Blood flow to the brown adipose tissue of conscious young rabbits during hypoxia in cold and warm conditions

 Brown adipose tissue (BAT) non-shivering thermogenesis is stimulated by cold temperature and depressed by hypoxia. We investigated the extent to which changes in metabolic rate during cold and hypoxia, singly or combined, were accompanied by changes in BAT perfusion. One-month-old rabbits were instrumented for measurements of regional blood flow by the coloured microsphere technique. One group of rabbits was tested in warm (24 °C, n=17), and the other in cold (13 °C, n=9) conditions, first in normoxia (inspired oxygen concentration FIO₂ about 21%, arterial oxygen saturation S _aO₂ approximately 88%) followed by hypoxia (FIO₂ approximately 10%, S _aO₂ approximately 54%). In warm conditions, oxygen consumption (V·O₂, measured by an open-flow method) averaged 22 ml·kg^–1·min^–1 (STPD), and BAT blood flow 98 ml·100g^–1·min^–1. In hypoxia, V·O₂ dropped on average to 87%, whereas BAT flow dropped to 43% of the normoxic values. In the cold during normoxia, V·O₂ averaged 31 ml·kg^–1·min^–1 (STPD), and BAT blood flow was 155 ml·100g^–1·min^–1. In cold and hypoxia V·O₂ dropped to 19 ml·kg^–1·min^–1 (STPD) (i.e. 60% of the normoxic value), whereas BAT blood flow was not altered significantly (148 ml·100g^–1·min^–1). Hence, BAT blood flow decreased in hypoxia in absence of cold stimuli, whereas it remained high when hypoxia occurred during cold, despite the major drop in V·O₂. We conclude that cold is more important than hypoxia in determining BAT perfusion, and that changes in BAT blood flow are not a mechanism for the hypoxic control of V·O₂. Received: 24 June 1998 / Received after revision: 21 September 1998 / Accepted: 29 September 1998     

Plasmakatecholaminkonzentrationen in akuter Hypoxie

Zusammenfassung Der Einfluß des Sauerstoffmangels auf die Plasmakatecholaminkonzentrationen des arteriellen und mischvenösen Blutes wurde fluorimetrisch nach Häggendal u. Klensch untersucht. Bei arteriellen O₂-Spannungen von etwa 38 mm Hg und venösen Spannungen von 23 mm Hg läßt sich weder eine Adrenalinausschüttung noch eine vermehrte Noradrenalinfreisetzung nachweisen. Der Katecholaminspiegel des Blutes erfährt im Bereich des kleinen Kreislaufs keine nachweisbare Änderung, weder bei Normalatmung noch in Hypoxie.

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Summary Catecholamine concentrations in arterial and mixed venous blood were estimated fluorimetrically during hypoxia. Arterial O₂-tensions of about 38 mm Hg and venous tensions of 23 mm Hg were reached by breathing 10% O₂ for 15 min. Increased release of Adrenaline or Noradrenaline could not be observed. Uptake or release of catecholamines within the pulmonary circulation were not observed, neither during breathing ambiant air nor during hypoxia.

     

Effects of low and high levels of moderate hypoxia on anaerobic energy release during supramaximal cycle exercise

The purpose of this study was to investigate whether hypoxia can alter anaerobic energy release during supramaximal exercise. Seven male subjects performed 12 submaximal cycling tests to establish the relationship between workload and O₂ demand. The subjects also performed 40 s Wingate tests (WT) under normoxia (room air), two levels of moderate hypoxia of 16.4% O₂ and 12.7% O₂. We measured the power output and oxygen uptake (VO₂) during each test and estimated the O₂ demand, O₂ deficit and percentage of anaerobic energy release (%AnAER). These data were analyzed for each 20 s interval. At all intervals, there were no differences in Pmean·body mass (BM)⁻¹, O₂ demand·BM⁻¹ or O₂ deficit·BM⁻¹ among the three O₂ conditions. However, under hypoxia of 12.7%, VO₂·BM⁻¹ was significantly decreased and %AnAER was significantly increased in the late phase (20–40 s) of the WT, compared to normoxia (P<0.05). There were no such significant differences between normoxia and hypoxia of 16.4%. Thus, the present results show that the degree of hypoxia affects the magnitude of the hypoxia-induced increase in anaerobic energy release in the late phase of the WT and suggest that certain degrees of hypoxia induce significant increases in the amount of anaerobic energy released, compared to normoxia.     

