Significance of ATP-sensitive K(+)-channel in the mechanism of antiarrhythmic and cardioprotective effect of adaptation to intermittent hypobaric hypoxia

Adult male Wistar rats were exposed to intermittent hypobaric hypoxia (5000 m, 6 h/day, 6 weeks). It has been found that such mode of adaptation increased cardiac tolerance to arrhythmogenic action of a 45-min coronary artery occlusion but did not change an infarct size/area at risk (IS/AAR) ratio. In a separate series, rats were exposed to stronger intermittent hypobaric hypoxia (7000 m, 8 h/day, 6 weeks) and subjected to 20-min coronary artery occlusion and 3-h reperfusion on the day after the last hypoxic exposure. It has been established that in this case adaptation decreased the IS/AAR ratio, increased cardiac tolerance to arrhythmogenic action of reperfusion but had no effect on the incidence of ventricular arrhythmias occurred during ischemic period. We found that cardioprotective and antiarrhythmic effect of adaptation to the "altitudes" of 7000 m and antiarrhythmic effect of adaptation to the "altitude" of 5000 m is mediated via K(ATP)-channel activation.     

Exposure to intermittent high altitude induces different changes in adenylyl cyclase activity in hearts of young and adult Wistar rats

This study investigates changes of adenylyl cyclase activity in the heart of young and adult Wistar rats exposed to experimental conditions simulating high altitude hypoxia as a model for interpretation of some adaptive changes of adenylyl cyclase observed in human. The exposure of rats to intermittent high altitude (IHA) hypoxia (5000 m) showed significant adaptive changes. The right ventricular weight and the ratio of right/left ventricular weights of adult rats exposed to IHA were significantly increased when compared to appropriate controls; adaptive changes of cardiac adenylyl cyclase being dependent on the age of the animals. The isoprenaline-stimulated activity was higher in the left than in the right ventricle, and in both ventricles it was higher in young rats than in adult rats. When compared to controls, isoprenaline stimulation was decreased in the right ventricles of adapted young rats and, by contrast, it was increased in the left ventricles of adapted adult rats. This decrease and increase of adenylyl cyclase activity evoked by isoprenaline was paralleled by forskolin-induced adenylyl cyclase activity in these experimental groups. It seems therefore that the changes in the pattern of total adenylyl cyclase activity observed under IHA hypoxia may at least be partially explained by the changes of beta-adrenergic receptor susceptibility following IHA hypoxia.     

Changes in the expression and/or activation of regulatory proteins in rat hearts adapted to chronic hypoxia

Chronic intermittent high altitude (IHA) hypoxia results in long-term adaptation protecting the heart against acute ischemia/reperfusion injury; however, molecular mechanisms of this phenomenon are not completely elucidated so far. The present study was aimed at investigation of a modulating effect of IHA hypoxia on the expression and/or activation of selected regulatory proteins, with particular emphasis on differential responses in the right ventricle (RV) and left ventricle (LV). Adult male Wistar rats were exposed to IHA hypoxia of 7000 m simulated in a hypobaric chamber (8 h/day, 25 exposures), and protein contents and activities in myocardial fractions were determined by Western blot analysis. In markedly hypertrophic RV of hypoxic rats, gelatinolytic activity of MMP-2 and protein levels of carbonic anhydrase IX (a marker of hypoxia) were significantly enhanced. Study of mitogen-activated protein kinases (MAPKs) revealed no differences in the contents of total p38-MAPK in both ventricles between the IHA and normoxic control rats, whereas activation of p38-MAPK was decreased in the RV and moderately increased in the LV of IHA rats as compared to controls. Extracellular signal regulated kinase-2 (ERK-2) was partially up-regulated in the RV of IHA rats, and, in addition, expression of acidic fibroblast growth factor (aFGF), a potential activator of ERK cascade, was also significantly increased. In contrast, expression of ERKs in the LV as well as their activities in both ventricles, were not affected by IHA hypoxia. Differential effects of IHA hypoxia on c-Jun-N-terminal protein kinases (JNKs) in the RV and LV were also observed. As compared with the controls, total content of JNKs was increased in the RV of the IHA rats, while expression of JNKs in the LV was down-regulated. IHA hypoxia changed neither total levels of Akt kinase in both RV and LV, nor Akt kinase activity in the RV. However, increased levels of activated phospho-Akt kinase were found in the LV of IHA rats. The results demonstrate that adaptation of rat hearts to chronic IHA hypoxia is associated with disctinct changes in the levels and/or activation of several regulatory proteins in two ventricles. The latter could be attributed to both myocardial remodeling and cardioprotection induced by chronic hypoxia.     

