation to the duration of hypoxia exposure. Conclusion Chronic (≥5 days) and not acute systemic hypoxia in an experimental rat model leads to increase in Apelin-13, APJ and BNP-45 levels. Apelin-13 and BNP-45 were found to significantly increase from 5 days onwards. Apelin mRNA expression was found to show significant increase earlier compared to BNP-45 mRNA expression. Hence, Apelin may serve as a new candidate biomarker for detection of HF due to oxidative stress compared to BNP-45. Exposure to chronic systemic hypoxia can serve as an easily replicable rat model for heart failure. Acknowledgement/Funding Department of Biochemistry and Molecular Biology, Faculty of Medicine, Tarumanagara University, Jakarta, Indonesia

Hemoglobin β93 Cysteine Is Not Required for Export of Nitric Oxide Bioactivity From the Red Blood Cell.

Nitrosation of a conserved cysteine residue at position 93 in the hemoglobin β chain (β93C) to form S-nitroso (SNO) hemoglobin (Hb) is claimed to be essential for export of nitric oxide (NO) bioactivity by the red blood cell (RBC) to mediate hypoxic vasodilation and cardioprotection. To test this hypothesis, we used RBCs from mice in which the β93 cysteine had been replaced with alanine (β93A) in a number of ex vivo and in vivo models suitable for studying export of NO bioactivity. In an ex vivo model of cardiac ischemia/reperfusion injury, perfusion of a mouse heart with control RBCs (β93C) pretreated with an arginase inhibitor to facilitate export of RBC NO bioactivity improved cardiac recovery after ischemia/reperfusion injury, and the response was similar with β93A RBCs. Next, when human platelets were coincubated with RBCs and then deoxygenated in the presence of nitrite, export of NO bioactivity was detected as inhibition of ADP-induced platelet activation. This effect was the same in β93C and β93A RBCs. Moreover, vascular reactivity was tested in rodent aortas in the presence of RBCs pretreated with S-nitrosocysteine or with hemolysates or purified Hb treated with authentic NO to form nitrosyl(FeII)-Hb, the proposed precursor of SNO-Hb. SNO-RBCs or NO-treated Hb induced vasorelaxation, with no differences between β93C and β93A RBCs. Finally, hypoxic microvascular vasodilation was studied in vivo with a murine dorsal skin-fold window model. Exposure to acute systemic hypoxia caused vasodilatation, and the response was similar in β93C and β93A mice. RBCs clearly have the fascinating ability to export NO bioactivity, but this occurs independently of SNO formation at the β93 cysteine of Hb.

Responses of Angiogenic Regulators to Resistance Exercise Under Systemic Hypoxia.

Kon, M, Ikeda, T, Homma, T, and Suzuki, Y. Responses of angiogenic regulators to resistance exercise under systemic hypoxia. J Strength Cond Res 35(2): 436-441, 2021-Resistance exercise and hypoxia powerfully affect the secretions of angiogenic regulators. However, the effects of resistance exercise under acute systemic hypoxia on circulating levels of angiogenic regulators are unknown. Therefore, we investigated the effects of resistance exercise under systemic hypoxia on angiogenic regulator responses. Twelve healthy male subjects completed 2 experimental trials: (a) resistance exercise under normoxia (NRE), and (b) resistance exercise under systemic hypoxia (13% oxygen) (HRE) using a hypoxic generator. The subjects performed 2 consecutive resistance exercises (bench press and bilateral leg press), consisting of 5 sets with 10 repetitions at 70% of 1 repetition maximum with a 1-minute rest between sets. Serum vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-2, MMP-9, and endostatin concentrations were measured before exercise (and before exposure to hypoxia in the HRE trial) and at 0, 15, and 30 minutes after the resistance exercises. In both trials, serum VEGF, MMP-2, MMP-9, and endostatin concentrations significantly increased after the exercises compared with preexercise values (p < 0.05). At 0 minutes after exercise, the percentage change in VEGF concentration was significantly higher in the HRE trial compared with that in the NRE trial (p < 0.05). However, the exercise-induced changes in MMP-2, MMP-9, and endostatin concentrations did not differ between trials. The present results demonstrate that acute systemic hypoxia induces a greater resistance exercise-induced VEGF response, suggesting that hypoxia plays an important role in increasing the VEGF response to a bout of resistance exercise.

Administration of ghrelin associated with decreased expression of matrix metalloproteinase-9 following normobaric systemic hypoxia in the brain.

