急性重复低氧对小鼠脑组织中糖酵解和线粒体氧化磷酸化以及能量负荷的影响

目的 探讨小鼠在重复急性低氧暴露后脑组织中的糖酵解、线粒体氧化磷酸化及能量负荷的变化。方法 成年Balb/c小鼠重复低氧暴露5次，测定每次低氧暴露时的平均耐受时间、体温及第0，1，3，5次低氧暴露后脑组织中的磷酸果糖激酶（PFK）、丙酮酸激酶（PK）、线粒体复合体I活性和磷酸腺苷水平。结果 重复低氧暴露使小鼠低氧耐受性增强，体温降低，脑组织中PFK和PK活性先增高后降低，复合体I活性持续降低，能量负荷保持稳定。结论 重复急性低氧使小鼠脑组织的糖酵解活性出现规律性变化，线粒体的氧化磷酸化受抑制，但能量负荷保持稳定。     

Vertebrate brains at the pilot light

While the brains of most vertebrates are unable to tolerate more than a few minutes of anoxia, some freshwater turtles (Trachemys and Chrysemys), crucian carp (Carassius carassius) and frogs (Rana pipens and Rana temporaria) can survive anoxia for hours to months. Obviously, anoxia tolerance has evolved separately several times and this is also reflected in the divergent strategies these animals utilize to survive without oxygen. The turtles and crucian carp defend their brain ATP levels and avoid a loss of ion homeostasis by reducing ATP use. In the turtles, the early release of adenosine and the activation of K(ATP) channels, a progressive release of GABA and a drastic reduction in electric activity and ion fluxes send the brain into a comatose like state. The crucian carp displays a more modest depression of ATP use, probably achieved through a moderated release of GABA and adenosine, allowing the animal to maintain physical activity in anoxia. The anoxic frog, on the other hand, seems to rely on mechanisms that greatly retard the anoxia induced fall in ATP levels and loss of ion homeostasis, so that the brain can be saved as long as the anoxia is limited to a few hours. The sequence of events characterizing the anoxic frog brain is similar to that of failing anoxic mammalian brain, although over a greatly extended time frame, allowing the frog to die slowly in anoxia, rather than survive. By contrast the only factor that limits anoxic survival in turtles and crucian carp may be the final depletion of their glycogen reserves.     

急性重复低氧对小鼠脑组织血氧饱和度、线粒体功能以及ATP水平的影响

目的： 探讨急性重复低氧对脑组织血氧饱和度与线粒体功能的影响。方法: 将BALB/c小鼠置于低氧密闭罐中，通过小鼠呼吸消耗罐内氧造成罐内低氧，以小鼠出现喘呼吸为低氧耐受极限，然后将小鼠转到另一低氧密闭罐中，依此类推，连续进行5次低氧。记录小鼠每次的缺氧耐受时间、局部脑组织血氧饱和度，测定每次低氧暴露结束时的脑组织的线粒体复合体I活性和ATP含量。结果: 小鼠的缺氧耐受时间随缺氧暴露次数增加而显著延长。脑组织血氧饱和度在第1、2次缺氧暴露时急剧下降，但在第3、4、5低氧暴露时先小幅度下降再逐渐恢复至正常水平，然后再缓慢降低。脑组织线粒体复合体I的活性随着缺氧次数的增加逐渐被抑制，ATP含量在第1次低氧暴露结束时低于正常水平，在第3、5次低氧暴露结束时高于正常水平。结论: 急性重复低氧导致脑组织血氧饱和度降低的速度减慢、线粒体功能抑制以及脑组织ATP水平增高，后者很可能是动物脑组织耐缺氧能力增强的重要机制。     