Exposure to Intermittent High Altitude Induces Different Changes in Adenylyl Cyclase Activity in Hearts of Young and Adult Wistar Rats

Abstract

This study investigates changes of adenylyl cyclase activity in the heart of young and adult Wistar rats exposed to experimental conditions simulating high altitude hypoxia as a model for interpretation of some adaptive changes of adenylyl cyclase observed in human. The exposure of rats to intermittent high altitude (IHA) hypoxia (5000 m) showed significant adaptive changes. The right ventricular weight and the ratio of right/left ventricular weights of adult rats exposed to IHA were significantly increased when compared to appropriate controls; adaptive changes of cardiac adenylyl cyclase being dependent on the age of the animals. The isoprenaline‐stimulated activity was higher in the left than in the right ventricle, and in both ventricles it was higher in young rats than in adult rats. When compared to controls, isoprenaline stimulation was decreased in the right ventricles of adapted young rats and, by contrast, it was increased in the left ventricles of adapted adult rats. This decrease and increase of adenylyl cyclase activity evoked by isoprenaline was paralleled by forskolin‐induced adenylyl cyclase activity in these experimental groups. It seems therefore that the changes in the pattern of total adenylyl cyclase activity observed under IHA hypoxia may at least be partially explained by the changes of beta‐adrenergic receptor susceptibility following IHA hypoxia.     

DNA synthesis in the ventricular myocardium of young rats exposed to intermittent high altitude (IHA) hypoxia. An autoradiographic study.

Intermittent high altitude (IHA) hypoxia (7000 m) increased the wet weight of the right ventricular myocardium of 30-day-old rats after two 4 h/day exposures. During the same period the number of DNA-synthesizing nuclei of both muscle and non-muscle cell types increased proportionally. After 4 such exposures to hypoxia the number of 3H-thymidine-labelled nuclei in both cell types increased further. In addition, the number of labelled nuclei increased significantly in the yet un-enlarged left ventricle. While there was no difference in the number of DNA-synthesizing cells between the right and left ventricles in control animals, a significant increase in the number of cells involved in DNA synthesis in the right ventricle was found in both groups of animals exposed to IHA hypoxia. These results show that DNA synthesis in myonuclei of the ventricular myocardium can be stimulated in 30-day-old rats, i.e. at the very end of the weaning period.     

间歇性低氧防止缺血再灌注损伤引起的线粒体结构损伤和mtDNA片段缺失

本文用离体Ｌａｎｇｅｎｄｏｒｆｆ灌流大鼠心脏造成急性心肌缺血／再灌注损伤模型,观察间歇性低氧暴露保护心肌线粒体的作用。以聚合酶链式反应（ＰＣＲ）方法和电子显微镜技术,观察线粒体ＤＮＡ（ｍｔＤＮＡ＾４８３４）片段缺失和超微结构的变化。大鼠暴露于模拟海拔５０００米低氧环境（６ｈ／ｄ,２８ｄ）明显降低ｍｔＤＮＡ＾４８３４缺失的发生率（２８．５７％,ｖｓ常氧对照组８７．５％ Ｐ〈０．０５）;而且能够明显减     

MCC-134, a blocker of mitochondrial and opener of sarcolemmal ATP-sensitive K+ channels, abrogates cardioprotective effects of chronic hypoxia

We examined the effect of MCC-134, a novel inhibitor of mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channels and activator of sarcolemmal ATP-sensitive K(+) (sarcK(ATP)) channels, on cardioprotection conferred by adaptation to chronic hypoxia. Adult male Wistar rats were exposed to intermittent hypobaric hypoxia (7000 m, 8 h/day, 5-6 weeks) and susceptibility of their hearts to ventricular arrhythmias and myocardial infarction was evaluated in anesthetized open-chest animals subjected to 20-min coronary artery occlusion and 3-h reperfusion on the day after the last hypoxic exposure. MCC-134 was administered intravenously 10 min before ischemia and 5 min before reperfusion in a total dose of 0.3 mg/kg or 3 mg/kg divided into two equal boluses. The infarct size (tetrazolium staining) was reduced from 59.2+/-4.4 % of the area at risk in normoxic controls to 43.2+/-3.3 % in the chronically hypoxic group. Chronic hypoxia decreased the reperfusion arrhythmia score from 2.4+/-0.5 in normoxic animals to 0.7+/-0.5. Both doses of MCC-134 completely abolished the antiarrhythmic protection (score 2.4+/-0.7 and 2.5+/-0.5, respectively) but only the high dose blocked the infarct size-limiting effect of chronic hypoxia (54.2+/-3.7 %). MCC-134 had no effect in the normoxic group. These results support the view that the opening of mitoKATP channels but not sarcKATP channels plays a crucial role in the mechanism by which chronic hypoxia improves cardiac tolerance to ischemia/reperfusion injury.     

