Cerebral haemodynamics in long-term adaptation to hypercapnic hypoxia

The intervals in hypercapnic hypoxia were accompanied by increase of the cerebral vascular resistance, by decline of the reactivity of cerebral vessels to hypercapnia, by increase of collector reserve and speed of self-verification of cerebral blood circulation. These changes are an important component of the increasing mechanism of the brain resisten to the cerebral ischemic under the influence of drills with hypercapnion hypoxia.     

Microcirculatory changes during chronic adaptation to hypoxia

Microcirculatory changes in the window chamber preparation in Syrian golden hamsters, secondary to chronic hypoxia adaptation, are presented herein. Adaptation was attained by keeping animals in a 10% oxygen environment for 1 wk and 5% the following week. The following groups were studied: group 1, adapted to chronic hypoxia and kept in a 5% oxygen environment throughout the experiment; group 2, adapted to chronic hypoxia and kept in a 21% oxygen environment 24 h before and during the experiment; and group 3, control. Adaptation caused venule enlargement and hematocrit increase (68.6 +/- 2.44 in group 1, 70 +/- 2.66 in group 2, and 43.27 +/- 2.30 in group 3; P < 0.05). Whereas heart rate decreased in adapted animals, blood pressure remained constant. Group 1 presented alkalosis, hypocapnia, and hypoxemia. The adapted groups had decreased blood flow velocity in arterioles and veins. We found no difference in microvasculature oxygen tension between groups 2 and 3; however, the number of capillaries with flow was markedly reduced in group 1 but significantly increased in group 2. Our findings suggest that, as an adaptation to hypoxia, erythropoiesis may prove beneficial by increasing blood viscosity and shear stress, leading to vasodilatation, in addition to the increase in oxygen-carrying capacity. Calculations show that oxygen extraction in the tissue of the window chamber model was significantly lowered in adapted animals breathing 5% oxygen, but was unchanged from the control when breathing 21% oxygen, even though blood hemoglobin content was increased from 14.5 +/- 0.07 g/dl at control to 21.04 +/- 1.24 g/dl in the adapted animals (P < 0.05).     

Respiratory adaptation to chronic hypoxia in newborn rats

Newborn rats were maintained in an hypoxic chamber (10% O2 in N2) from the day of birth up to 2 wk of postnatal life. Body weight (BW) and nose-tail length were less in the hypoxic exposed (H) rats than in control (C) animals growing in air. Hematocrit rose from about 37% to about 51%. Oxygen consumption (VO2), measured with a manometric method, was lower in H than in C rats; the difference remained at 5-7 days even after normalization by BW. At 5-7 days ventilation, measured with an airflow plethysmograph, was much more elevated in H rats (whether breathing 10% O2 or air) than in C rats, with an increase in both tidal volume and frequency. This indicates that the biphasic ventilatory response, characterized by an initial rise and then a fall of ventilation toward normoxic values, commonly observed in newborns during acute hypoxic challenge is an immediate but only transient response. The dry lung weight-to-BW ratio and alveolar size were larger in H than in C rats. Lung volumes at 20 cmH2O were similar, despite the smaller BW of the H rats. Hence, in the rat, chronic hypoxia in the immediate postnatal period increases O2-carrying capacity, decreases metabolic demands, increases alveolar O2 availability, and promotes structural changes in the lung that protect the gas exchange area and optimize the structure-function relationship of the lung. These results may also suggest that the lung structural alterations with chronic hypoxia should not be attributed to changes in VO2 but, eventually, to the ventilatory action of the organ.     

Brain adaptation to chronic hypobaric hypoxia in rats.

