Erythropoietin response to acute hypobaric or anaemic hypoxia in gentamicin-administered rats

In an attempt to assess the erythropoietin (Epo) production site(s) in rat kidney, Epo response to hypoxia and renal histopathological changes were studied in rats administered with graded doses of gentamicin. Male Sprague-Dawley rats of 9 to 11 weeks old were used. Following a 14-day subcutaneous administration (67.5 or 33.8 mg kg^-1 day^-1) of gentamicin, a nephrotoxic aminoglycoside, selective proximal tubular lesions were produced. These gentamicin-administered rats were compared with normal rats with respect to Epo response to hypoxia. Two different kinds of hypoxic load, either 0.35 atm hypobaric hypoxia (P_IO2= 46 torr) or acute anaemia (Ht: 29.3 ± 0.2% and [Hb]: 9.7 ± 0.3 g dl^-1) by withdrawing of blood corresponding to 1–2% of body weight was used. During the hypoxic period of up to 48 h, the peak renal venous plasma Epo titres of 3.1 ± 0.6 and 4.3 ± 0.6 U ml^-1 was observed at the 6th h in normal hypobaric hypoxic and anaemic rats, compared with the prehypoxic value of 0.7 ± 0.1 U ml^-1. The Epo titres then declined gradually. In the rats which were administered gentamicin, Epo response pattern was the same as that observed in the normal rats, but the peak value decreased significantly to 0.8 ± 0.3 and 1.1 ± 0.4 U ml^-1 in hypoxic and anaemic rats (P < 0.05). Histological examination revealed the selective damage to renal proximal convoluted tubules. The Epo response was reduced by the tissue damages, and restoration of the gentamicin-induced tissue injury was accompanied with restored Epo response to hypoxia. The results suggest that renal proximal convoluted tubules are involved in Epo production under hypoxia.     

Behavioral peculiarities and reactions of brain dopaminergic systems in rats with different resistance to acute hypobaric hypoxia

Locomotor activity in the open field test did not correlate with rat resistance to acute hypobaric hypoxia; there was a correlation between this resistance and rat behavior during acute stress. Immobility was characteristic of rats with low and particularly medium resistance to hypoxia; this reaction can be abolished by antidepressants. by contrast, highly resistant rats were mainly hyperactive. The resistance to hypoxia was associated with extreme parameters of dopaminergic neuron functioning. In low-resistant rats locomotor stereotypia was maximal, while perioral stereotypia was the minimal; highly resistant rats were characterized by an opposite pattern, and medium-resistant rats occupied an intermediate position.     

Impact of acute hypobaric hypoxia on blood flow distribution in brain

Aim: Acute hypobaric hypoxia is well known to alter brain circulation and to cause neuropsychological impairment. However, very few studies have examined the regional changes occurring in the brain during acute exposure to extreme hypoxic conditions. Methods: Regional cerebral blood flow (rCBF) response to hypoxia was investigated in six healthy subjects exposed to either normobaric normoxia or hypobaric hypoxia with ambient pressure/inspired oxygen pressure of 101/21 kPa and 50/11 kPa respectively. After 40 min at the desired pressure they were injected ^99mTc‐HMPAO and subsequently underwent single photon emission computed tomography. Regional cerebral blood flow distribution changes in the whole brain were assessed by Statistical Parametric Mapping, a well established voxel‐based analysis method. Results: Hypobaric hypoxia increased rCBF distribution in sensorymotor and prefrontal cortices and in central structures. PCO₂ correlated positively and SatO₂ negatively with rCBF in several temporal, parahippocampal, parietal and central structures. Conclusions: These findings underscore the specific sensitivity of the frontal lobe to acute hypobaric hypoxia and of limbic and central structures to blood gas changes emphasizing the involvement of these brain areas in acute hypoxia.     