Differential role of PI3K/Akt pathway in the infarct size limitation and antiarrhythmic protection in the rat heart

Endogenous cardiac protection against prolonged ischemic insult can be achieved by repeated brief episodes of ischemia (hypoxia) or by cardiac adaptation to various stresses such as chronic hypoxia. Activation of phosphatidylinositol 3-kinase (PI3K)/Akt is involved in antiapoptotic effects, however, it is not clear whether it is required for overall heart salvage including protection against myocardial infarction and arrhythmias. We focussed on the potential common role of PI3K/Akt in anti-infarct protection, in the experimental settings of long-term adaptation to chronic intermittent hypobaric hypoxia (IHH; 8 h/day, 25–30 exposures, in vivo rats) and acute ischemic preconditioning (IP; Langendorff-perfused hearts). In addition, we explored the role of PI3K/Akt in susceptibility to ischemic ventricular arrhythmias. In normoxic open-chest rats, PI3K/Akt inhibitor LY294002 (LY; 0.3 mg/kg) given 5 min before test occlusion/reperfusion (I/R) did not affect infarct size (IS) normalized to the size of area at risk (AR). In hypoxic rats, LY partially attenuated IS-limiting effect of IHH (IS/AR 59.7 ± 4.1% vs. 51.8 ± 4.4% in the non-treated rats; p > 0.05) and increased IS/AR to its value in normoxic rats (64.9 ± 5.1%). In the isolated hearts, LY (5 μM) applied 15 min prior to I/R completely abolished anti-infarct protection by IP (IS/AR 55.0 ± 4.9% vs. 15.2 ± 1.2% in the non-treated hearts and 42.0 ± 5.5% in the non-preconditioned controls; p < 0.05). In the non-preconditioned hearts, PI3K/Akt inhibition did not modify IS/AR, on the other hand, it markedly suppressed arrhythmias. In the LY-treated isolated hearts, the total number of ventricular premature beats and the incidence of ventricular tachycardia (VT) was reduced from 518 ± 71 and 100% in the controls to 155 ± 15 and 12.5%, respectively (p < 0.05). Moreover, bracketing of IP with LY did not reverse antiarrhythmic effect of IP. These results suggest that activation of PI3K/Akt cascade plays a role in the IS-limiting mechanism in the rat heart, however, it is not involved in the mechanisms of antiarrhythmic protection.     

Myocardial infarct size-limiting effect of chronic hypoxia persists for five weeks of normoxic recovery

We examined cardioprotective effect of chronic hypoxia and the time course of its recovery under normoxic conditions. Adult male Wistar rats were exposed to intermittent hypobaric hypoxia (7000 m, 8 h/day, 35 exposures) and susceptibility of their hearts to ischemia-induced ventricular arrhythmias and myocardial infarction was evaluated in anesthetized open-chest animals subjected to 30-min coronary artery occlusion and 4-h reperfusion on the day after the last hypoxic exposure and at 7, 35 and 90 days of normoxic recovery. The infarct size was reduced from 69.2+/-1.7 % of the area at risk in normoxic controls to 48.0+/-2.2 % in the chronically hypoxic group and to 61.6+/-2.3 % in the group recovered for 7 days. This residual protection persisted for at least 35 days of normoxic recovery but it was absent after 90 days. In contrast to the infarct size-limitation, the antiarrhythmic protection disappeared already during the first week; the incidence of ventricular fibrillation was even significantly increased 7 and 90 days after the last hypoxic exposure. In conclusion, the duration of cardioprotection induced by chronic hypoxia differs markedly, depending on the end point of ischemia/reperfusion injury examined. Whereas the increased tolerance to lethal myocardial injury persists for at least 5 weeks after the termination of hypoxia, the antiarrhythmic protection rapidly vanishes, being replaced with transient proarrhythmic effect.     

