Certain mechanisms of development of types of body tolerance to acute hypobaric hypoxia

The regulatory mechanisms of individual rat resistance to acute hypobaric hypoxia were studied using the functional indices of the central nervous system (neurochemical and behavioral) and the hematopoietic system. The resistance to hypoxia was evaluated by the time of attitudinal reflex maintenance and recovery after decompression to a simulated altitude of 11 200 m. Animals with different types of tolerance to hypoxia demonstrated different metabolic backgrounds of neurochemical processes (which were most balanced in moderately resistant rats). This agrees with the differences in active behavior and adaptive efficiency of these animals exposed to mild open-field stress. High functional activity of erythropoiesis and early leukocytic response were observed in hypoxia-tolerant rats.     

氯氨酮和L-NAME抑制模拟高原低氧大鼠下丘脑NOS和生长抑素mRNA的表达

用高原低氧模型及原位杂交、ＮＡＤＰＨ－ｄ组织化学法,探讨氯氨酮和Ｌ－ＮＡＭＥ对急性高原低氧大鼠下丘脑一氧化氮合酶（ＮＯＳ）和生长抑素ｍＲＮＡ（ＳＳ ｍＲＮＡ）表达的影响。结果表明,急性高原低氧引起下丘脑ＮＯＳ和ＳＳ ｍＲＮＡ过度表达,如先用ＮＭＤＡ受体拮抗剂氯氨酮和ＮＯＳ抑制剂Ｌ－ＮＡＭＥ预处理,ＮＯＳ和ＳＳ ｍＲＮＡ的表达均明显被抑制。结果提示,ＮＭＤＡ受体参与了急生高原低氧引起的下丘脑ＮＯＳ和     

Changes in autonomic response and resistance to acute graded hypoxia during intermittent hypoxic training

A placebo-controlled study was performed to examine the effects of intermittent normobaric hypoxic preconditioning on the autonomic regulation of blood flow, as well as on heart rate variability (HRV) response and resistance to acute hypoxia, in healthy male volunteers. Intermittent hypoxic training (IHT) increased the efficiency of the mechanisms of autonomic regulation of heart rate (HR) at rest by increasing the parasympathetic control and optimized changes in HRV during simulated acute hypoxia. The hypoxic preconditioning contributed to increased resistance of the body to simulated acute hypoxia, as reflected by less marked hemoglobin desaturation and a smaller increase in the HR. The training effects of the IHT were more pronounced in the subjects with an initially low resistance to a hypoxic factor as compared to those resistant to acute hypoxia.     

Chronic hypoxia increases fetoplacental vascular resistance and vasoconstrictor reactivity in the rat

An increase in fetoplacental vascular resistance caused by hypoxia is considered one of the key factors of placental hypoperfusion and fetal undernutrition leading to intrauterine growth restriction (IUGR), one of the serious problems in current neonatology. However, although acute hypoxia has been shown to cause fetoplacental vasoconstriction, the effects of more sustained hypoxic exposure are unknown. This study was designed to test the hypothesis that chronic hypoxia elicits elevations in fetoplacental resistance, that this effect is not completely reversible by acute reoxygenation, and that it is accompanied by increased acute vasoconstrictor reactivity of the fetoplacental vasculature. We measured fetoplacental vascular resistance as well as acute vasoconstrictor reactivity in isolated perfused placentae from rats exposed to hypoxia (10% O(2)) during the last week of a 3-wk pregnancy. We found that chronic hypoxia shifted the relationship between perfusion pressure and flow rate toward higher pressure values (by approximately 20%). This increased vascular resistance was refractory to a high dose of sodium nitroprusside, implying the involvement of other factors than increased vascular tone. Chronic hypoxia also increased vasoconstrictor responses to angiotensin II (by approximately 75%) and to acute hypoxic challenges (by >150%). We conclude that chronic prenatal hypoxia causes a sustained elevation of fetoplacental vascular resistance and vasoconstrictor reactivity that are likely to produce placental hypoperfusion and fetal undernutrition in vivo.     

Effect of past stress on the resistance of the myocardium to hypoxia

The effect of emotional painful stress on myocardial contractility and resistance to hypoxia was studied on the rat isolated atrium. It was established that in stress-exposed rats, myocardial resistance to hypoxia was reduced and contractility was depressed. It was manifested in accelerated development and greater degree of hypoxic contracture, as well as in a slower recovery of myocardial contractility under reoxygenation. The decreased myocardial resistance to hypoxia under stress is suggested to be related to the stress-induced alterations in glycolysis and calcium transport in cardiomyocytes.     

