低氧暴露下高原鼠兔血液中三种内源性气体分子含量的变化

内源性NO和CO以及H2S是目前发现的三种气体信号分子,在血管收缩调节和血管重构反应中发挥重要作用,影响肺血管收缩反应(HPV).本实验模拟5 000 m海拔高度,对高原鼠兔(Ochotona curzoniae)和SD大鼠进行不同时间的低氧处理,分别测定平均肺动脉压、右心指数和血液中内源性NO和CO以及H2S的浓度,以揭示三种气体分子在高原鼠兔低氧适应中的作用.研究结果显示:(1)随着低氧时间的增加,高原鼠兔肺动脉压没有出现显著性差异(P＞0.05),右心指数并未出现显著性变化(P＞0.05);SD大鼠肺动脉压在低氧7 d时出现极显著性增加(P＜0.01),并且随着低氧时间的增加肺动脉压持续升高,右心指数出现极显著性增加(P＜0.01);(2)高原鼠兔和SD大鼠血液中CO的水平在各处理间维持相对稳定(P＞0.05).高原鼠兔在低氧7 d时血液中NO浓度出现极显著性增加(P＜0.01),低氧21 d时NO浓度又恢复到正常水平(P＞0.05);SD大鼠在低氧1 d时血液中NO浓度出现显著性降低(P＜0.05),低氧7 d和21 d时NO浓度又恢复到正常水平(P＞0.05).高原鼠兔在低氧1 d时血液中H2S浓度无显著性差异(P＞0.05),低氧7d和21 dH2S浓度出现极显著性增加(P＜0.01);SD大鼠在低氧1 d时血液中H2S浓度出现极显著性增加(P＜0.01),低氧7 d、21 dH2S浓度与正常水平相比显著性降低(P＜0.05).结果表明,高原鼠兔提高血液中H2S的水平可能对其维持正常的肺动脉压和氧气传输具有重要作用.     

高原鼢鼠和高原鼠兔心脏对低氧环境的适应

为了探讨高原鼢鼠和高原鼠兔心脏对低氧环境的适应机制,以Sprague-Dawley (SD)大鼠为对照,测量三者的心脏/体重比(HW/BW)、右心室/(左心室 室间隔)重量比[RV/(LV S)];应用免疫组织化学方法测定心肌微血管密度(microvessel density, MVD);通过显微体视学技术比较线粒体的面数密度(NA,单位面积中线粒体数目)、体密度(Vv,单位体积心肌纤维中线粒体的体积密度)、面密度(Sv,单位体积心肌纤维中线粒体外膜的面积密度)、比表面(δ,线粒体外膜面积与其自身体积的比);用分光光度法测定心肌中的肌红蛋白(myoglobin, Mb)含量、乳酸(lactic acid, LD)含量和乳酸脱氢酶(lactate dehydrogenase, LDH)活力;聚丙烯酰胺凝胶电泳观察LDH同工酶谱.结果显示:高原鼢鼠和高原鼠兔HB/WB显著大于SD大鼠(P<0.05), RV/(LV S)显著小于SD大鼠(P<0.05).高原鼢鼠、高原鼠兔和SD大鼠心肌MVD和线粒体NA依次递减(P<0.05);高原鼢鼠线粒体Vv显著低于高原鼠兔和SD大鼠(P<0.05),高原鼠兔与SD大鼠之间没有明显差异;高原鼢鼠线粒体Sv显著高于SD大鼠(P<0.05),与高原鼠兔相比无明显差异;高原鼠兔和SD大鼠的线粒体δ无显著差异,但均明显低于高原鼢鼠(P<0.05).高原鼢鼠和高原鼠兔心肌Mb含量显著高于SD大鼠(P<0.05);高原鼢鼠心肌LD含量显著高于高原鼠兔和SD大鼠(P<0.05);两种高原动物心肌LDH活力显著低于SD大鼠(P<0.05).同工酶谱显示,高原鼢鼠、高原鼠兔和SD大鼠的LDH中H亚基所占比例依次递减.以上结果提示,高原鼢鼠和高原鼠兔通过增加心肌线粒体Sv、MVD以及Mb含量提高其在低氧环境获取氧的能力;同时,由于生境和习性上的不同,两者线粒体指标又表现出差异性.     