Carbon monoxide inhibits hypoxic pulmonary vasoconstriction in rats by a cGMP-independent mechanism

 Hypoxia activates erythropoietin-producing cells, chemoreceptor cells of the carotid body and pulmonary artery smooth muscle cells (PSMC) with a comparable arterial PO₂ threshold of some 70 mmHg. The inhibition by CO of the hypoxic responses in the two former cell types has led to the proposal that a haemoprotein is involved in the detection of the PO₂ levels. Here, we report the effect of CO on the hypoxic pulmonary vasoconstriction (HPV). Pulmonary arterial pressure (PAP) was measured in an in situ, blood-perfused lung preparation. PAP in normoxia (20% O₂, 5% CO₂) was 15.2±1.8 mmHg, and hypoxia (2% O₂, 5% CO₂) produced a ΔPAP of 6.3±0.4 mmHg. Addition of 8% or 15% CO to the hypoxic gas mixture reduced the ΔPAP by 88.3±2.7% and 78.2±6.1% respectively. The same levels of CO did not affect normoxic PAP nor reduced the ΔPAP produced by angiotensin II. The effect of CO was studied after inhibition of the NO-cyclic guanosine monophosphate (cGMP) cascade with N-methyl-l-arginine (5·10^–5 M) or methylene blue (1.4·10^–4 M). It was found that both inhibitors more than doubled the hypoxic ΔPAP without altering the effectiveness of CO to inhibit the HPV. In in vitro experiments we verified the inhibition of guanylate cyclase by measuring the levels of cGMP in segments of the pulmonary artery. Cyclic GMP levels were 1.4±0.2 (normoxia), 2.5±0.3 (hypoxia) and 3.3±0.5 pmole/mg tissue (hypoxia plus 8% CO); sodium nitroprusside increased normoxic cGMP levels about fourfold. Methylene blue reduced cGMP levels to less than 10% in all cases, and abolished the differences among normoxic, hypoxic and hypoxic plus CO groups. It is concluded that CO inhibits HPV by a NO-cGMP independent mechanism and it is proposed that a haemoprotein could be involved in O₂-sensing in PSMC. Received: 17 March 1997 / Received after revision: 10 June 1997 / Accepted: 11 July 1997     

Effects of hypobaric hypoxia on vascular endothelial growth factor and the acute phase response in subjects who are susceptible to high-altitude pulmonary oedema

In order to investigate whether vascular endothelial growth factor (VEGF) and inflammatory pathways are activated during acute hypobaric hypoxia in subjects who are susceptible to high-altitude pulmonary oedema (HAPE-S), seven HAPE-S and five control subjects were exposed to simulated altitude corresponding to 4000 m in a hypobaric chamber for 1 day. Peripheral venous blood was taken at 450 m (Zürich level) and at 4000 m, and levels of erythropoietin (EPO), VEGF, interleukin-6 (IL-6) and the acute-phase proteins complement C3 (C3), α₁-antitrypsin (α₁AT), transferrin (Tf ) and C-reactive protein (CRP) were measured. Peripheral arterial oxygen saturation (S _aO₂) was recorded. Chest radiography was performed before and immediately after the experiment. EPO increased during altitude exposure, correlating with S _aO₂, in both groups (r = −0.86, P < 0.001). Venous serum VEGF did not show any elevation despite a marked decrease in S _aO₂ in the HAPE-S subjects [mean (SD) HAPE-S: 69.6 (9.1)%; controls: 78.7 (5.2)%]. C3 and α₁AT levels increased in HAPE-S during hypobaric hypoxia [from 0.94 (0.11) g/l to 1.07 (0.13) g/l, and from 1.16 (0.08) g/l to 1.49 (0.27) g/l, respectively; P < 0.05], but remained within the clinical reference ranges. No significant elevations of IL-6, Tf or CRP were observed in either group. The post-exposure chest radiography revealed no signs of oedema. We conclude that VEGF is not up-regulated in HAPE-S and thus does not seem to increase critically pulmonary vascular permeability during the 1st day at high altitude. Furthermore, our data provide evidence against a clinically relevant inflammation in the initial phase of exposure to hypoxia in HAPE-S, although C3 and α₁AT are mildly induced. Accepted: 25 October 1999     

Prostaglandin D2 and J2-series (PGJ2, Δ12-PGJ2) prostaglandins stimulate IL-6 and MCP-1, but inhibit leptin, expression and secretion by 3T3-L1 adipocytes