反复低氧对小鼠脑内神经肽Y免疫反应活性的影响

目的:观察反复低氧对小鼠脑内神经肽Y(NPY)免疫反应活性的影响。方法:昆明小鼠40只随机分为对照组、低氧1次(H₁)组、低氧2次(H₂)组、低氧3次(H₃)组和低氧4次(H₄)组。对低氧各组动物分别行不同次数的反复低氧。各组动物脑内NPY的免疫反应活性采用放射免疫测定法测定。结果:小鼠对低氧的标准耐受时间随反复低氧次数的增加而显著增加。经1次低氧和2次低氧后小鼠脑内NPY的免疫反应活性明显提高,分别为正常对照组的145.5%±3.2%和147.3%±2.5%(P＜0.01);而低氧3次后则降到正常对照水平。结论:反复低氧通过预适应能显著提高小鼠对低氧的耐受性,并可诱导小鼠脑内NPY免疫反应活性在预适应形成的早期一过性地上升。     

ATP and cytochrome c-dependent activation of caspase-9 during hypoxia in the cerebral cortex of newborn piglets

In previous studies, we have shown that cerebral hypoxia results in increased activity of caspase-9, the initiator caspase, and caspase-3, in the cytosolic fraction of the cerebral cortex of newborn piglets. The present study examines the mechanism of caspase-9 activation during hypoxia and tests the hypothesis that the ATP and cytochrome c-dependent activation of caspase-9 increases in the cytosol of the cerebral cortex of newborn piglets. Newborn piglets were divided into normoxic (Nx, n=4), and hypoxic (Hx, n=4) groups. Anesthetized, ventilated animals were exposed to an FiO(2) of 0.21 (Nx) or 0.07 (Hx) for 60 min. Cerebral tissue hypoxia was documented biochemically by determining levels of ATP and phosphocreatine (PCr). Cytosolic fraction was isolated and passed through a G25-Sephadex column to remove endogenous ATP and cytochrome c. Fractions were collected and protein determined by UV spectrophotometry at 280 nm. Eluted high-molecular weight samples from normoxic and hypoxic animals were divided into four subgroups: subgroup 1 (control), incubated without added ATP and cytochrome c; subgroup 2, incubated with added ATP; subgroup 3, incubated with added cytochrome c; and subgroup 4, incubated with added ATP and cytochrome c. The incubation was carried out at 37 degrees C for 30 min. Following incubation, the protein was separated by 12% SDS-PAGE and active caspase-9 was detected using specific active caspase-9 antibody. Protein bands were detected by enhanced chemiluminescence. Protein density was determined by imaging densitometry and expressed as absorbance (OD x mm(2)). ATP (mumol/g brain) level was 4.7 +/- 0.18 in normoxic, as compared to 1.53 +/- 0.16 in hypoxic (p < 0.05 vs. Nx). PCr (mumol/g brain) level was 4.03 +/- 0.11 in the normoxic and 1.1 +/- 0.3 in the hypoxic brain (p < 0.05 vs. Nx). In the normoxic preparations, active caspase-9 density increased by 9, 4 and 20% in the presence of ATP, cytochrome c and ATP+cytochrome c, respectively. In the hypoxic preparations, active caspase-9 density increased by 30, 45 and 60% in the presence of ATP, cytochrome c and ATP+cytochrome c, respectively. These results show that incubation with ATP, cytochrome c and ATP+cytochrome c result in a significantly increased activation of caspase-9 in the hypoxic group (p < 0.05). We conclude that the ATP and cytochrome c dependent activation of caspase-9 is increased during hypoxia. We propose that the ATP and cytochrome c sites of apoptotic protease activating factor I that mediate caspase-9 activation are modified during hypoxia.     

When the brain goes diving: glial oxidative metabolism may confer hypoxia tolerance to the seal brain

Deep diving mammals have developed strategies to cope with limited oxygen availability when submerged. These adaptations are associated with an increased neuronal hypoxia tolerance. Brain neurons of the hooded seal Cystophora cristata remain much longer active in hypoxic conditions than those of mice. To understand the cellular basis of neuronal hypoxia tolerance, we studied neuroglobin and cytochrome c in C. cristata brain. Neuroglobin, a respiratory protein typically found in vertebrate neurons, displays three unique amino acid substitutions in hooded seal. However, these substitutions unlikely contribute to a modulation of O₂ affinity. Moreover, there is no significant difference in total neuroglobin protein levels in mouse, rat and seal brains. However, in terrestrial mammals neuroglobin resided exclusively in neurons, whereas in seals neuroglobin is mainly located in astrocytes. This unusual localization of neuroglobin is accompanied by a shift in the distribution of cytochrome c. In seals, this marker for oxidative metabolism is mainly localized in astrocytes, whereas in terrestrial mammals it is essentially found in neurons. Our results indicate that in seals aerobic ATP production depends significantly on astrocytes, while neurons rely less on aerobic energy metabolism. This adaptation may imbue seal neurons with an increased tolerance to hypoxia and potentially also to reactive oxygen species, and may explain in part the ability of deep diving mammals to sustain neuronal activity during prolonged dives.     