Effect of adaptation to altitude hypoxia in early ontogeny on the indices of higher nervous activity]

Newborn male and female Wistar rats were adapted to hypoxia in a pressure chamber. Adaptation was started from the "altitude" of 1000 m, 1 hour daily, and then the time and the intensity of hypoxic actions were gradually increased: beginning from the 17th day the animals were subjected to adaptation to the "altitude" of 5000 m, for 5 hours, 5 days a week. The defence conditioned reflex of active avoidance was provoked in the animals after 2-month adaptation. A tendency to a more rapid elaboration of the reflex and a markedly enhanced degree of its retention in comparison with control was revealed in the adapted males. No significant changes in the elaboration and rentention of the reflex were found in the female animals adapted to hypoxia under analogous conditions.     

Excitability changes of cortical neurons during the postnatal period in rats exposed to prenatal hypobaric hypoxia

Pregnant rats were exposed to intermittent hypobaric hypoxia (at a simulated altitude of 7000 m or 5000 m) and the excitability of cortical neurons of their pups was tested. Stimulation of the sensorimotor cortex of rats prenatally exposed to hypoxia shortened the duration of cortical afterdischarges in 12-day-old rats, but did not change the excitability in 25-day-old animals. Shortening of the first afterdischarge in 35-day-old rats but the prolongation of the first afterdischarge in adult rats (as compared to the duration of cortical afterdischarges in rats not exposed to prenatal hypoxia) were registered. The possible mechanisms of different excitability of cortical neurons in rats prenatally exposed to hypobaric hypoxia are discussed.     

Intermittent high altitude hypoxia protects the heart against lethal Ca2+ overload injury

Adaptation to intermittent high altitude (IHA) hypoxia can protect the heart against ischemia-reperfusion injury. In view of the fact that both Ca2+ paradox and ischemia-reperfusion injury are associated with the intracellular Ca2+ overload, we tested the hypothesis that IHA hypoxia may protect hearts against Ca2+ paradox-induced lethal injury if its cardioprotection bases on preventing the development of intracellular Ca2+ overload. Langendorff-perfused hearts from normoxic and IHA hypoxic rats were subjected to Ca2+ paradox (5 min of Ca2+ depletion followed by 30 min of Ca2+ repletion) and the functional, biochemical and pathological changes were investigated. The Ca2+ paradox incapacitated the contractility of the normoxic hearts, whereas the IHA hypoxic hearts significantly preserved contractile activity. Furthermore, the normoxic hearts subjected to Ca2+ paradox exhibited a marked reduction in coronary flow, increase in lactate dehydrogenase release, and severe myocyte damage. In contrast, these changes were significantly prevented in IHA hypoxic hearts. We, then, tested and confirmed our hypothesis that the protective mechanisms are mediated by mitochondria ATP-sensitive potassium channels (mitoKATP) and Ca2+/calmodulin-dependent protein kinase II (CaMKII), as the protective effect of IHA hypoxia was abolished by 5-hydroxydecanoate, a selective mitoKATP blocker, and significantly attenuated by KN-93, a CaMKII inhibitor. In conclusion, our studies offer for the first time that IHA hypoxia confers cardioprotection against the lethal injury of Ca2+ paradox and give biochemical evidence for the protective mechanism of IHA hypoxia. We propose that researches in this area may lead a preventive regimen against myocardial injury associated with Ca2+ overload.     

Programmed electrical stimulation-induced arrhythmias in isolated hearts from adult and senescent rats

In isolated hearts from normal rats, we previously demonstrated an age-related increase of spontaneous ventricular arrhythmias. The aim of the present experiments was to test the possible effect of aging on ventricular arrhythmias induced by programmed electrical stimulation. Experiments were performed in isolated cardiac preparations of 6- and 24-month-old normal Wistar rat hearts. Programmed electrical stimulation (single or double premature stimuli following a stimuli train) was tested in isolated Langendorff perfused hearts during control perfusion, after left anterior descending coronary artery ligature and during global hypoxia. No significant differences were observed between adult and senescent hearts in the incidence of programmed electrical stimulation-induced ventricular arrhythmias during these three different situations. These experiments demonstrate that the cardiac "physiological" aging process is not associated with a greater propensity to programmed electrical stimulation-induced arrhythmias.     