Chronic hypoxia attenuates nitric oxide-dependent hemodynamic responses to acute hypoxia

Alterations in the nitric oxide (NO) pathway have been implicated in the pathogenesis of chronic hypoxia-induced pulmonary hypertension. Chronic hypoxia can either suppress the NO pathway, causing pulmonary hypertension, or increase NO release in order to counteract elevated pulmonary arterial pressure. We determined the effect of NO synthase inhibitor on hemodynamic responses to acute hypoxia (10% O(2)) in anesthetized rats following chronic exposure to hypobaric hypoxia (0.5 atm, air). In rats raised under normoxic conditions, acute hypoxia caused profound systemic hypotension and slight pulmonary hypertension without altering cardiac output. The total systemic vascular resistance (SVR) decreased by 41 +/- 5%, whereas the pulmonary vascular resistance (PVR) increased by 25 +/- 6% during acute hypoxia. Pretreatment with N(omega)-nitro-L-arginine methyl ester (L-NAME; 25 mg/kg) attenuated systemic vasodilatation and enhanced pulmonary vasoconstriction. In rats with prior exposure to chronic hypobaric hypoxia, the baseline values of mean pulmonary and systemic arterial pressure were significantly higher than those in the normoxic group. Chronic hypoxia caused right ventricular hypertrophy, as evidenced by a greater weight ratio of the right ventricle to the left ventricle and the interventricular septum compared to the normoxic group (46 +/- 4 vs. 28 +/- 3%). In rats which were previously exposed to chronic hypoxia (half room air for 15 days), acute hypoxia reduced SVR by 14 +/- 6% and increased PVR by 17 +/- 4%. Pretreatment with L-NAME further inhibited the systemic vasodilatation effect of acute hypoxia, but did not enhance pulmonary vasoconstriction. Our results suggest that the release of NO counteracts pulmonary vasoconstriction but lowers systemic vasodilatation on exposure to acute hypoxia, and these responses are attenuated following adaptation to chronic hypoxia.     

Erythrocyte ion transport in rats subjected to acute and chronic hypobaric hypoxia

Our study addresses selected parameters of rat erythrocyte ion transport (Na(+)-K(+) pump, Na(+)-K(+)-2Cl- cotransport, and passive cation fluxes) after acute or chronic hypoxia exposure. We did not find any significant change of ion transport after acute hypoxia. However, chronic hypoxia could modify ion transport because the affinity of Na(+)-K(+) pump for intracellular Na(+) seems to be decreased.     

The role of noradrenaline in regulating myocardial oxidative metabolism in rats with different resistances to hypoxia]

The effects of noradrenaline infusion on the regulation of oxidative metabolism in isolated rat heart were studied. It appeared that functional and metabolic parameters of heart of non-resistant and high-resistant to hypoxia rats were different. Noradrenaline changed the balance between aerobic and anaerobic processes in rat heart. It is evident that heart adrenoreceptors are involved in regulation of oxidative metabolism responsible for individual resistance of rat heart to hypoxia.     

Cardiovascular responses to hypoxia and hypercapnia in barodenervated rats

Experiments were performed to examine the role of the arterial baroreceptors in the cardiovascular responses to acute hypoxia and hypercapnia in conscious rats chronically instrumented to monitor systemic hemodynamics. One group of rats remained intact, whereas a second group was barodenervated. Both groups of rats retained arterial chemoreceptive function as demonstrated by augmented ventilation in response to hypoxia. The cardiovascular effects to varying inspired levels of O2 and CO2 were examined and compared between intact and barodenervated rats. No differences between groups were noted in response to mild hypercapnia (5% CO2); however, the bradycardia and reduction in cardiac output observed in intact rats breathing 10% CO2 were eliminated by barodenervation. In addition, hypocapnic hypoxia caused a marked fall in blood pressure and total peripheral resistance (TPR) in barodenervated rats compared with controls. Similar differences in TPR were observed between the groups in response to isocapnic and hypercapnic hypoxia as well. It is concluded that the arterial baroreflex is an important component of the overall cardiovascular responses to both hypercapnic and hypoxic stimuli in the conscious rat.     

NO-dependent mechanisms of adaptation to hypoxia.