Prostaglandin D₂ and its derivatives PGJ₂ and Δ¹²-PGJ₂ strongly stimulate the synthesis and secretion by white adipocytes of the neurotrophin NGF. Here we have explored whether PGD₂ and the J₂-series prostaglandins have pervasive effects on adipokine production. The influence of these prostaglandins on the production of the adipocyte hormones leptin and adiponectin, and the inflammatory factors IL-6 and monocyte chemoattractant protein 1 (MCP-1), were examined in 3T3-L1 adipocytes. PGD₂ induced a reduction in adiponectin and leptin mRNA, and the secretion of these adipokines was also inhibited, the effect being greater with leptin (up to 10-fold) than with adiponectin (twofold). In contrast, PGD₂ induced a marked stimulation of IL-6 and MCP-1 expression; with IL-6, this was rapid, the mRNA level increasing by >50-fold by 1 h. The rise in mRNA was accompanied by an increase in IL-6 and MCP-1 release (up to 100- and 6.5-fold, respectively). The effects of PGD₂ were generally mirrored by PGJ₂ and Δ¹²-PGJ₂; Δ¹²-PGJ₂ was a particularly strong stimulator of IL-6 production. These results indicate that PGD₂ and the J₂-series prostaglandins PGJ₂ and Δ¹²-PGJ₂ can have major effects on the synthesis and release of key adipokines. Such effects could be important in the inflammatory response in adipose tissue.     

Effects of high-altitude exposure on vascular endothelial growth factor levels in man

Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen and permeability factor that is inducible by hypoxia. Its contribution to high-altitude illness in man is unknown. We measured VEGF levels in 14 mountaineers at low altitude (490 m) and 24 h after their arrival at high altitude (4,559 m). At high altitude, VEGF increased from [mean (SEM)] 32.5 (9.2) to 60.9 (18.5) pg·ml^–1 (P<0.004) in the arterial blood, and from 15.9 (2.9) to 49.3 (15.9) pg·ml^–1 (P=0.0001) in the mixed venous blood. Whereas at low altitude venous and arterial VEGF levels were not statistically different from each other (P=0.065), the VEGF concentration was significantly lower in venous than in arterial blood samples at high altitude (P=0.004). The pulmonary capillary VEGF concentration remained unchanged at high altitude [14.8 (2.5) vs 17.1 (5.4) pg·ml^–1, P=0.85]. VEGF levels in the nine mountaineers who developed symptoms of acute mountain sickness (AMS), and in the six subjects who had radiographic evidence of high-altitude pulmonary edema were similar to those in subjects without symptoms. VEGF was not correlated with either AMS scores, mean pulmonary arterial pressures, arterial partial pressure of O₂, or alveolar-arterial O₂ gradients. We conclude that VEGF release is stimulated at high altitude, but that VEGF is probably not related to high-altitude illness. Electronic Publication     

Inhibition of histone deacetylase down-regulates the expression of hypoxia-induced vascular endothelial growth factor by rheumatoid synovial fibroblasts

Objective: To investigate the effect of FK228 on the in vitro expression of hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) by rheumatoid arthritis synovial fibroblasts (RASFs), and on the in vivo expression of VEGF and angiogenesis in the synovial tissue of mice with collagen-antibody-induced arthritis (CAIA). Methods: RASFs were stimulated with IL-1β and TNFα and then incubated under hypoxia (1 % O₂) with various concentrations of FK228. The effects of FK228 on the expression of HIF-1α and VEGF mRNA were examined by quantitative real-time PCR. Changes in HIF-1α protein expression and the secretion of VEGF protein into the culture medium were examined by Western blot analysis and ELISA, respectively. Immunohistochemical analysis was carried out to investigate the expression and distribution of VEGF in synovial tissues of CAIA mice. Results: The cytokine-stimulated expression of HIF-1α and VEGF mRNA was inhibited by FK228 in a dose-dependent manner. FK228 also reduced the expression of HIF-1α and VEGF protein. Intravenous administration of FK228 (2.5 mg/kg) suppressed VEGF expression, and also blocked angiogenesis in the synovial tissue of CAIA. Conclusion: FK228 may exhibit a therapeutic effect on RA by inhibition of angiogenesis through down-regulation of angiogenesis related factors, HIF-1α and VEGF. Received 28 February 2007; returned for revision 19 March 2007; accepted by J. Di Battista 11 July 2007     

Influence of peripheral chemodenervation on the complexity of respiratory patterns during early maturation