低氧暴露条件下高原鼠兔和大鼠HPA轴活动的比较

采用人工模拟低气压低氧的方法比较研究了不同程度（模拟海拔5 km和7 km)和不同时间（24d和5d）低氧暴露,对大鼠和高原鼠兔（Ochotona curzoniae）下丘脑-垂体-肾上腺皮质 (hypothalamo-pituitary-adrenalcortex,HPA)轴活动的影响。结果如下：7 km低氧暴露24 h,大鼠下丘脑的促肾上腺皮质激素释放激素（corticotropin-releasing actor,CRF）和肾上腺皮质激素皮质酮分泌显著增加,大鼠HPA低氧暴露对大鼠HPA 轴活动无显著差异。低氧暴露5天后,大鼠7 km、5 km组的HPA轴活动与对照相比无明显差异。低氧暴露对高原鼠兔的HPA轴无明显影响。上述结果表明：低氧暴露的时间和程度与大鼠HPA的活动密切相关;从HPA的活动来看,高原鼠兔表现出较强的低氧耐受性。     

高原鼢鼠、鼠兔及大鼠心肌和骨骼肌乳酸脱氢酶活力及同工酶谱

为了探讨高原鼢鼠和鼠兔的低氧适应机理,用紫外分光光度法测定了高原鼢鼠、鼠兔及大鼠心肌和骨骼肌乳酸脱氢酶(Lactate Dehydrogenase,LDH)的活力,通过聚丙烯酰胺凝胶电泳分离了LDH同工酶.结果显示:鼢鼠、鼠兔、大鼠心肌LDH活力分别为16.90±2.00 U/mg pro,20.55±2.46 U/mg pro,38.26±6.78 U/mg pm,鼢鼠和鼠兔差异不显著(P>0.05),大鼠与鼠兔差异显著(P<0.05),大鼠与鼢鼠差异极显著(P<0.01);骨骼肌LDH活力,鼢鼠、鼠兔、大鼠分别为39.34±3.74 U/mg pro,78.33±9.54 U/mg pro,67.80±10.89 u/mg pr0,大鼠和鼠兔差异不显著(P>0.05),二者均极显著高于鼢鼠(P<0.01).高原鼠兔与鼢鼠LDH同工酶M亚基的迁移率较为相近,而H亚基差别较大;鼢鼠和大鼠H亚基的迁移率较为相近,而M亚基差别较大.鼢鼠和鼠兔心肌LDH同工酶亚基组成以H亚基为主,M亚基含量较低,而骨骼肌LDH同工酶亚基组成以M业基为主,H业基含量较低.大鼠心肌和骨骼肌LDH同工酶H亚基和M亚基含量均很丰富.说明高原鼢鼠和鼠兔虽然生活在极其缺氧的环境中,但它们的组织并不缺氧;高原鼢鼠和鼠兔以不同的策略适应高原缺氧.     

血管活性物质对大鼠低氧性肺血管结构重建作用的研究

目的：探讨内皮素-1（ET-1）、血管内皮生长因子（VEGF）在低氧性肺血管结构重建中的调节作用。方法：将2260m处的Wistar大鼠带到3417m的高度饲养24h,2周、3周后进行实验并和在当地捕捉到的高原鼠兔进行比较。取血,测定血液中的ET-1、VEGF的含量,然后取肺组织固定切片染色,40倍光镜下计数整个切片内的肺泡水平位上直径小于100μm的肌性动脉（AM）、部分肌性动脉（PAM）和非肌性动脉（NMA）的数目,分别计算它们各占肺小血管总数的百分比。左右心室室间隔分别称重．计算右室／左室＋室间隔。结果：高原鼠兔与缺氧不同时间大鼠VEGF及ET-1经组间方差分析均有显著差异（P〈0．01,随着缺氧时间的延长,大鼠MA及PMA的比例增加,NMA减少,RV／LV＋S逐渐增加（和高原鼠免比P〈0．01）,经组间方差分析亦有显著差异（P〈0．01）。结论：低氧环境下VEGF及ET-1共同参与了肺小血管的肌化过程,在低氧性肺动脉高压的发生发展中起到了重要作用,但在高原鼠兔体内仅具有维持组织器官发育和维持其正常功能的作用。     

高原鼢鼠和高原鼠兔肺细叶的结构特征

高原鼢鼠和高原鼠兔是青藏高原土著动物,对低氧具有很好的适应性.为了探讨在低氧环境中两者肺细叶结构的适应特征,应用体视学方法测量了肺细叶相关指标.结果发现 :高原鼢鼠和高原鼠兔肺单位面积肺泡数显著高于SD大鼠,单个肺泡面积和弹性纤维/肺实质比显著低于SD大鼠;高原鼢鼠肺泡隔厚度最厚,高原鼠兔最薄,且三种动物具显著差异; 高原鼢鼠和高原鼠兔气-血屏障的算术平均厚度(Ta)和调和平均厚度(Th) 均显著低于SD 大鼠;在三个级别的微血管中,高原鼠兔中膜肌层厚度显著低于高原鼢鼠,两种高原动物均显著低于SD大鼠;高原鼢鼠和高原鼠兔的微血管密度(MVD)显著高于SD大鼠.以上结果表明,高原鼢鼠和高原鼠兔肺细叶结构特征表现出一定趋同,这些特征有利于在低氧条件下提高肺气体扩散容量;但是,肺泡隔厚度和微血管中膜肌层厚度/血管外径比又表现出明显的差异,可能是不同生境造成的[动物学报 54(3):531-539,2008].     