In studying NO-dependent mechanisms of resistance to hypoxia, it was shown that (1) acute hypoxia induces NO overproduction in brain and leaves unaffected NO production in liver of rats; (2) adaptation to hypoxia decreases NO production in liver and brain; and (3) adaptation to hypoxia prevents NO overproduction in brain and potentiates NO synthesis in liver in acute hypoxia. Dinitrosyl iron complex (DNIC, 200 microg/kg, single dose, iv), a NO donor, decreases the resistance of animals to acute hypoxia by 30%. Nomega-nitro-L-arginine (L-NNA, 50 mg/kg, single dose, ip), a NO synthase inhibitor, and diethyl dithiocarbamate (DETC, 200 mg/kg, single dose, iv), a NO trap, increases this parameter 1.3 and 2 times, respectively. Adaptation to hypoxia developed against a background of accumulation of heat shock protein HSP70 in liver and brain. A course of DNIC reproduced the antihypoxic effect of adaptation. A course of L-NNA during adaptation hampered both accumulation of HSP70 and development of the antihypoxic effect. Therefore, NO and the NO-dependent activation of HSP70 synthesis play important roles in adaptation to hypoxia.     

Comparative analysis of ECG characteristics in pregnant rats subjected to acute hypoxia in the period of organogenesis

Various ECG characteristics are investigated in white rats subjected to acute hypobaric hypoxia on the 9th–10th day of gestation corresponding to the period of organogenesis. The hypoxia-induced changes in the ECG characteristics are different in groups with a low, middle, and high resistance to acute hypoxia.     

Hypoxic pulmonary vasoconstriction and pulmonary artery tissue cytokine expression are mediated by protein kinase C

Pulmonary arteries exhibit a marked vasoconstriction when exposed to hypoxic conditions. Although this may be an adaptive response to match lung ventilation with perfusion, the potential consequences of sustained pulmonary vasoconstriction include pulmonary hypertension and right heart failure. Concomitant production of proinflammatory mediators during hypoxia may exacerbate acute increases in pulmonary vascular resistance. We hypothesized that acute hypoxia causes pulmonary arterial contraction and increases the pulmonary artery tissue expression of proinflammatory cytokines via a protein kinase C (PKC)-mediated mechanism. To study this, isometric force displacement was measured in isolated rat pulmonary artery rings during hypoxia in the presence and absence of the PKC inhibitors calphostin C or chelerythrine. In separate experiments, pulmonary artery rings were treated with the PKC activator thymeleatoxin for 60 min. After hypoxia, with or without PKC inhibition, or PKC activation alone, pulmonary artery rings were subjected to mRNA analysis for TNF-alpha and IL-1beta via RT-PCR. Our results showed that, in isolated pulmonary arteries, hypoxia caused a biphasic contraction and increased expression of TNF-alpha and IL-1beta mRNA. Both effects were inhibited by PKC inhibition. PKC activation resulted in pulmonary artery contraction and increased the pulmonary artery expression of TNF-alpha and IL-1beta mRNA. These findings suggest that hypoxia induces the expression of inflammatory cytokines and causes vasoconstriction via a PKC-dependent mechanism. We conclude that PKC may have a central role in modulating hypoxic pulmonary vasoconstriction, and further elucidation of its involvement may lead to therapeutic application.     

Adrenomedullin expression in a rat model of acute lung injury induced by hypoxia and LPS

Adrenomedullin (ADM) is upregulated independently by hypoxia and LPS, two key factors in the pathogenesis of acute lung injury (ALI). This study evaluates the expression of ADM in ALI using experimental models combining both stimuli: an in vivo model of rats treated with LPS and acute normobaric hypoxia (9% O2) and an in vitro model of rat lung cell lines cultured with LPS and exposed to hypoxia (1% O2). ADM expression was analyzed by in situ hybridization, Northern blot, Western blot, and RIA analyses. In the rat lung, combination of hypoxia and LPS treatments overcomes ADM induction occurring after each treatment alone. With in situ techniques, the synergistic effect of both stimuli mainly correlates with ADM expression in inflammatory cells within blood vessels and, to a lesser extent, to cells in the lung parenchyma and bronchiolar epithelial cells. In the in vitro model, hypoxia and hypoxia + LPS treatments caused a similar strong induction of ADM expression and secretion in epithelial and endothelial cell lines. In alveolar macrophages, however, LPS-induced ADM expression and secretion were further increased by the concomitant exposure to hypoxia, thus paralleling the in vivo response. In conclusion, ADM expression is highly induced in a variety of key lung cell types in this rat model of ALI by combination of hypoxia and LPS, suggesting an essential role for this mediator in this syndrome.     