急、慢性缺氧对大鼠脑线粒体能量代谢的影响

目的:探讨缺氧大鼠脑线粒体能量代谢的特点。方法:雄性Wistar大鼠随机分为急性缺氧组(AH)、慢性缺氧组(CH)和对照组。急、慢性缺氧组动物分别连续暴露于模拟4000m高原3d(AH)和40d(CH)。分离脑线粒体,分别测定线粒体呼吸功能、线粒体内腺苷酸池含量、ATP生成能力和F₀F₁-ATP酶活性。结果:急性缺氧大鼠IV态呼吸(ST₄)显著升高,伴呼吸控制率(RCR)降低,同时线粒体内ATP含量、ATP生成率和F₀F₁-ATP酶活性均显著降低;慢性缺氧大鼠ST₄、RCR、线粒体ATP含量和F₀F₁-ATP酶活性部分恢复。结论:急性缺氧脑线粒体代谢是以功能受损为特点,而慢性缺氧时则表现为功能的部分代偿。     

Amelioration of hypoxia-induced striatal 5-HT(2A) receptor, 5-HT transporter and HIF1 alterations by glucose, oxygen and epinephrine in neonatal rats

Alterations in neurotransmitters and its receptors expression induce brain injury during neonatal hypoxic insult. Molecular processes regulating the serotonergic receptors play an important role in the control of respiration under hypoxic insult. The present study focused on the serotonergic regulation of neonatal hypoxia and its resuscitation methods. Receptor binding assays and gene expression studies were done to evaluate the changes in 5HT_2A receptors and its transporter in the corpus striatum of hypoxic neonatal rats and hypoxic rats resuscitated with glucose, oxygen and epinephrine. Total 5HT and 5HT_2A receptor number was increased in hypoxic neonates along with an up regulation of 5HT_2A receptor and 5HT transporter gene. The enhanced striatal 5HT_2A receptors modulate the ventilatory response to hypoxia. Immediate glucose resuscitation was found to ameliorate the receptor and transporter alterations. Hypoxia induced ATP depletion mediated reduction in blood glucose levels can be encountered by glucose administration and oxygenation helps in overcoming the anaerobic condition. The adverse effect of immediate oxygenation and epinephrine supplementation was also reported. This has immense clinical significance in establishing a proper resuscitation for the management of neonatal hypoxia.     

Redox state ol the cellular free NAD pools,phosphorylation state of the adenylate system and the (Na+-K+)-stimulated ATP-ase in rat liver

The effect of hypoxia (30 min 10% or 8%, O₂,) on the phosphorylation state and redox state of the cytosol and mitochondria of rat liver were studied. Measurements were made both from normal animals and animals which had been exposed to the reduced partial pressure of oxygen (50.5 kPa or 40.8 kPa of air) for one or seven days. Cytosolic free NAD was reduced in the liver both in acute hypoxia and in hypoxia after one or seven days, i.e. the lactate/pyruvate and sn-glycerol-3-phosphate/dioxyacetonephosphate ratios increased markedly. A marked reduction in the mitochondrial free NAD pool occurred only in acute hypoxia and only a slight reduction was observed in animals kept at 40.8 kPa for one or seven days, as evaluated from the hepatic hydroxybutyrate/acetoacetate ratio. Liver ATP concentration decreased rapidly in acute hypoxia without any significant recovery during one or seven days at 40.8 kPa. The hepatic ATP/ADP× P_i ratio decreased significantly, with a simultaneous decrease in the total adenine nucleotide concentration. A tendency was observed for the ATP/ADP× P_i ratio to return to normal after seven days, i.e. the values in acute hypoxia were significantly smaller than those noted in hypoxia after seven days, demonstrating an adaptation of the energy metabolism during prolonged hypoxia. Hepatic (Na⁺-K⁺)-stimulated ATP-ase activity was not affected by hypoxia.     