高原鼢鼠和高原鼠兔红细胞低氧适应特征

为探讨高原鼢鼠对低氧高二氧化碳洞道生境及高原鼠兔对高海拔低氧生境的适应机制,用Sysmex SF-3000血细胞分析仪及聚丙烯酰胺凝胶电泳对两种高原动物的血常规及血红蛋白类型进行分析,后者采用聚丙烯酰胺凝胶电泳法。结果表明,高原鼢鼠和高原鼠兔的红细胞数(RBC)、红细胞压积(HCT)及平均红细胞容积(MCV)组间无显著差异(P>0.05),但高原鼢鼠和高原鼠兔的红细胞数显著高于SD大鼠,红细胞压积及平均红细胞容积均显著低于SD大鼠(P<0.05);高原鼢鼠的血红蛋白浓度(HBC)与SD大鼠无显著差异(P>0.05),但显著高于高原鼠兔的HBC(P<0.05)。高原鼢鼠血红蛋白主要有2种类型,高原鼠兔血红蛋白主要有3种类型,而SD大鼠血红蛋白主要有5种类型。从血红蛋白电泳迁移来看,2种高原动物血红蛋白类型有明显的趋同特征并与SD大鼠具有明显的差异。上述结果提示,长期适应高海拔低氧环境的高原动物的红细胞和血红蛋白表现出趋同进化,同时因生境和习性的差异又表现出各自的特异性。     

低氧对动物组织糖原含量和血糖水平的影响

比较不同年龄组大鼠和高原鼠兔(Ochotona curzoniae)的心肌、骨骼肌和脑皮层组织的糖原含量,以及血糖浓度在模拟高原低氧的变化,发现急性高原低氧暴露24小时,老年组大鼠心肌、骨骼肌糖原含量在海拨8000米高度时有不同程度升高。血糖水平在8000米高度也有明显上升。成年组大鼠心肌、骨骼肌和脑皮层组织糖原含量随海拔升高而增加。慢性低氧暴露25天,大鼠脑组织糖原含量在海拔7000米时略有升高,心肌和骨骼肌糖原含量在海拔7000米时明显升高。低氧暴露7天和48小时,大鼠血糖浓度无明显变化。 高原鼠兔在急性低氧暴露期间,成年组脑糖原含量在海拔5000米和8000米高度时均有明显下降,心肌糖原在8000米高度时明显升高。骨骼肌糖原含量随海拔升高而略有降低。幼年组高原鼠兔脑糖原含量随海拔升高而下降,心肌和骨骼肌糖原在海拔升高时有增加倾向。成年和幼年组鼠兔血糖水平则随海拔上升而升高。     