Effect of adaptation to hypoxia on the resistance of rats to the epileptogenic action of penicillin

The influence of adaptation to moderate hypoxia on anticonvulsive resistance of low tolerant rats has been investigated. Focal epilepsy was induced by penicillin application to sensorimotor cortex of the rat brain. Adaptation to hypoxia has been shown to increase the resistance of rats to epileptogenic penicillin effect which is manifested in the prolongation of the latent period of epileptiform discharges and less frequent epileptic fits. The mechanisms of the resistance increase remains to be investigated.     

Protective effect of malonic acid in hypoxic hypoxia]

Malonic acid injection causes an increase in the survival of rats with acute hypoxic hypoxia. Endogenic malonic acid is supposed to be of great importance in stimulating tissue resistance to hypoxia.     

Comparative investigation of the delayed effects of prenatal hypoxia in the period of progestation and organogenesis

The aim of the present study was to compare the survival, physical development and spontaneous behavior of rat pups born from white rats subjected to acute hypobaric hypoxia on the 3rd-5th days of gestation (progestation) period or on the 9-10th day of gestation (period of early organogenesis). It was shown that the delayed effects of progestation hypoxia were less expressed than those following acute hypoxia modeled in the early organogenesis. In latter case, hypoxia led to the increased mortality among rat pups of both sexes while hypoxia-induced delay in physical development and changes in spontaneous behavior and anxiety level were registered up to the 57th day of postnatal period.     

Stress Reaction and Biochemical Shock as Interrelated and Unavoidable Components in the Formation of High Radioresistance of the Body in Acute Hypoxia

Stress reactions with activation of the sympathetic-adrenal system due to acute hypoxia reflects the degree of sensitivity of the body to this extreme factor. Succinate dehydrogenase (SDH) activation in cells as an adaptive response to acute hypoxia is closely associated with the degree of disturbance of tissue respiration through a lack of oxygen in the tissues, including the manifestation of “biochemical shock,” which is an unavoidable component of implementation of the protective effect of radioprotectors. In experiments on mice, rats, and dogs, the correlation between the manifestation of the radioprotective effect of acute hypoxia and SDH activation in blood lymphocytes, caused primarily by adrenergic stimulation during stress reactions, is confirmed. The degree of SDH activation in blood lymphocytes by hypoxia of different origins including that induced by radioprotectors may indicate its radioprotective potential irrespective of the differences in the oxygen consumption intensity and the resistance to acute hypoxia in animals and humans.     

急、慢性缺氧对大鼠凝血机能的影响

本文讨论了实验性缺氧对大鼠凝血机能产生的影响。实验结果表明,大鼠在模拟8000米高度两小时后,血小板凝聚性、血小板因子3活性明显增加,纤溶活性下降,同时,纤维蛋白原含量和因子X也明显下降。大鼠在模拟7000米经36天间歇性慢性缺氧,血小板计数、血小板凝聚性,血小板因子3活性、纤维蛋白原含量、因子X活性均显著增加,部分凝血活酶时间缩短、纤溶活性下降,明显地出现凝血增强的趋势。本文还讨论了抗缺氧药物复方党参、异叶青兰对人鼠急性缺氧时凝血机能的影响。     

Participation of cholinergic systems in the recovery period following acute hypobaric hypoxia

The influence of some cholinergic drugs has been studied during prophylactic treatment and the recovery period after acute hypobaric hypoxia (AHBH) on AHBH model. Cholinolytics and cholinomimetics were shown to produce different effects on the animal resistance to AHBH, their role in the formation of resistance to hypoxia depending on the type of animal, the extent of hypoxic damage and duration of the recovery period after primary AHBH. The experiments performed suggest an important role of cholinergic system in the formation of hypoxic resistance in animals.     

Naloxone accelerates the rate of ventilatory acclimatization to hypoxia in awake rats

During ventilatory acclimatization to hypoxia in rats, PaCO2 progressively falls from about 40 torr in normoxia (PIO2 approximately equal to 150 torr) to a new steady-state at about 23 torr in chronic hypoxia (24 or more hours at PIO2 approximately equal to 90 torr). In acute (20 or 60 minutes) hypoxia naloxone treatment caused a hyperventilation greater than that caused by acute hypoxia alone. Following 20 minutes hypoxia, naloxone treated rats had a PaCO2 = 28.6 +/- 0.7 torr (mean +/- 95% confidence limits) which was significantly lower (P less than .001) than the saline treated PaCO2 = 31.0 +/- 0.6 torr. In contrast, in normoxia and at 24 hour hypoxia and at 20 minute return to normoxia following 24 hours hypoxia, naloxone treatment had no effect on PaCO2. We conclude that in the rat about one third of the ventilatory acclimatization to hypoxia is due to a progressively decreasing endogenous opioid-like inhibition of ventilation.