Comparison of cardiopulmonary responses of male and female rats to intermittent high altitude hypoxia

Intermittent high altitude hypoxia (8 hours a day, 5 days a week, stepwise up to the altitude of 7000 m, total number of exposures 24) induced in male and female rats, chronic pulmonary hypertension and right ventricular hypertrophy. No significant sex differences were found in both these parameters. A significant sex difference was demonstrated in the resistance of the cardiac muscle to acute anoxia in vitro: the myocardium of control female rats proved to be significantly more resistant to oxygen deficiency. Intermittent altitude hypoxia resulted in significantly enhanced resistance in both sexes, yet the sex difference was maintained. Sex differences were further observed in the growth response of experimental animals to the acclimatization process. Whereas the body weight of male rats exposed to intermittent altitude hypoxia was significantly lower, hypoxic females had body weights comparable to those of control animals.     

Protective effects of dexrazoxane against acute ischaemia/reperfusion injury of rat hearts

Dexrazoxane (DEX), an inhibitor of topoisomerase II and intracellular iron chelator, is believed to reduce the formation of reactive oxygen species (ROS) and protects the heart from the toxicity of anthracycline antineoplastics. As ROS also play a role in the pathogenesis of cardiac ischaemia/reperfusion (I/R) injury, the aim was to find out whether DEX can improve cardiac ischaemic tolerance. DEX in a dose of 50, 150, or 450?mg·(kg body mass)(-1) was administered intravenously to rats 60?min before ischaemia. Myocardial infarct size and ventricular arrhythmias were assessed in anaesthetized open-chest animals subjected to 20?min coronary artery occlusion and 3?h reperfusion. Arrhythmias induced by I/R were also assessed in isolated perfused hearts. Only the highest dose of DEX significantly reduced infarct size from 53.9%?± 4.7% of the area at risk in controls to 37.5%?± 4.3% without affecting the myocardial markers of oxidative stress. On the other hand, the significant protective effect against reperfusion arrhythmias occurred only in perfused hearts with the dose of DEX of 150?mg·kg(-1), which also tended to limit the incidence of ischaemic arrhythmias. It is concluded that DEX in a narrow dose range can suppress arrhythmias in isolated hearts subjected to I/R, while a higher dose is needed to limit myocardial infarct size in open-chest rats.     

Intermittent high altitude hypoxia - induced structural changes in the pulmonary myocardium in young mice

Seven-day-old mice, strain H, were exposed to intermittent high altitude hypoxia (IHA) in a barochamber (7,000 m, 4 h/day, 5 days a week); a total number of exposures was 10. It has been shown that the layer of cardiac musculature in the adventitia of the pulmonary veins, the so-called pulmonary myocardium, reacts to IHA hypoxia by enlargement even sooner than the right ventricular myocardium. The average thickness of the layer of pulmonary myocardium was significantly greater in animals exposed to IHA hypoxia as compared with the controls. Furthermore, IHA hypoxia induces the extension of the pulmonary myocardium to the periphery of the pulmonary venous bed. Ultrastructural investigation of the pulmonary myocardium in hypoxic animals revealed the presence of unoriented myofilaments in the peripheral myofibril-free sarcoplasma, increase in the number of ribosomes and appearance of profiles of granular endoplasmic reticulum. Our data provide quantitative support for the hypothesis that it is not only the contraction of pulmonary arteries, but also venoconstriction which contribute to the hypoxic pressure response in mice.     

不同海拔高原低压缺氧环境下大鼠肠道病理损伤特点

目的:探讨不同海拔高度的高原低压缺氧环境下大鼠肠道病理损伤的特点。方法:将30只SD雄性大鼠随机分5组:平原对照组、5000米海拔高度10天组、5000米海拔高度21天组、6500米海拔高度10天组、6500米海拔高度21天组,每组6只。大鼠在平原环境或模拟高原环境中常规饲养,在相应时间点,深度麻醉受试大鼠致死,取材,固定、HE染色后镜检并进行病理学损伤评分。结果:各高原组空、回肠病理损伤评分均显著高于平原对照组(P0.01),5000 m暴露21d组空肠、回肠、结肠病理损伤评分显著高于5000 m暴露10 d组,明显低于6500 m暴露21d组,6500 m暴露10d组空肠、回肠、结肠病理损伤评分显著高于5000 m暴露10 d组(P0.01或P0.05)。5000 m暴露10 d组结肠损伤病理评分与平原对照组比较差异无统计学意义外,其余高原组结肠病理损伤评分均显著高于平原对照组(P0.01或P0.05)。5000 m暴露21 d组空肠与结肠病理损伤评分存在显著性差异(P0.05);6500 m暴露21 d组空肠和回结肠均与结肠病理损伤评分存在显著性差异(P0.05,P0.01)。结论:肠道粘膜随着海拔高度和缺氧时间的延长而损伤加重。在相同的情况下,小肠的损伤较结肠严重,但空肠和回肠的损伤无明显差异,结肠损伤的发生较晚且与高原环境停留时间具有明显关系,提示在进入高原早期应将小肠病理损伤的防治作为重点。     