高原鼢鼠、高原鼠兔和大鼠肺表面活性物质组成和含量的比较

本研究通过分析肺表面活性物质(pulmonary surfactant,PS)组成和含量探讨高原鼢鼠(Myospalax baileyi)和高原鼠兔(Ochotona curzoniae)的低氧适应机制。高原鼢鼠和高原鼠兔各36只,捕捉于海拔3600 m左右的青海省海南州贵德县拉脊山地区,36只Sprague-Dawley(SD)大鼠购自海拔1500 m左右的兰州大学实验动物中心。所有动物麻醉后通过肺循环进行肺灌洗,充分洗净肺组织中的血液,取出完整的肺组织灌洗得到肺泡灌洗液。应用高效液相色谱法分析三种动物PS中磷脂的组成和含量;应用G-250考马斯亮蓝法、聚丙烯酰胺凝胶电泳(PAGE)和质谱测序分析PS蛋白质的含量和种类;应用溶氧电极测定了PS溶液中的溶氧量。结果表明:高原鼢鼠、高原鼠兔和SD大鼠PS中,总磷脂含量依次显著增加(P<0.05),总蛋白含量依次显著减少(P<0.05);三种动物PS中均含有亚油酰棕榈酰胆碱(linoleic palmitoylphosphatidylcholine,LPPC)、二棕榈酰磷脂酰胆碱(dipalmitoylphosphatidylcholine,DPPC)、磷脂酰甘油(phosphatidylglycerol,PG)、磷脂酰肌醇(phosphatidylinositol,PI)和磷脂酰丝氨酸(phosphatidylserine,PSe)等5种磷脂成分,但其相对含量明显不同;在高原鼢鼠、高原鼠兔和SD大鼠中,LPPC所占比例依次显著增加(P<0.01);高原鼢鼠PS磷脂中,DPPC、PG和PI所占比例极显著高于高原鼠兔(P<0.01),高原鼠兔与SD大鼠之间没有显著差异(P>0.05);高原鼢鼠与高原鼠兔PS磷脂中,PSe所占比例没有显著差异(P>0.05),但均极显著高于SD大鼠(P<0.01)。三种动物PS中均含有血清白蛋白(serum albumin,SA),高原鼢鼠和高原鼠兔PS中含有血红蛋白β亚基构成的含血红素的同源四聚体蛋白,高原鼢鼠和SD大鼠PS中含有免疫球蛋白(immunoglobulin,Ig)重链残基,高原鼢鼠Ig重链残基含量极显著高于SD大鼠(P<0.01),含血红素蛋白含量显著高于高原鼠兔(P<0.05)。高原鼢鼠、高原鼠兔和SD大鼠PS溶液中溶氧量依次显著减小(P<0.01),但均显著高于生理盐水(P<0.01)。以上结果提示,高原鼢鼠和高原鼠兔PS中总蛋白含量显著增加,总磷脂含量显著减少,蛋白成分中含有高含量的含血红素同源四聚体蛋白,且高原鼢鼠主要磷脂成分DPPC的相对含量显著增加,这种PS成分和含量的变化增强了这两种高原动物对低氧环境的适应性。     

高原低氧对高原鼠兔和大白鼠肺泡Ⅱ型细胞及表面活性物质超微结构的影响

本文报道高原低氧(海拔3300米)对高原鼠兔、移居高原大鼠、急进高原大鼠的肺泡Ⅱ型细胞及表面活性物质超微结构的影响。发现高原鼠兔肺占体重的百分比低于移居高原大鼠(P>0.05)和急进高原大鼠(P<0.001)。透射电镜和扫描电镜观察,表明急进高原大鼠肺泡Ⅱ型细胞微绒毛减少,线粒体变性肿胀,板层体排空、合成减少。而高原鼠兔未出现上述超微结构改变。移居高原大鼠的微细结构变化介乎于高原鼠兔与急进高原大鼠之间。     

The NO donor molsidomine reduces endothelin-1 gene expression in chronic hypoxic rat lungs

We investigated the effects of the nitric oxide (NO) donor molsidomine and the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) on pulmonary endothelin (ET)-1 gene expression and ET-1 plasma levels in chronic hypoxic rats. Two and four weeks of hypoxia (10% O2) significantly increased right ventricular systolic pressure, the medial cross-sectional vascular wall area of the pulmonary arteries, and pulmonary ET-1 mRNA expression (2-fold and 3.2-fold, respectively). ET-1 plasma levels were elevated after 4 wk of hypoxia. In rats exposed to 4 wk of hypoxia, molsidomine (15 mg x kg(-1) x day(-1)) given either from the beginning or after 2 wk of hypoxia significantly reduced pulmonary hypertension, pulmonary vascular remodeling, pulmonary ET-1 gene expression, and ET-1 plasma levels. L-NAME administration (45 mg x kg(-1) x day(-1)) in rats subjected to 2 wk of hypoxia did not modify these parameters. Our findings suggest that in chronic hypoxic rats, exogenously administered NO acts in part by suppressing the formation of ET-1. In contrast, inhibition of endogenous NO production exerts only minor effects on the pulmonary circulation and pulmonary ET-1 synthesis in these animals.     

Standardization of Nitric Oxide Aqueous Solutions by Modified Saltzman Method

Nitric oxide (NO) aqueous solutions were prepared by saturating pure NO gas and hydrolyzing 1 mM 1-hydroxy-2-oxo-3-(N-methyl-3-aminoethyl)-3-methyl-1-triazene (NOC-7), a NO donor, under anerobic conditions. The modified Saltzman method was employed for standardization of the NO aqueous solutions. NO and NO(2) in the solutions were driven with nitrogen gas stream into the first Saltzman solution to measure NO(2) and the leaked NO was driven with air stream through an oxidizing solution into the second Saltzman solution to measure NO, and NO(-)(2) and NO(-)(3) in the residual solutions were determined directly and after reduction with nitrate reductase, respectively. The concentrations of nitrogen oxide species in the NO solutions were about 1.8 mM NO/0.01 mM NO(2)/0.1 mM NO(-)(2)/0.1 mM NO(-)(3), and unchanged during keeping at 20 degrees C for 1 h under anerobic conditions but became 0.05 mM NO/0.01 mM NO(2)/1.7 mM NO(-)(2)/0.1 mM NO(-)(3) by keeping at 20 degrees C for 10 min under aerobic conditions. Instability of NO under aerobic conditions was supported by consumption of 1/4 equivalent amount of dissolved oxygen, and by loss of ability to convert 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO) to carboxy-PTI. Simultaneous quantification of nitrogen oxide species by the modified Saltzman method was found to be useful for practical standardization of NO aqueous solutions.     