Pathophysiological hypoxia affects the redox state and IL‐2 signalling of human CD4+ T cells and concomitantly impairs survival and proliferation

Inflamed areas are characterized by infiltration of immune cells, local hypoxia and alterations of cellular redox states. We investigated the impact of hypoxia on survival, proliferation, cytokine secretion, intracellular energy and redox state of human CD4⁺ T cells. We found that pathophysiological hypoxia (<2% O₂) significantly decreased CD4⁺ T‐cell survival after mitogenic stimulation. This effect was not due to an increased caspase‐3/7‐mediated apoptosis or adenosine‐5′‐triphosphate (ATP) consumption/depletion. However, the ability of stimulated T cells to proliferate was reduced under hypoxic conditions, despite increased expression of CD25. Pathophysiological hypoxia was also found to modify intracellular ROS (iROS) levels in stimulated T cells over time as compared with levels found in normoxia. Physiological hypoxia (5% O₂) did not decrease CD4⁺ T‐cell survival and proliferation or modify iROS levels as compared with normoxia. We conclude that pathophysiological hypoxia affects T‐cell proliferation and viability via disturbed IL‐2R signalling downstream of STAT5a phosphorylation, but not as a result of impaired cellular energy homeostasis. We suggest iROS links early events in T‐cell stimulation to the inhibition of the lymphoproliferative response under pathophysiological hypoxic conditions. The level of iROS may therefore act as a mediator of immune functions leading to down‐regulation of long‐term T‐cell activity in inflamed tissues.     

Hypoxia-induced Bax and Bcl-2 protein expression, caspase-9 activation, DNA fragmentation, and lipid peroxidation in mitochondria of the cerebral cortex of newborn piglets: the role of nitric oxide

The present study tests the hypothesis that cerebral hypoxia results in increased ratio of Bax/Bcl-2, activation of caspase-9, lipid peroxidation, and DNA fragmentation in mitochondria of the cerebral cortex of newborn piglets and that the inhibition of nitric oxide synthase by N-nitro-L-arginine during hypoxia will prevent the events leading to mitochondrial DNA fragmentation. To test this hypothesis, six piglets, 3-5 days old, were divided into three groups: normoxic (n=5), hypoxic (n=5), and hypoxic-nitric oxide synthase (n=4). Hypoxic animals were exposed to a FiO2 of 0.6 for 60 min. Nitric oxide synthase (40 mg/kg) was infused over 60 min prior to hypoxia. Tissue hypoxia was confirmed by measuring levels of ATP and phosphocreatine. Cerebral cortical tissue mitochondria were isolated and purified using a discontinuous ficoll gradient. Mitochondrial Bax and Bcl-2 proteins were determined by Western blot. Caspase-9 activity in mitochondria was determined spectro-fluorometrically using fluorogenic substrate for caspase-9. Fluorescent compounds, an index of mitochondrial membrane lipid peroxidation, were determined spectrofluorometrically. Mitochondrial DNA was isolated and separated by electrophoresis on 1% agarose gel and stained with ethidium bromide. ATP levels (micromol/g brain) were 4.52+/-0.34 in normoxic, 1.18+/-0.29 in hypoxic (P<0.05) and 1.00+/-0.26 in hypoxic-nitric oxide synthase animals (P<0.05 vs. normoxic). Phosphocreatine levels (micromol/g brain) were 3.61+/-0.33 in normoxic, 0.70+/-0.20 in hypoxic (P<0.05 vs. normoxic) and 0.57+/-0.14 in hypoxic-nitric oxide synthase animals (P<0.05 vs. normoxic, P=NS vs. hypoxic). Bax density in mitochondrial membranes was 160+/-28 in normoxic and 324+/-65 in hypoxic (P<0.001 vs. normoxic). Bcl-2 density mitochondria was 96+/-18 in normoxic and 98+/-20 in hypoxic (P=NS vs. normoxic). Mitochondrial caspase-9 activity (nmol/mg protein/h) was 1.32+/-0.23 in normoxic and 2.25+/-0.24 in hypoxic (P<0.01 vs. normoxic). Levels of fluorescent compounds (microg of quinine sulfate/g protein) were 12.48+/-4.13 in normoxic and 37.92+/-7.62 in hypoxic (P=0.003 vs. normoxic). Densities (ODxmm2) of low molecular weight DNA fragments were 143+/-38 in normoxic, 365+/-152 in hypoxic, (P<0.05 vs. normoxic) and 163+/-25 in hypoxic-nitric oxide synthase animals (P<0.05 vs. hypoxic, P=NS vs. normoxic). The data demonstrate that hypoxia results in increased mitochondrial proapoptotic protein Bax, increased mitochondrial caspase-9 activity, increased mitochondrial lipid peroxidation, and increased fragmentation of DNA in mitochondria of the cerebral cortex of newborn piglets. The administration of a nitric oxide synthase inhibitor, nitric oxide synthase, prior to hypoxia prevented fragmentation of mitochondrial DNA, indicating that the hypoxia-induced mitochondrial DNA fragmentation is NO-mediated. We propose that NO free radicals generated during hypoxia lead to NO-mediated altered expression of Bax leading to increased ratio of pro-apoptotic/anti-apoptotic protein resulting in modification of mitochondrial membrane, and subsequently Ca2+-influx and fragmentation of mitochondrial DNA.     