Previous studies in humans have revealed that, during development, the fetus/neonate may be susceptible to environmental perturbations such as overheating, smoking, hypercapnia and hypoxia (Lewis andBosque, 1995;Maskery, 1995). In particular, alterations in behavioural states during early development can result in permanent alterations in their organisational states and subsequent abnormalities in the regulation of the cardiovascular and respiratory systems. The influence of the peripheral chemoreceptor afferent input on the approximate entropy (complexity) of the phrenic neurogram in the piglet was investigated in three different age groups: 3–7 days (n-7), 10–16 days (n=6) and 25–31 days (n=4). The phrenic neurogram was recorded from piglets during control (40% O₂) and severe hypoxia (gasping) (5–10% O₂), before and after peripheral chemodenervation, and was analysed using the approximate entropy (ApEn) method. The results show that the complexity values of the phrenic neurogram during eupnea and gasping did not change significantly before and after chemodenervation, regardless of postnatal age. The complexity values during gasping were not significantly influenced by the carotid chemodenervation for the 3–7 day-old group, but they were significantly decreased by the carotid chemodenervation for the 10–16 day-old age group (p<0.01) and the 25–31 day-old age group (p<0.05). However, the complexity values significantly decreased when the O₂ concentration was shifted from eupnea to gasping (p<0.001), both before and after the chemodenervation (p<0.001), regardless of the postnatal age. These results suggest that the peripheral chemodenervation reduces the complexity of the phrenic neurograms during gasping only for the 10–16 day-old and 25–31 day-old age groups, and it has no significant influence on the 3–7 day-old age group. Therefore it is speculated that the peripheral chemoreceptors may be inactive for the first seven days of postnatal life and become more active after seven days.     

Divergent regulation of vascular endothelial growth factor and of erythropoietin gene expression in vivo

There is accumulating evidence from in vitro experiments that the gene expression of the vascular endothelial growth factor (VEGF) is, like that of the erythropoietin (EPO) gene, regulated by the oxygen tension and by divalent cations such as cobalt. Since the information about the regulation of VEGF gene expression in vivo is rather scarce, this study aimed to examine the influence of hypoxia and of cobalt on VEGF gene expression in different rat organs and to compare it with that on EPO gene expression. To this end male Sprague-Dawley rats were exposed to carbon monoxide (0.1% CO), hypoxia (8% O₂ ) or to cobalt chloride (12 and 60 mg/kg s.c.) for 6 h. mRNA levels for VEGF- 188, -164, and -120 amino acid isoforms in lungs, hearts, kidneys and livers were semiquantitated by RNase protection. For these organs we found a rank order of VEGF mRNA abundance of lung >> heart > kidney = liver. EPO mRNA levels were semiquantitated in kidneys and livers. Hypoxia, CO and cobalt increased EPO mRNA levels 60-fold, 140-fold and 5-fold, respectively, in the kidneys, and 11-fold, 11-fold and 3-fold, respectively, in the livers. None of these manoeuvres caused significant changes of VEGF mRNA in lung, heart or kidneys. Only in the livers did hypoxia lead to a significant (50%) increase of VEGF mRNA. These findings suggest that, in contrast to the in vitro situation, the expression of the VEGF gene in normal rat tissues is rather insensitive to hypoxia. In consequence, the in vivo regulation of the VEGF and the EPO genes appear to differ substantially, suggesting that the regulation of the VEGF and EPO genes may not follow the same essential mechanisms in vivo. Received: 31 July 1995/Received after revision: 20 November 1995/Accepted: 27 November 1995     

Der zentrale Venendruck des Menschen bei akuter arterieller Hypoxie

Zusammenfassung An sechs kreislaufgesunden, nicht höhenadaptierten Versuchspersonen wurde das Verhalten des, nach der Methode von Gauer u. Sieker bestimmten zentralen Venendrucks während 10–24 min dauernder Atmung von O₂-Mangelgemischen mit 8,3–12,3% O₂ in N₂ untersucht.Bei insgesamt 13 Versuchen kam es nur in einem Fall zu einer eindeutigen Zunahme des zentralen Venendrucks, während in den übrigen Versuchen eine leichte Tendenz zum Absinken zu beobachten war. Eine Abhängigkeit der Reaktionsweise des zentralen Venendrucks von der Schwere des O₂-Mangels war im untersuchten O₂-Mangelbereich nicht nachzuweisen.Die erhobenen Befunde werden in Zusammenhang mit der, bei akuter arterieller Hypoxie eintretenden Constriction der Handvenen diskutiert.