慢性间歇性低压低氧对老年大鼠纹状体多巴胺含量及行为的影响

目的:探讨慢性间歇性低压低氧(CIHH)对老年大鼠纹状体多巴胺(DA)及其代谢产物含量以及相关行为的影响。方法:用CIHH氧仓处理大鼠30 d,通过黏附物去除实验、倾斜面实验和水平绳实验检测大鼠行为的改变,通过液相色谱-串联质谱(L,C-MS/MS)分析DA及其代谢产物二羟苯乙酸(DOPAC)和高香草酸(HVA)的含量。结果:老年组大鼠黏附物去除实验、倾斜面实验和水平绳实验中各行为参数均较成年组大鼠显著下降,CIHH处理后上述行为参数均有改善,但没有达到成年组水平;老年组大鼠DA及其代谢产物DOPAC和HVA含量均较成年组大鼠显著下降,老年CIHH组DA及其代谢产物DOPAC和HVA均升高,但没有达到正常成年组水平。结论:CIHH改善老年大鼠纹状体DA含量及行为衰退。     

Osteopontin expression in normal and hypobaric hypoxia-exposed rats

Aim: Experimental pulmonary hypertension induced in a hypobaric hypoxic environment (HHE) is characterized by structural remodelling of the heart and pulmonary arteries. Osteopontin (OPN) has emerged as a key factor in cardiovascular remodelling in response to pressure or volume overload. We studied the possible effects of HHE on the OPN synthesis system. Methods: One hundred and forty‐eight male Wistar rats were housed in a chamber with conditions equivalent of an altitude of 5500 m for up to 21 days. Results: Plasma OPN protein level was found to be significantly decreased on day 0.5 of exposure to HHE, as was the level in the adrenal gland (which secreted highest levels of OPN protein). In the right ventricle of the heart (mRNA) and the lung (protein), OPN expression was found to be significantly increased only on day 1 and day 5, respectively, of exposure to HHE. By immunohistochemistry, the distribution and intensity of OPN protein in several organs were found to alter during exposure to HHE. However, these changes in OPN synthesis did not coincide with the moderate increase in pulmonary arterial pressure (PAP) (maximal mean PAP, 24.5 mmHg) during HHE. Conclusion: Pulmonary hypertension in HHE with conditions equivalent of an altitude of 5500 m may induce little or no OPN in heart and lung. Sustained induction may require a more severe PAP overload.     

慢性间歇性低压低氧对老年大鼠自发运动行为及黑质多巴胺能神经元的影响

目的:用慢性间歇性低压低氧(CIHH)模型,探讨CIHH对老年大鼠自发运动行为以及黑质多巴胺能神经元的影响。方法:用CIHH模型处理老年大鼠30 d,通过旷场实验检测大鼠自发运动行为的改变,通过实时定量PCR和免疫印迹检测黑质多巴胺能神经元酪氨酸羟化酶(TH)和多巴胺转运体(DAT)表达的变化。结果:老年组大鼠旷场实验中闻嗅行为、探索行为、运动行为和理毛行为与成年组相比均显著下降,CIHH处理后理毛行为没有改变,闻嗅行为、探索行为和运动行为显著改善,但没有达到成年组水平;老年组大鼠黑质多巴胺能神经元TH和DAT的表达与成年组相比均显著下降,老年CIHH组TH和DAT的表达升高,但没有达到成年组水平。结论:CIHH可改善老年大鼠闻嗅行为、探索行为和运动行为,并提高黑质多巴胺能神经元TH和DAT的表达。     

Sensitivity to hypobaric hypoxia in mice selected for high and low brain weights

We studied the effect of hypobaric hypoxia on mice with various brain weights. Mice with low brain weight were more resistant to hypoxia than animals with high brain weight.     

间歇性低压缺氧预处理对大鼠全脑缺血/再灌注海马CA1区Ngb和Bcl-2蛋白表达的影响

 目的：探讨间歇性低压缺氧预处理对大鼠全脑缺血/再灌注海马CA1区脑红蛋白（Ngb）和Bcl-2蛋白表达的影响。方法：将Wistar大鼠随机分为假手术组、低压缺氧预处理对照组、全脑缺血/再灌注组、低压缺氧预处理+全脑缺血/再灌注组4组,将间歇暴露于低压缺氧环境的大鼠作为低压缺氧预处理对照组。采用Pulsinelli四血管闭塞法复制大鼠全脑缺血/再灌注模型,夹闭颈总动脉造成全脑缺血8 min后再灌注。用硫堇染色法和免疫组织化学方法分别观察大鼠海马组织学改变和海马组织Ngb、Bcl-2蛋白表达变化。结果：低压缺氧预处理+全脑缺血/再灌注组大鼠海马CA1区存活细胞数较全脑缺血/再灌注组明显增加,其海马组织Ngb和Bcl-2蛋白表达量较全脑缺血/再灌注组显著升高。结论：间歇性低压缺氧预处理可能通过上调海马组织Ngb和Bcl-2蛋白的表达,减少全脑缺血再灌注后海马神经元的死亡而发挥神经保护作用。     