缺氧时星形胶质细胞定量mRNA表达的内部参照标准研究

目的:观察缺氧对脑星形胶质细胞(AC)守家基因甘油醛-3-磷酸-脱氢酶(GAPDH)和β-肌动蛋白(actin)mRNA表达的影响,进一步观察内皮素转换酶(ECE)-2mRNA可否作为该条件下的内部参照标准。方法:从新生小鼠大脑获原代AC培养,分别在缺氧和正常氧条件下培养24h,提取mRNA,以溴化乙啶染色的28S及18SrRNA作内部参照,用Northernblot杂交技术定量测定GAPDH、β-actin和ECE-2mRNA水平。结果:缺氧24h,ACGAPDHmRNA的表达显著增加,β-actinmRNA表达明显下降;缺氧前后ECE-2的mRNA水平无明显差异。结论:在缺氧缺血条件下,GAPDH和β-actin不宜作为AC定量mRNA分析的内部参照标准,ECE-2可作为其替代。     

Effect of neuronal nitric oxide synthase inhibition on CA2+/calmodulin kinase kinase and CA2+/calmodulin kinase IV activity during hypoxia in cortical nuclei of newborn piglets

The present study tests the hypothesis that cerebral tissue hypoxia results in increased Ca(2+)/calmodulin (CaM) kinase kinase activity and that the administration of nitric oxide synthase inhibitors (N-nitro-l-arginine [NNLA], or 7-nitroindazole sodium [7-NINA]) prior to the onset of hypoxia will prevent the hypoxia-induced increase in the enzyme activity. To test this hypothesis, CaM kinase kinase and CaM kinase IV activities were determined in normoxic, hypoxic, NNLA-treated hypoxic, and 7-NINA-treated hypoxic piglets. Hypoxia was induced (FiO(2)=0.05-0.08x1 h) and confirmed biochemically by tissue levels of ATP and phosphocreatine. CaM kinase kinase activity was determined in a medium containing protein kinase and phosphatase inhibitors, calmodulin, and a specifically designed CaM kinase kinase target peptide. CaM kinase IV activity was determined by (33)P-incorporation into syntide-2 in a buffer containing protein kinase and phosphatase inhibitors. Compared with normoxic animals, ATP and phosphocreatine levels were significantly lower in all hypoxic piglets whether or not pretreated with nitric oxide synthase inhibitors. There was a significant difference among CaM kinase kinase activity (pmol/mg protein/min) in normoxic (76.84+/-14.1), hypoxic (138.86+/-18.2, P<0.05 vs normoxia), NNLA-pretreated hypoxic (91.34+/-19.3; P=NS vs normoxia, P<0.05 vs hypoxia) and 7-NINA-pretreated hypoxic animals (100.12+/-23.3; P=NS vs normoxia, P<0.05 vs hypoxia). There was a significant difference among CaM kinase IV activity (pmol/mg protein/min) in normoxia (1270.80+/-126.1), hypoxia (2680.80+/-136.7; P<0.05 vs normoxia), NNLA-pretreated hypoxia (1666.00+/-154.8; P<0.05 vs normoxia, P<0.05 vs hypoxia), and 7-NINA-pretreated hypoxic (1712.9+/-231.5; P=NS vs normoxia, P<0.05 vs hypoxia). We conclude that the hypoxia-induced increase in CaM kinase kinase and CaM kinase IV activity is mediated by neuronal NOS-derived NO.     