According to our previous studies, ghrelin protects blood brain barrier (BBB) integrity and it attenuates hypoxia-induced brain edema in the hypoxic conditions. However, the underlying mechanisms remain poorly understood. Several studies suggest a role for matrix metal-loproteinase-9 (MMP9) in the BBB disruption and cerebral edema formation. The present study was conducted to determine the effect of ghrelin on MMP9 protein expression in the model of acute and chronic systemic hypoxia. Adult male Wistar rats were divided into acute or chronic controls, acute or chronic hypoxia and ghrelin-treated acute or chronic hypoxia groups. The hypoxic groups were kept in the hypoxic chamber (10-11% O2) for two (acute) or ten days (chronic). Effect of ghrelin on MMP9 protein expression was assessed using immunoblotting. Our results showed that acute and chronic systemic hypoxia increased the MMP9 protein expression in the brain (p<0.001). Treatment with ghrelin significantly attenuated this expression in the cerebral hypoxia (p<0.05). Our results demonstrate that the neuroprotective effects of ghrelin may be mediated, in part, by decreasing in MMP9 production in the hypoxic brain.

Systemic Hypoxia Increases Circulating Concentration of Apelin in Humans.

Apelin is a hormone that regulates cardiovascular function, and its concentration is increased by hypoxia based on cell culture and animal studies. As it remains unknown as to whether hypoxia could affect apelin levels in humans, we investigated whether breathing normobaric hypoxic gas mixture increases the circulating apelin concentration in healthy male subjects. Ten healthy young men (age 29 ± 5 years, body mass index 24.7 ± 2.8 kg/m2) breathed normobaric hypoxic gas mixture (11% O2/89% N2) for 1 hour. Venous blood samples were obtained immediately before, and 2 and 24 hours after the start of the hypoxic exposure and analyzed for circulating apelin concentrations. Arterial oxygen saturation decreased steadily from a baseline value of 99% ± 1% after the initiation hypoxia challenge and reached a steady-state level of 73% ± 6% within 20-30 minutes. Baseline apelin concentration was 3.3 ± 1.3 pmol/L and remained comparable (3.3 ± 1.4 pmol/L) to the baseline concentration at a 2-hour time point. However, apelin concentration at the 24-hour time point (5.5 ± 2.8 pmol/L) was significantly (by ∼67%) higher as compared with at both baseline and 2-hour time points (p < 0.05). In conclusion, in line with cell culture and animal studies, acute systemic hypoxia increases circulating apelin concentration also in humans.

Ghrelin ameliorates blood-brain barrier disruption during systemic hypoxia.

What is the central question of this study? Is an anti-oedematous effect of ghrelin associated with increased expression of tight junction proteins in the hypoxic brain? What is the main finding and its importance? We showed that injection of ghrelin during acute and chronic systemic hypoxia is associated with increased expression of tight junction proteins and protection of the blood-brain barrier. Ghrelin appears to be a new therapeutic strategy for protection of the blood-brain barrier from disruption and prevention of brain oedema in hypoxic conditions. The blood-brain barrier, which serves to protect the homeostasis of the CNS, is formed by tight junction proteins. Several studies have indicated that systemic hypoxia leads to cerebral oedema through disruption of tight junction proteins, such as occludin and zonula occludens-1 (ZO-1). According to our previous studies, ghrelin attenuates cerebral oedema in the hypoxic brain. However, the mechanism is not completely understood. The present study was designed to determine the effect of ghrelin on occludin and ZO-1 in the hypoxic brain. Adult male Wistar rats were divided into acute and chronic control, acute or chronic hypoxia, and ghrelin-treated acute or chronic hypoxia groups. Hypoxic groups were kept in a hypoxic chamber (10-11% O2 ) for 2 (acute) or 10 days (chronic). Effects of ghrelin on occludin and ZO-1 protein levels were assessed using Western blotting. Western blot analysis revealed that the protein expression of ZO-1 and occludin decreased significantly in acute and chronic hypoxia. Ghrelin significantly increased ZO-1 protein expression in both acute and chronic hypoxia (P<0.05). Ghrelin also increased occludin protein expression in chronic hypoxia (P<0.05) but did not effectively change it in acute hypoxia. Our data showed that ghrelin injection maintains occludin and ZO-1 tight junction proteins, which may improve the integrity of the blood-brain barrier in hypoxic conditions.

Effects of Acute Systemic Hypoxia and Hypercapnia on Brain Damage in a Rat Model of Hypoxia-Ischemia.