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Summary In six healthy subjects not acclimatized to high altitudes the behavior of central venous pressure was examined, using the method of Gauer and Sieker, during acute arterial hypoxia of 10–24 min duration induced by respiration of gas mixtures containing 8.3–12.3% O₂ in N₂.In only one of a total of 13 experiments was there a consistent increase in central venous pressure. In the great majority of the experiments, a tendency towards a slight fall of central venous pressure was observed. These reactions of the central venous pressure were not related to the degree of oxygen lack within the range of hypoxia used.The results are discussed in relation to the constriction of the hand veins usually observed under severe acute arterial hypoxia.

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Mit Unterstützung des European Office, U. S. Air Research and Development Command.     

Hypoxia but not cigarette smoke modulates VEGF secretion from human T cells

Vascular endothelial growth factor (VEGF) is an important mitogen with multiple functions. In the present study we investigated whether T cell secreted VEGF and inflammatory cytokines were modulated by cigarette smoke and by a hypoxic microenvironment.

T cells from peripheral blood of healthy donors were activated under normoxia (21% O₂) or hypoxia (1–2% O₂) with or without exposure to cigarette smoke extract. T cells were also obtained from patients with chronic obstructive pulmonary disease (COPD), a smoking-related disease characterized by accumulation of both CD4+ and CD8+T cells.

Hypoxia stimulated VEGF secretion from activated T cells, whereas the release of IL-4, IL-6, IL-10, IL-13, IFN-γ and tumour necrosis factor were not altered. Cigarette smoke extract did not affect VEGF secretion neither in hypoxia nor in normoxia, whereas the secretion of all cytokines was inhibited by the extract in both conditions. When recombinant VEGF was added the smoke-induced inhibition of the IFN-γ and IL-13 was not observed. Activated T cells from COPD-patients secreted significantly (p < 0.05) more VEGF compared to T cells from healthy individuals.

Our data suggest that both cigarette smoke extract and hypoxia modulate the T cell response. This may be of importance in diseases characterized by T cell accumulation, such as COPD.     

Human erythropoietin response to hypocapnic hypoxia,normocapnic hypoxia,and hypocapnic normoxia

This study investigated the human erythropoietin (EPO) response to short-term hypocapnic hypoxia, its relationship to a normoxic or hypoxic increase of the haemoglobin oxygen affinity, and its suppression by the addition of CO₂ to the hypoxic gas. On separate days, eight healthy male subjects were exposed to 2 h each of hypocapnic hypoxia, normocapnic hypoxia, hypocapnic normoxia, and normal breathing of room air (control experiment). During the control experiment, serum-EPO showed significant variations (ANOVAP = 0.047) with a 15% increase in mean values. The serum-EPO measured in the other experiments were corrected for these spontaneous variations in each individual. At 2 h after ending hypocapnic hypoxia (10% O₂ in nitrogen), mean serum-EPO increased by 28% [baseline 8.00 (SEM 0.84) U · 1⁻¹, post-hypoxia 10.24 (SEM 0.95) U · 1⁻¹, P = 0.005]. Normocapnic hypoxia was produced by the addition of CO₂ (10% Co₂ with 10% O₂) to the hypoxic gas mixture. This elicited an increased ventilation, unaltered arterial pH and haemoglobin oxygen affinity, a lower degree of hypoxia than during hypocapnic hypoxia, and no significant changes in serum-EPO (ANOVAP > 0.05). Hypocapnic normoxia, produced by hyperventilation of room air, elicited a normoxic increase in the haemoglobin oxygen affinity without changing serum-EPO. Among the measured blood gas and acid-base parameters, only the partial pressures of oxygen in arterial blood during hypocapnic hypoxia were related to the peak values of serum-EPO (r = −0.81,P = 0.01). The present human EPO responses to hypoxia were lower than those which have previously been reported in rodents and humans. In contrast with the earlier rodent studies, it was found that human EPO production could not be triggered by short-term increases in pH and haemoglobin oxygen affinity per se, and the human EPO response to hypoxia could be suppressed by concomitant normocapnia without acidosis.     