Adaptive responses of vertebrate neurons to anoxia--matching supply to demand

Oxygen depleted environments are relatively common on earth and represent both a challenge and an opportunity to organisms that survive there. A commonly observed survival strategy to this kind of stress is a lowering of metabolic rate or metabolic depression. Whether metabolic rate is at a normal or a depressed level the supply of ATP (glycolysis and oxidative phosphorylation) must match the cellular demand for ATP (protein synthesis and ion pumping), a condition that must of course be met for long-term survival in hypoxic and anoxic environments. Underlying a decrease in metabolic rate is a corresponding decrease in both ATP supply and ATP demand pathways setting a new lower level for ATP turnover. Both sides of this equation can be actively regulated by second messenger pathways but it is less clear if they are regulated differentially or even sequentially with the onset of anoxia. The vertebrate brain is extremely sensitive to low oxygen levels yet some species can survive in oxygen depleted environments for extended periods and offer a working model of brain survival without oxygen. Hypoxia tolerant vertebrate brain will be the primary focus of this review; however, we will draw upon research involving hypoxia/ischemia tolerance mechanisms in liver and heart to offer clues to how brain can tolerate anoxia. The issue of regulating ATP supply or demand pathways will also be addressed with a focus on ion channel arrest being a significant mechanism to reduce ATP demand and therefore metabolic rate. Furthermore, mitochondria are ideally situated to serve as cellular oxygen sensors and mediator of protective mechanisms such as ion channel arrest. Therefore, we will also describe a mitochondria based mechanism of ion channel arrest involving ATP-sensitive mitochondrial K(+) channels, cytosolic calcium and reaction oxygen species concentrations.     

Hypoxia modulates gene expression of IP3 receptors in rodent cerebellum

Hypoxic brain cell injury is a complex process that results from a series of intracellular events. In this work, we tested whether severe hypoxia for 6 h can affect gene expression and protein levels of intracellular calcium channels, ryanodine receptors, and inositol 1,4,5-trisphosphate receptors in mouse cerebellum. In addition, we tested the effect of hypoxia on cerebellar granular cells of rats. We have found that gene expression of types 1 and 2 IP₃ receptors is significantly increased after the exposure of mice to hypoxic stimulus for 6 h and also in rat cerebellar granular cells. Increased gene expression of IP₃ receptors was reflected in increased protein levels of these channels as well. In this process, reactive oxygen species are most probably involved, as antioxidant quercetin abolished hypoxia-induced increase in both types 1 and 2 IP3 receptor. Ryanodine receptors of types 1 and 2 and sarco(endo)plasmic reticulum Ca²⁺-ATPase were not affected by hypoxia on the level of messenger RNA. To test physiological consequences, we measured levels of intracellular calcium. We observed significantly elevated calcium level in hypoxic compared to normoxic cells. Deeper understanding of mechanisms, through which hypoxia regulates intracellular calcium, could point towards the development of new therapeutic approaches to reduce or suppress the pathological effects of cellular hypoxia, such as those seen in stroke or ischemia.     