Rats were exposed to hypobaric hypoxia (0.5 atm) for up to 3 wk. Hypoxic rats failed to gain weight but maintained normal brain water and ion content. Blood hematocrit was increased by 48% to a level of 71% after 3 wk of hypoxia compared with littermate controls. Brain blood flow was increased by an average of 38% in rats exposed to 15 min of 10% normobaric oxygen and by 23% after 3 h but was not different from normobaric normoxic rats after 3 wk of hypoxia. Sucrose space, as a measure of brain plasma volume, was not changed under any hypoxic conditions. The mean brain microvessel density was increased by 76% in the frontopolar cerebral cortex, 46% in the frontal motor cortex, 54% in the frontal sensory cortex, 65% in the parietal motor cortex, 68% in the parietal sensory cortex, 68% in the hippocampal CA1 region, 57% in the hippocampal CA3 region, 26% in the striatum, and 56% in the cerebellum. The results indicate that hypoxia elicits three main responses that affect brain oxygen availability. The acute effect of hypoxia is an increase in regional blood flow, which returns to control levels on continued hypoxic exposure. Longer-term effects of continued moderate hypoxic exposure are erythropoiesis and a decrease in intercapillary distance as a result of angiogenesis. The rise in hematocrit and the increase in microvessel density together increase oxygen availability to the brain to within normal limits, although this does not imply that tissue PO2 is restored to normal.     

塞来昔布对慢性低O_2高CO_2大鼠肺动脉高压的影响及其机制研究

目的：探讨塞来昔布对慢性低O2高CO2大鼠肺动脉高压的作用。方法：将SD大鼠分为正常对照组,慢性低O2高CO2组,慢性低O2高CO2＋塞来昔布组。用电镜、放免等方法,观察各组大鼠肺动脉平均压、颈动脉平均压、肺细小动脉显微结构、血浆和肺匀浆血栓素B2（TXB2）及6-酮-前列腺素F1α（6-keto-PGF1α）含量的变化。结果：①慢性低O2高CO2组平均肺动脉压（mPAP）比正常组显著升高,塞来昔布组的mPAP比慢性低O2高CO2组显著升高,3组间平均颈动脉压（mCAP）比较差异无显著性。②慢性低O2高CO2组与正常对照组相比血浆和肺匀浆TXB2浓度、TXB2/6-keto-PGF1α比值显著增高,6-keto-PGF1α浓度显著下降;塞来昔布组与慢性低O2高CO2组相比血浆和肺匀浆TXB2浓度无明显变化、TXB2/6-keto-PGF1α显著升高,6-keto-PGF1α显著下降。③光镜下慢性低O2高CO2组与正常组相比,肺细小动脉管壁面积/管总面积（WA/TA）和肺细小动脉中膜厚度（PAMT）均显著增高。塞来昔布组与慢性低O2高CO2组相比WA/TA和PAMT显著增高。④电镜下慢性低O2高CO2组大鼠肺细小动脉内皮细胞吞饮小泡增多,血管壁增厚,中膜平滑肌细胞增生,纤维细胞增多,肺泡II型上皮细胞微绒毛脱落;塞来昔布组中膜平滑肌细胞增大、增多,胞浆肌丝丰富,平滑肌细胞间隙增宽,肺泡隔胶原纤维增生明显。结论：塞来昔布可能有加重慢性低O2高CO2性肺动脉高压和肺血管结构重建倾向,过度抑制COX-2,使TXA2/PGI2比值升高可能是其作用机制之一。     

Molecular mechanisms of cardiac protection by adaptation to chronic hypoxia

Effective protection of the heart against ischemia/reperfusion injury is one of the most important goals of experimental and clinical research in cardiology. Besides ischemic preconditioning as a powerful temporal protective phenomenon, adaptation to chronic hypoxia also increases cardiac tolerance to all major deleterious consequences of acute oxygen deprivation such as myocardial infarction, contractile dysfunction and ventricular arrhythmias. Although many factors have been proposed to play a potential role, the detailed mechanism of this long-term protection remains poorly understood. This review summarizes current limited evidence for the involvement of ATP-sensitive potassium channels, reactive oxygen species, nitric oxide and various protein kinases in cardioprotective effects of chronic hypoxia.     