慢性间歇性低压低氧对家兔窦房结肾上腺素能受体反应性的影响

目的:通过细胞内记录方法研究慢性间歇性低压低氧(CIHH)对家兔窦房结肾上腺素能受体反应性的影响。方法:新西兰大白兔随机分为对照组(Con)、CIHH14d组(CIHH14)、CIHH28d组(CIHH28)3组。CIHH组动物置于低压氧舱,分别接受14、28d模拟5000米高原的低压低氧处理(6h/d)。制备离体窦房结标本、描记窦房结自律细胞的生物电活动。通过累加给药法,观察不同浓度的β-肾上腺素能受体激动剂异丙肾上腺素(ISO)(0.01、0.1、1μmol/L)和α1肾上腺素能受体激动剂苯肾上腺素(PE)(0.01、0.1、1μmol/L)对家兔窦房结自律细胞动作电位的影响。结果:(1)CIHH对基础状态下窦房结细胞动作电位各参数无明显影响;(2)ISO浓度依赖性增加窦房结细胞动作电位0期最大除极速率(Vmax)、动作电位幅值(APA)、放电频率(RPF)、舒张期自动去极化速率(VDD),对其它参数无明显影响;(3)CIHH处理动物窦房结细胞对ISO的反应性降低;最大浓度ISO(1μmol/L)下,CIHH14和CIHH28组的VDD、RPF、APA和Vmax的增加明显小于对照组(P0.05);(4)α1肾上腺素能受体激动剂PE(0.01、0.1、1μmol/L)对窦房结细胞动作电位各项参数均无影响。结论:CIHH降低家兔窦房结β肾上腺素能受体反应性,对α1肾上腺素能受体反应性无影响。     

Effect of melatonin on the relationship between lipid peroxidation and proteolytic activity in basal nuclei of rat brain during acute hypoxia

We studied the effect of melatonin on the relationship between LPO intensity and proteolytic activity in basal nuclei (caudate nucleus, globus pallidus, amygdaloid complex, and nucleus accumbens septi) of rat brain during acute hypobaric hypoxia. Acute hypoxia was accompanied by LPO activation and increase in proteolytic activity. It should be emphasized that the intensity of proteolysis was higher in structures responding by more pronounced LPO activation (nucleus accumbens septi and globus pallidus). Intraperitoneal injection of 1 mg/kg melatonin 30 min before acute hypoxia inhibited LPO and prevented the increase in proteolysis in basal nuclei of the brain. The effect of melatonin was most pronounced in basal nuclei highly sensitive to acute hypoxia. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 142, No. 7, pp. 94–96, July, 2006     

Effect of hypobaric hypoxia on the development of long-term posttetanic potentiation in slices of rat olfactory cortex: Correction with hypoxic preconditioning

We studied the effect of in vivo hypobaric hypoxia on the development (after 3 h) of in vitro long-term posttetanic potentiation in Wistar rats. Severe hypoxia suppressed induction of posttetanic potentiation in slices of the olfactory cortex. Preconditioning exposure (moderate hypobaric hypoxia) prevented inhibition of posttetanic potentiation induced by severe hypoxia. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 142, No. 11, pp. 487–489, November, 2006     

Thioredoxin-1 expression levels in rat hippocampal neurons in moderate hypobaric hypoxia