<Superscript>31</Superscript>P magnetic resonance spectroscopy study of the human visual cortex during stimulation in mild hypoxic hypoxia

Effects of mild hypoxic hypoxia on cerebral energy state, as assessed by phosphocreatine (PCr)/γ-ATP and inorganic phosphate (P_i)/(P_i + PCr) ratios and intracellular pH (pH_i) in the human visual cortex, were studied using ³¹P nuclear magnetic resonance spectroscopy (MRS) at 3 T. The working hypothesis that, during compromised O₂ availability obtained by hypoxic hypoxia, both cerebral energy state and pH_i decline due to insufficient O₂ supply for energy metabolism was addressed. Under baseline hypoxic hypoxia, with blood O₂ saturation ranging from 0.95 to 0.83, neither the PCr/γ-ATP and P_i/(P_i + PCr) ratios nor pH_i was affected, thus, showing that cerebral energy metabolism was maintained. Contrary to the formulated hypothesis, visual stimulation during hypoxic hypoxia influenced neither the indicator ratios for energy state nor pH_i in the occipital cortex. Taking these results, together with previous observations showing that cerebral blood flow responses are the same in size both in euoxia and in hypoxia at this depth (Mintun et al. in Proc Natl Acad Sci USA 98:6859–6864, 2001; Tuunanen et al. in J Cereb Blood Flow Metab 26:263–273, 2006a), it is concluded that O₂ delivery to the brain during mild hypoxic hypoxia meets the demand by the energy metabolism both under baseline and stimulated states.     

Changes in hemodynamics and respiration in rats with different resistance to acute hypoxia

Effects of acute hypoxia on hemodynamics and respiration were studied in acute experiments on narcotized rats. The animals were divided into groups characterized by high, low-, and medium- resistance to hypoxia by the time of respiration arrest during inhalation of gas mixture containing 3% O₂. Hemodynamic parameters of highly resistant animals were higher than in low-resistant rats throughout the entire hypoxic period. The development of a rare (with prolonged inspiratory phase) respiratory rhythm in highly resistant rats is an adaptive reaction, which allows them longer tolerate hypoxia compared to low-resistant animals. Translated fromByulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 138, No. 7, pp. 24–28, July, 2004     

Abnormal product of corneal explants from patients with macular corneal dystrophy.

The effects of experimental coronary atherosclerosis on myocardial high energy phosphates and regional coronary perfusion and oxygen delivery were studied. Hypercholesterolemic (HC) New Zealand white rabbits developed mild to moderate coronary vascular disease in 4 months when serum cholesterol levels were maintained at 1500--2000 mg/dl. Resting left ventricular levels of creatine phosphate, adenosine triphosphate (ATP), and the cellular energy charge were unaltered after 2 months of diet but were decreased after 4 and 6 months. Tissue lactate and the lactate/pyruvate ratio were increased after 4 months, suggesting mild tissue ischemia. The regional blood flow rate was measured in rabbits given pentobarbital after 6 months of diet using labeled microspheres, and the response to stress was tested after 5 minutes of hypoxic ventilation (5% O2/N2). The percentage of cardiac output to subendocardium (endo) and subepicardium (epi) in HC rabbits and that in control animals were similar at rest, but unlike that of control animals, the endo perfusion did not increase significantly in HC animals during hypoxic stress. Baseline regional left ventricular oxygen deliveries were similar between groups, but the baseline endo/epi oxygen delivery ratio was reduced in HC rabbits. In control rabbits hypoxia did not alter total O2 delivery, and the endo/epi oxygen delivery ratio was constant, whereas hypoxia in HC animals produced a decrease in total oxygen delivery and a further decrease in the endo/epi oxygen delivery ratio. Thus, moderate long-term coronary occlusive disease produced alterations in the distribution of coronary perfusion that are similar to those after acute partial occlusion, ie, selective reductions in blood flow and oxygen delivery to subendocardium. These results may relate to the pathogenesis of subendocardial infarction in man, which often occurs in the absence of complete coronary occlusion.