Therapeutic hypercapnia has the potential for neuroprotection after global cerebral ischemia. Here we further investigated the effects of different degrees of acute systemic hypoxia in combination with hypercapnia on brain damage in a rat model of hypoxia and ischemia. Adult wistar rats underwent unilateral common carotid artery (CCA) ligation for 60 min followed by ventilation with normoxic or systemic hypoxic gas containing 11%O2,13%O2,15%O2 and 18%O2 (targeted to PaO2 30–39 mmHg, 40–49 mmHg, 50–59 mmHg, and 60–69 mmHg, respectively) or systemic hypoxic gas containing 8% carbon dioxide (targeted to PaCO2 60–80 mmHg) for 180 min. The mean artery pressure (MAP), blood gas, and cerebral blood flow (CBF) were evaluated. The cortical vascular permeability and brain edema were examined. The ipsilateral cortex damage and the percentage of hippocampal apoptotic neurons were evaluated by Nissl staining and terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5′-triphosphate-biotin nick end labeling (TUNEL) assay as well as flow cytometry, respectively. Immunofluorescence and western blotting were performed to determine aquaporin-4 (AQP4) expression. In rats treated with severe hypoxia (PaO2 < 50 mmHg), hypercapnia augmented the decline of MAP with cortical CBF and damaged blood–brain barrier permeability (p < 0.05). In contrast, in rats treated with mild to moderate hypoxia (PaO2 > 50 mmHg), hypercapnia protected against these pathophysiological changes. Moreover, hypercapnia treatment significantly reduced brain damage in the ischemic ipsilateral cortex and decreased the percentage of apoptotic neurons in the hippocampus after the CCA ligated rats were exposed to mild or moderate hypoxemia (PaO2 > 50 mmHg); especially under mild hypoxemia (PaO2 > 60 mmHg), hypercapnia significantly attenuated the expression of AQP4 protein with brain edema (p < 0.05). Hypercapnia exerts beneficial effects under mild to moderate hypoxemia and augments detrimental effects under severe hypoxemia on brain damage in a rat model of hypoxia-ischemia.

Effect of acute nitrate ingestion on central hemodynamic load in hypoxia

Acute hypoxia results in local vasodilation that may temporarily unload the left ventricle (LV) through nitric oxide (NO)-mediated mechanisms. Whether increasing NO levels augments LV unloading and improves ventricular-vascular coupling in hypoxia remains unknown. PurposeInvestigate the effect of acute nitrate ingestion on central hemodynamic load in hypoxia. Methods20 Healthy men (23 ± 3 yrs, BMI 24.6 ± 2.8 kg m−2) consumed 70 mL of either a) 0.45 g nitrate (NIT) or b) an inert placebo (PLA) prior to 105 min of normobaric hypoxia (11.6 ± 0.1%) in this randomized, double-blind, crossover-design study. Wave reflection index (RIX; ratio of forward to reflected wave pressure), augmentation index (AIX75) and pulse wave velocity were calculated as measures of wave reflection magnitude and aortic stiffness, respectively, from the aortic blood pressure (BP) waveform. LV wasted pressure effort (WPE) was calculated as an index of LV work due to wave reflections. Subendocardial viability ratio (SEVR) was assessed a measure of myocardial O2 supply/demand ratio. ResultsAortic diastolic BP decreased in hypoxia compared to normoxia (p < 0.05). Aortic RIX, AIX75, and LV WPE significantly decreased in hypoxia compared to normoxia (p < 0.05). Aortic systolic BP, SEVR, and PWV were unaffected by hypoxia (p > 0.05). Compared to placebo, nitrate ingestion did not significantly alter central hemodynamics in hypoxia (p > 0.05). ConclusionsAcute hypoxic exposure unloads the LV (WPE, AIX75, and RIX) without disturbing myocardial O2 supply-demand ratio (SEVR). Reductions in LV work with hypoxia are likely due to reductions in pressure from wave reflections as hypoxia had negligible effects on aortic stiffness. Nitrate ingestion did not affect the central hemodynamic response to acute systemic hypoxia.

Interactions between local dilator and sympathetic vasoconstrictor influences in skeletal muscle in acute and chronic hypoxia.