知母宁对慢性低O2高CO2大鼠肺动脉高压的影响及其机制研究

目的：研究知母宁对慢性低氧高二氧化碳性肺动脉高压的抑制作用及其作用机制。方法：将SD大鼠分为正常对照组,4周低O2高CO2组,4周低O2高CO2^ 知母宁组（知母宁组）。用透射电镜、图像分析、免疫组化、组织原位杂交技术等方法,观察各组大鼠肺动脉平均压（mPAP)、颈动脉平均压（mCAP)、肺细小动脉显微和超微结构、血CO浓度、血红素氧合酶－1（HO－1）及其基因表达的变化。结果：①低O2高CO2组mPAP比正常组显著增高,知母宁组mPAP比低O2高CO2组显著降低;3组间mCAP比较差异无显著性。②全血CO浓度低O2高CO2组比正常组显著增高,知母宁组比低O2高CO2组增高。③光镜下低O2高CO2组与正常组相比,肺细小动脉管壁面积／管总面积、肺细小动脉中膜平滑肌细胞核密度、肺细小动脉中膜厚度均显著升高,知母宁组与低O2高CO2组相比以上指标显著降低。④电镜下知母宁组肺细小动脉中膜平滑肌细胞增生、面积增大、染色质增多、外膜胶原纤维增生均较低O2高CO2组明显减轻。⑤免疫组化、原位杂交发现低O2高CO2组大鼠肺细小动脉HO－1及mRNA与正常组比较均明显增加,知母宁组大鼠肺细小动脉HO－1及mRNA表达均较低O2高CO2组为高。结论：知母宁有抑制慢性低氧高二氧化碳性肺动脉高压和肺血管结构重建的作用,上调HO－1及其基因表达、使CO合成增多可能为其重要作用机制。     

Growth of cardiac muscle cells during rat adaptation to altitude hypoxia

The weight of the right heart ventricle in 1.5-month-old rats kept after birth in the mountains of 3400 m altitude is higher and its muscle cell cytoplasm mass is much larger compared to those in 1.5-month-old animals raised at 800 m altitude. The hypertrophy of cells is not due to their polyploidization. Only a small increase in the relative number of polyploid cells takes place under high altitude hypoxia. The weight of the right ventricle and myocyte mass in 3-month-old rats kept 1.5-3 months after the birth at 3400 m altitude also increases, although this augmentation is significantly less than in the animals grown in the mountains for 1.5 months immediately after the birth. The myocyte ploidy of adult animals adapted to hypoxia does not essentially differ from that of 1.5- and 3-month-old control rats: about 80 per cent of these cells are polyploid. Thus, the growth of cardiac myocytes under the heart hyperfunction in the case of high altitude hypoxia proceeds mainly on the ground of the stable polyploid genome, as well as normal ontogenetic growth of these cells.     

动物对高原低氧的适应性研究进展

本文从血液学、肺动脉、心肺发育及其它方面简要介绍了动物对高原低氧适应的生理、生化及形态学特征,同时也对其中低氧诱导因子的作用及其遗传性方面的研究进行了概述。关于高原低氧适应的遗传机制仍需进一步的深入研究。     

Developmental adaptation to high altitude hypoxia

Experimental studies on animals and humans exposed to hypoxic stress have been reviewed. These data suggest that the influence of hypoxic stress, and the organism's response to it, are greater during growth than during adulthood. The organism's responses include alterations in the quantity and size of the alveolar units of the lungs, enlargement of the right ventricle of the heart, slower somatic growth as measured by birth weight and body size, increased aerobic capacity during maximal work, and greater control of ventilation. It is postulated that the organism is more sensitive to the influence of environmental factors during growth and development than during adulthood. Consequently, adaptive traits acquired during the developmental period have profound, long-term consequences, which are reflected in the physiological and morphological characteristics of the adult organism. It is concluded that the differences between the highland and lowland natives in their physiological performance and morphology are mostly due to adaptations acquired during the developmental period.Attention is called to the fact that the principle of developmental sensitivity and plasticity does not imply equally adaptive responses in all biological parameters. In other words, what we consider a deficiency in a given variable may actually reflect the indirect influence of the adaptive success of another variable.Presented at the Seventh International Biometeorological Congress, 17–23 August 1975, College Park Maryland, USA.     