Previous studies have demonstrated that preconditioning (PC) with three sessions of moderate hypoxia significantly increases the expression of the antioxidant protein thioredoxin-1 (Trx-1) in the rat hippocampus by 3 h after subsequent acute severe hypoxia as compared with non-preconditioned animals. However, it remained unclear whether this increase in Trx-1 accumulation during PC is induced before severe hypoxia or is a modification of the response to severe hypoxia. This question was addressed in the present investigation using experiments on 12 adult male Wistar rats with studies of Trx-1 expression after PC without subsequent severe hypoxia. Immunocytochemical studies were performed 3 and 24 h after three episodes of moderate hypobaric hypoxia (three sessions of 2 h at 360 mmHg with 24-h intervals). Immunoreactivity to Trx-1 24 h after the last session was significantly decreased in neurons in all the areas of the hippocampus studied (CA1, CA2, CA3, and the dentate gyrus). Immunoreactivity in CA3 was also decreased 3 h after hypoxia. These results provide evidence that moderate preconditioning hypoxia itself not only does not increase, but even significantly decreases Trx-1 expression. Thus, increases in Trx-1 contents in the hippocampus of preconditioned animals after severe hypoxia are not associated with the accumulation of this protein during PC, but with a PC-induced modification of the reaction to severe hypoxia. Translated from Morfologiya, Vol. 133, No. 1, pp. 20–24, January–February, 2008.     

Adrenomedullin expression is up-regulated by acute hypobaric hypoxia in the cerebral cortex of the adult rat

Hypobaric hypoxia can produce neuropsychological disorders such as insomnia, dizziness, memory deficiencies, headache and nausea. Here we report the changes in adrenomedullin (AM) expression observed in rats exposed to hypobaric hypoxia and different times of reoxygenation. AM immunoreactivity was transiently elevated in the cerebral cortex after 7 h of exposure to a simulated altitude of 8325 m (27 000 ft). This higher expression was seen in all pyramidal cells and in a subset of small interneurons. AM-positive nonpyramidal neurons contained also calbindin and calretinin, but no parvalbumin immunoreactivity, thus identifying them as bipolar and double bouquet cells. Small blood vessels and related astroglia also became immunoreactive following the hypobaric insult. AM up-regulation decreased progressively with the time of reoxygenation, reaching almost control levels after 5 days. Real-time PCR quantification of AM mRNA and Western blotting confirmed the up-regulation of AM expression following hypobaria. In addition, hypobaria modulates alternative splicing of the AM gene resulting in a higher production of AM. Our data show that AM expression regulation constitutes a cortical response to hypobaria, suggesting that AM modulation may provide new therapeutic avenues to prevent and/or treat the symptoms produced by hypobaria.     

急、慢性高原缺氧对成年大鼠空间学习和记忆功能的影响

 目的： 探讨急性和慢性高原缺氧对成年大鼠空间学习和记忆功能的影响。方法： 研究分三部分。实验一：成年雄性SD大鼠分为平原组（A组）和急性高原缺氧组（B组）（n=15）,B组于低压舱模拟海拔7 000 m高原连续暴露72 h后返回平原,24 h后两组同时进行Morris水迷宫定位巡航实验,连续训练3 d,每天4次,记录大鼠寻找平台的时间,第4天撤除平台,进行空间探索实验并记录大鼠穿越平台的次数和在目标象限停留的时间。实验二：成年雄性SD大鼠分为平原组（C组）和慢性高原缺氧组（D组）（n=13）,D组置于低压舱模拟海拔6 000 m高原连续暴露35 d后返回平原,24 h后两组同时进行Morris水迷宫定位巡航实验,连续训练5 d,每天4次,第6天进行空间探索实验。实验三：成年雄性SD大鼠先进行Morris水迷宫定位巡航实验和空间探索实验(方法同实验二）,于空间探索实验后随机分为平原组（E组）和急性高原缺氧组（F组）（n=15）,F组于低压舱模拟海拔7 000 m高原连续暴露72 h后返回平原,2 h后两组再同时进行空间探索实验。结果： B组缺氧暴露后第1天寻找平台的时间较A组显著缩短（P<0.05）,B组穿越平台次数和在目标象限停留时间百分比与A组比较差异无统计学意义。D组寻找平台潜伏期时间、穿越平台次数及在目标象限停留时间的百分比与C组相比,差异均无统计学意义。F组与E组缺氧前的各项指标均无显著差异,缺氧暴露后,F组穿越平台次数和在目标象限停留时间的百分比与E组相比差异无统计学意义。结论： 在本实验观察期内,急、慢性模拟高原缺氧对成年雄性大鼠对空间位置觉和方向觉（空间定位）的学习和记忆能力无显著影响（P>0.05）。急、慢性高原缺氧对工作记忆和空间参考记忆等功能的影响有待进一步研究。     