Increased expression and altered subcellular distribution of PKC-delta in chronically hypoxic rat myocardium: involvement in cardioprotection

We examined the role of protein kinase C (PKC) in the cardioprotective mechanism induced by long-term adaptation to chronic intermittent hypoxia. Adult male Wistar rats were exposed to hypobaric hypoxia of 7,000 m for 8 h/day, 5 days/wk; the total number of exposures was 24-32. A control group was kept under normoxic conditions. Western blot analysis of PKC isoforms-delta and -epsilon was performed in the cytosol and three particulate fractions of left ventricular myocardium. Infarct size was determined in open-chest animals subjected to 20-min coronary artery occlusion and 3-h reperfusion. The PKC inhibitors chelerythrine (1 or 5 mg/kg) or rottlerin (selective for PKC-delta isoform; 0.3 mg/kg) were administered intravenously as a single bolus 15 min before ischemia. Chronic hypoxia had no effect on the expression and distribution of PKC-epsilon. The relative amount of PKC-delta increased in the cytosol and nuclear-cytoskeletal, mitochondrial, and microsomal fractions of chronically hypoxic myocardium by 100%, 212%, 237%, and 146%, respectively, compared with corresponding normoxic values. Chronic hypoxia decreased the size of myocardial infarction (normalized to the area at risk) by about one-third on the average (P < 0.05). Both doses of chelerythrine tended to reduce infarction in controls, and only the high dose completely abolished the improvement of ischemic tolerance in hypoxic hearts (P < 0.05). Rottlerin attenuated the infarct size-limiting effect of chronic hypoxia (P < 0.05), and it had no effect in controls. These results suggest that chronic intermittent hypoxia-induced cardioprotection in rats is partially mediated by PKC-delta; the contribution of other isoforms remains to be determined.     

Shift of anaerobic to aerobic metabolism in the rats acclimatized to hypoxia

1. Metabolic acclimatization by repeated exposure to a simulated altitude of 4000, 5000 and 6000 m for 2 hr per day throughout 2 to 11 days was evaluated by the increased formation of ketone bodies as a marker of fatty acid oxidation and the decreased production of lactate and uric acid, the indicators of anaerobic metabolism in rats exposed to an altitude of 8000 m. 2. Pre-exposure of rats to an altitude of 5000 m and over caused an acclimatization to hypoxia. The rise of the altitude to which rats were pre-exposed reduced the period until the acquisition of metabolic acclimatization. 3. Acclimatized rats showed an increased activity of mitochondrial glutamate dehydrogenase without changes in glycolytic enzyme activity in skeletal muscle, heart and liver. 4. Acclimatization to high altitude hypoxia is concluded to involve a shift of the anaerobic glycolysis to aerobic metabolism by the increase in the oxidative enzymes.     

慢性高原低氧对高原鼠兔和大鼠肝脏的作用

我们曾经发现,移入高原的实验大鼠子一代和高原鼠兔(Ochotona curzoniae)对高原低气压低氧有完全不同的适应能力和适应机理(杜继曾等,1982)。我们还观察到,在24小时急性高原低氧时,由低地移入2300米高原的大鼠后裔在5000米和8000米的高度上,出现了以转氨酶、肝溶酶体酸性磷酸酶活力升高、肝糖原和蛋白质含量下降的肝脏代谢异常和肝脏病理变化,而高原鼠兔只是在8000米高度时,才始出现部分指标的轻度变异(杜继曾等,1982),从而揭示了高原鼠兔的肝细胞代谢在细胞水平上对低氧的适应机制优越于移入高原的实验大鼠后代。慢性低氧又如何作用于大鼠和高原鼠兔的肝脏代谢?迄今尚无人研究。因此对这一作用规律的认识和阐明,在环境适应生理学领域、人类高原活动和畜牧业生产上都是十分重要的。