Mechanisms of human adaptation to hypoxia

The effects of adaptation to cold-and-hypoxic exposure on the cardiovascular system, lipid peroxidation and concentrations of adaptogenesis involved hormones were studied in male students. The two weeks cold- and hypoxic training was shown to be accompanied by a significant increase of apnea duration, reduced velocity of bradycardia development and a more rapid ECG post-cold and- hypoxic exposure normalization, as well as by inhibition of activation of adrenal cortex and thyroid gland after stress of different nature. The changes of the character of influences between the indices under study, were demonstrated. The correlation analysis showed an increase of the human's adaptive potential and a decrease of its dependence on the adrenal cortex hormones.     

Interactions between hypoxia and hypercapnic acidosis on calcium signaling in carotid body type I cells

The effects of hypercapnic acidosis and hypoxia on intracellular Ca(2+) concentration ([Ca(2+)](i)) were determined with Indo 1 in enzymatically isolated single type I cells from neonatal rat carotid bodies. Type I cells responded to graded hypoxic stimuli with graded [Ca(2+)](i) rises. The percentage of cells responding was also dependent on the severity of the hypoxic stimulus. Raising CO(2) from 5 to 10 or 20% elicited a significant increase in [Ca(2+)](i) in the same cells as those that responded to hypoxia. Thus both stimuli can be sensed by each individual cell. When combinations of hypoxic and acidic stimuli were given simultaneously, the responses were invariably greater than the response to either stimulus given alone. Indeed, in most cases, the response to hypercapnia was slightly potentiated by hypoxia. These data provide the first evidence that the classic synergy between hypoxic and hypercapnic stimuli observed in the intact carotid body may, in part, be an inherent property of the type I cell.     

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.     

Systemic hemodynamics affecting cardiac output during hypocapnic and hypercapnic hypoxia

Systemic hemodynamic adjustments involved in the control of cardiac output (CO) were examined in chronically instrumented unanesthetized sheep inhaling gas mixtures resulting in hypocapnic hypoxia (H) [arterial pH (pHa) = 7.53, arterial partial pressure of O2 (Pao2) = 30 Torr, arterial partial pressure of CO2 (Paco2) = 29 Torr] or hypercapnic hypoxia (HCH) (pHa = 7.14, Pao2 = 34 Torr, Paco2 = 72 Torr) for 1 h. H (n = 7) and HCH (n = 6) resulted in 26% and 61% increases in CO, respectively, and mean systemic arterial pressure rose to a greater extent during HCH. Both H and HCH resulted in increased blood flow (microsphere method) to the peripheral systemic circulation including the brain, heart, diaphragm, and nonrespiratory skeletal muscle (the latter blood flow increased 120% during H and 380% during HCH). Gastrointestinal and renal blood flow remained unchanged during H and HCH. Transit time of green dye from the pulmonary artery to regional veins in the hindlimb and intestine was 5.0 and 8.2 s, respectively, during base-line conditions and remained unchanged with HCH. During HCH, regional O2 consumption increased 274% for the hindlimb and decreased 39% for the intestine. Total catecholamines rose 250% during H and 3,700% during HCH. During hypocapnic and hypercapnic hypoxia, CO is augmented in part by systemic hemodynamic adjustments that include a redistribution of blood flow and a translocation of blood volume to the fast transit time peripheral systemic circuit. The sympathetic nervous system may play an important role in mediating these systemic hemodynamic adjustments.