What is the topic of this review? This review considers how local dilator mechanisms and increased sympathetic nerve activity interact during acute systemic hypoxia and then reviews current understanding of some of the modifications induced by chronic hypoxia. What advances does it highlight? During acute hypoxia, local levels of hypoxia determine the release of vasodilators and magnitude of arteriolar dilatation, as well as the extent to which sympathetically evoked vasoconstriction is blunted, so maximizing distribution of O2 to muscle fibres. Chronic hypoxia in adult life and fetal programming induced by chronic hypoxia in utero lead to increased responsiveness to acute hypoxia and further blunting of sympathetic vasoconstriction, but are also associated with hypertension. In resting skeletal muscle, acute systemic hypoxia evokes vasodilatation, while vasoconstriction evoked by increased muscle sympathetic nerve activity is blunted, referred to herein as hypoxic sympatholysis. This review considers the contributions of adenosine, prostaglandin I2 , nitric oxide, ATP and endothelium-derived hyperpolarizing factors to the muscle vasodilatation, with particular attention being given to the release and actions of adenosine, which plays a dominant role. It is argued that the dilator substances are released in proportion to the local level of hypoxia, notably, allowing terminal arterioles to regulate O2 distribution through the capillaries. Correspondingly, hypoxic sympatholysis can be attributed to the ability of local hypoxia to blunt vasoconstriction evoked by noradrenaline acting on α1 - and α2 -adrenoceptors. The synergistic actions of ATP as cotransmitter may be depressed in parallel, but the actions of neuropeptide Y persist. Consideration is also given to the changes induced by chronic hypoxia in adult life and to the consequences in adult life of fetal programming induced by chronic hypoxia during pregnancy. In both conditions, dilator responsiveness to acute hypoxia is maintained, but the action or release of adenosine is altered in ways that are not yet understood. Both conditions are also accompanied by blunted sympathetically evoked vasoconstriction, tonically raised muscle sympathetic nerve activity, and increased muscular vascular tone and arterial blood pressure. With hypoxia-induced fetal programming, arterial pressure is increased in young adults and increases with age. The mechanisms underlying these changes are discussed, and it is argued that chronic hypoxia in adult life or in utero may facilitate development of hypertension.

Effect of acute systemic hypoxia on human cutaneous microcirculation and endothelial, sympathetic and myogenic activity

The regulation of cutaneous vascular tone impacts vascular vasomotion and blood volume distribution as a challenge to hypoxia, but the regulatory mechanisms yet remain poorly understood. A skin has a very compliant circulation, an increase in skin blood flow results in large peripheral displacement of blood volume, which could be controlled by local and systemic regulatory factors. The aim of this study was to determine the acute systemic hypoxia influence on blood flow in skin, local regulatory mechanism fluctuations and changes of systemic hemodynamic parameters. Healthy subjects (n=11; 24.9±3.7years old) participated in this study and procedures were performed in siting position. After 20min of acclimatization 15min of basal resting period in normoxia (pO2=21%) was recorded, followed by 20min in acute systemic hypoxia (pO2=12%), and after 15min of recovery period in normoxia (pO2=21%). HRV was used to evaluate autonomic nervous system activity to heart from systemic hemodynamic parameters which continuously evaluated cardiac output, total peripheral resistance and mean arterial blood pressure. Regional blood flow was evaluated by venous occlusion plethysmography and skin blood flow by laser-Doppler flowmetry. To evaluate local factor influences to cutaneous circulation wavelet analysis was used; fluctuations in the frequency intervals of 0.0095–0.021, 0.021–0.052, and 0.052–0.145Hz correspondingly represent endothelial, sympathetic, and myogenic activities. Our results from HRV data suggest that acute systemic hypoxia causes statistically significant increase of sympathetic (LF/HF; N1=0.46±0.25 vs. H=0.67±0.36; P=0.027) and decrease of parasympathetic (RMSSD; 80.0±43.1 vs. H=69.9±40.4, ms; P=0.009) outflow to heart. Acute hypoxia causes statistically significant increase of heart rate (RR interval; N1=960.3±174.5 vs. H=864.7±134.6, ms; P=0.001) and cardiac output (CO; N1=5.4 (5.2; 7.9) vs. H=6.7±1.4, l/min; P=0.020). Regional blood flow and vascular conductance were not changed during acute systemic hypoxia, but forearm skin blood flow (skin blood flow; N1=39.7 (34.0; 53.2) vs. H=51.6±13.9, PU; P=0.002) increases however local regulatory factor activity was not changed by acute systemic hypoxia. Acute systemic hypoxia causes sympathetic stimulation to heart which results in increased heart rate and larger cardiac output which could be the reason of forearm skin blood flow increase in acute systemic hypoxia without impact of local regulatory factors.