Changes in performance,maximal oxygen uptake and maximal accumulated oxygen deficit after 5, 10 and 15 days of live high:train low altitude exposure

Nineteen well-trained cyclists (14 males and 5 females, mean initial V˙O_2max 62.3 ml kg^–1 min^–1) completed a multistage cycle ergometer test to determine maximal mean power output in 4 min (MMPO_4min), maximal oxygen uptake (V˙O_2max) and maximal accumulated oxygen deficit (MAOD). The athletes were divided into three groups, each of which completed 5, 10 or 15 days of both a control condition (C) and live high:train low altitude exposure (LHTL). The C groups lived and trained at the ambient altitude of 610 m. The LHTL groups spent 8–10 h night^–1 in normobaric hypoxia at a simulated altitude of 2,650 m, and trained at the ambient altitude of 610 m. The changes to MMPO_4min, V˙O_2max and MAOD in response to LHTL altitude exposure were not significantly different for the 5-, 10- and 15-day treatment periods. For the pooled data from all three treatment periods, there were significant increases in MMPO_4min [mean (SD) 5.15 (0.83) W kg^–1 vs 5.34 (0.78) W kg^–1] and MAOD [50.1 (14.2) ml kg^–1 vs 54.9 (13.1) ml kg^–1] in the LHTL athletes between pre- and post-altitude exposure. There were no significant changes in MMPO_4min [5.09 (0.76) W kg^–1 vs 5.16 (0.86) W kg^–1] or MAOD [50.5 (14.1) ml kg^–1 vs 49.1 (13.0) ml kg^–1] in the C athletes over the corresponding period. There were significant increases in V˙O_2max in the athletes during both the LHTL [63.2 (9.0) ml kg^–1 min^–1 vs 64.1 (9.0) ml kg^–1 min^–1] and C [62.0 (8.6) ml kg^–1 min^–1 vs 63.4 (9.2) ml kg^–1 min^–1] conditions. In these athletes, there was no difference in the impact of 5, 10 or 15 days of LHTL on the increases observed in MMPO_4min, V˙O_2max or MAOD; and LHTL increased MMPO_4min and MAOD more than training at low altitude alone. Electronic Publication     

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 (O₂) 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. O₂ 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 μM at 2,438 m (P < 0.05) but remained similar at 16.4 ± 2.3 μM 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.     

Damage and activation of endothelial cells during in vitro hypoxia

We studied the effect of hypoxia on activation and stimulation of apoptosis in cultured endothelial cells. The effect of hypoxia was compared to that of apoptosis-inducing agents (tumor necrosis factor and bacterial lipopolysaccharide). Incubation of endothelial cells for 24 h under hypoxic conditions (2% O₂, 5% CO₂, and 93% N₂) increased secretion of von Willebrand factor, but had no effect on the expression of cell adhesion molecule ICAM-1. Tumor necrosis factor and lipopolysaccharide did not stimulate secretion of von Willebrand factor, but significantly increased the expression of ICAM-1. These data attest to significant differences in the mechanisms of endothelium activation under hypoxic conditions and during treatment with tumor necrosis factor or lipopolysaccharide. Hypoxia stimulated apoptosis in endothelial cells, which was seen from the increase in the number of annexin V-binding cells and activation of caspase-3. Similar changes were revealed in the presence of tumor necrosis factor and lipopolysaccharide. Hence, damage to endothelial cells caused by hypoxia and these compounds is mediated by similar mechanisms. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 144, No. 10, pp. 384–386, October, 2007     

Differences in tyrosine hydroxylase expression after short-term hypoxia,hypercapnia or hypercapnic hypoxia in rat carotid body

In the carotid body (CB), it has been reported that the expressions of tyrosine hydroxylase (TH) mRNA and TH protein are enhanced by exposure to hypoxia. However, it is not known whether CO₂ affects the expression of TH in the CB. We examined the expression of TH mRNA and the immunoreactivity for TH in the CB of rats exposed to hypoxia (10% O₂), hypercapnia (10% CO₂) and hypercapnic hypoxia (10% O₂ and 10% CO₂) for 2–24 h. The expression of TH mRNA in the CB was markedly enhanced in rats exposed to hypoxia for 4 h (6.6-fold), 6 h (6.0-fold) and 8 h (7.8-fold), and in rats exposed to hypercapnic hypoxia for 12 h (4.8-fold). The most intense TH immunoreactivity was observed in the CB from rats exposed to hypoxia for 12 and 24 h and to hypercapnic hypoxia for 24 h. The expressions of TH mRNA and the immunoreactivity for TH were not altered in the CB of rats exposed to hypercapnia. It is suggested that CO₂ does not affect TH expression in the CB, and that it inhibits hypoxia-enhanced TH expression.