Impairment of spermatogenesis in male rats during stress

Stress is followed by severe disturbances in maturation of male gametes in the testicles, which concerns all populations of cells in the spermatogenic epithelium and modulates the function of endocrine cells (Leydig cells). The observed changes result in reproductive dysfunction of male albino rats. __________ Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 145, No. 6, pp. 645–647, June, 2008     

低压低氧对大鼠下丘脑Orexin A表达及舌下神经放电的影响

目的:观察慢性间歇性低压低氧(chronic intermittent hypobaric hypoxia,CIHH)模型大鼠下丘脑OrexinA表达及舌下神经放电活动,探讨CIHH对呼吸活动调节的机制。方法:对正常成年雄性SD大鼠进行每天6 h的低压低氧处理,28 d后进行血气分析,采用免疫组织化学染色方法观察大鼠下丘脑Orexin A的表达,记录舌下神经放电作为观察呼吸活动的指标。结果:血气分析显示模型组大鼠的PO2下降,PCO2明显升高(P<0.05,n=6);模型组大鼠下丘脑Orexin A免疫阳性神经元的相对光密度值显著升高(P<0.01,n=5);舌下神经放电幅度积分面积减小(P<0.01,n=6),呼吸频率降低(P<0.05,n=6)。结论:CIHH使大鼠动脉血PO2下降、PCO2明显升高,舌下神经放电活动减弱。下丘脑Orexin A神经元表达的增加提示Orexin的确参与了对呼吸活动的调节,尤其在CIHH时发挥了重要作用。     

Effects of acute hypobaric hypoxia on the nitric oxide system of the rat cerebral cortex: Protective role of nitric oxide inhibitors

Exposure to hypobaric hypoxia produces neuropsychological disorders. The brain nitrergic system was investigated following hypobaric hypoxia in the presence or absence of nitric oxide synthase (NOS) inhibitors. Adult rats were exposed to a simulated altitude of 8325 m (27,000 ft) for 7 h and killed after 0, 1, 3, 5, and 10 days of recovery. In addition to normobaric controls, three experimental groups were studied: i) subjected to hypobaric hypoxia without inhibitors; ii) subjected to hypobaric hypoxia and treated with 7-nitroindazole; iii) subjected to hypobaric hypoxia and treated with N(omega)-nitro-l-arginine methyl ester (l-NAME). Cerebral cortex was assayed by immunohistochemistry, Western blotting, and enzymatic assays. In animals subjected to hypobaric hypoxia without inhibitors, there was an increase in neuronal nitric oxide synthase (nNOS) immunoreactivity and Ca(2+)-dependent NOS activity from 0 to 1 days of reoxygenation. In these animals, inducible nitric oxide synthase (iNOS) expression and Ca(2+)-independent activity were undetectable, but nitrotyrosine immunoreactivity was found in some neurons. Administration of either inhibitor prevented the increase in nNOS immunoreactivity and enzymatic activity provoked by hypobaric hypoxia. Concomitantly, nitrotyrosine immunoreactivity decreased progressively. In conclusion, activation of the nitrergic system constitutes a cortical response to hypobaric hypoxia and the administration of NOS inhibitors could provide new therapeutic avenues to prevent and/or treat the symptoms produced by hypobaric hypoxia.     

Preconditioning hypobaric hypoxia prevents anoxia-induced inhibition of generation of focal potentials in slices of olfactory cortex from rat brain

We studied the effect of in vivo exposure to hypobaric hypoxia of different depth on the resistance of neurons in brain slices to 10-min anoxia in vitro. Severe hypoxia simulating ascent to 11,000 m above sea level potentiated the adverse effect of 10-min anoxia and caused profound suppression of synaptic transmission. Moderate preconditioning hypoxia simulating ascent to 5000 m above sea level produced a long-lasting protective effect on synaptic activity.