Chronic hypoxia exposure depresses aortic endothelium-dependent vasorelaxation in both sedentary and trained rats: involvement of L-arginine.

This study was designed to test the hypothesis that the previously demonstrated training-induced improvement of the endothelium vasodilator function would be blunted under conditions of chronic hypoxia exposure as a result of deleterious effects of hypoxia per se on the nitric oxide pathway. Sea-level-native rats were randomly assigned to N (living in normoxia), NT (living and training 5 days/wk for 5 wk in normoxia), CH (living in hypoxia, 2,800 m), and CHT (living and training 5 days/wk for 5 wk in hypoxia, 2,800 m) groups. Concentration-response curves to acetylcholine (ACh; 10(-9) to 10(-4) M) with or without L-arginine (10(-3) to 10(-5) M) and/or nitro-L-arginine methyl ester (10(-5) M) were assessed on aortic isolated rings. The main finding was that chronic hypoxia severely depressed maximal ACh-responses of aortic rings in both sedentary and trained groups. However, chronic hypoxia did not interfere with training-induced increases in maximal ACh responses, considering that maximal ACh vasorelaxation was improved in CHT rats to the same extent as in NT rats when both groups were directly compared with their sedentary counterparts. It should be pointed out that the vasodilator response to ACh was restored in CH and CHT rats to the level obtained in N and NT rats, respectively, by an in vitro L-arginine addition. A hypoxia-induced decrease in L-arginine bioavailability resulting from acclimatization at altitude may be involved in this limitation of the NO pathway in CH and CHT rats. These results are of importance for aerobic performance as the specific vascular adaptations to training at altitude could contribute to limit peripheral vasodilatation and subsequently blood flow during exercise.     

幽门螺杆菌感染与胃癌中p21和p27表达的关系

探讨胃癌中p21~(WAF1)和p27~(KIP1)的表达及其临床意义,并分析幽门螺杆菌(Hp)感染和p21~(WAF1)、p27~(KIP1)表达的关系。采用免疫组化法检测了89例胃癌组织中p21~(WAF1)和p27~(KIP1)表达水平,并采用快速尿素酶试验和组织病理学检测两种方法检查这些胃癌病例的Hp感染情况。实验结果显示,胃癌组织p21~(WAF1)的表达水平在不同病例组织中有所差异。结合临床病理学指数分析显示,降低的p21~(WAF1)表达与较深的肿瘤侵袭密切相关(P<0.05)。免疫组织化学结果显示,p27~(KIP1)无论在细胞浆中还是细胞核内都有表达,p27~(KIP1)核表达水平与胃癌的组织病理学分型密切相关(P<0.05)。此外,还发现Hp阳性病例的p27~(KIP1)阳性表达率明显低于Hp阴性者(P<0.05),而p21~(WAF1)表达阳性率在Hp阳性和阴性胃癌病例中无显著差异(P>0.05)。结果提示,胃癌的进展与细胞周期调节蛋白p21~(WAF1)和p27~(KIP1)的表达下调有关,Hp感染的致癌过程中可能有p27~(KIP1)参与。     

模拟海拔5 500 m低压低氧环境对大鼠HPT轴和肠道菌群的影响*

目的: 探究模拟海拔5 500 m低压低氧环境对大鼠下丘脑-垂体-甲状腺(HPT)轴和肠道菌群的影响及两者间关联。方法: 采用低压低氧舱模拟海拔5 500 m高度,构建成年雄性SD大鼠低氧模型,设置1、3、7、14、21和28 d低氧组和常氧组,并设置1 d和3 d低氧后常氧恢复组(每组大鼠8只,低氧时间为每天24 h)。记录大鼠每日体重和平均摄食量,采用16 s rDNA测序分析肠道菌群、ELISA检测血清HPT轴激素水平,进行肠道菌群与HPT轴激素相关性分析。结果: 与常氧组相比,低氧组大鼠体重和摄食量显著降低(P＜0.01)。1 d、3 d低氧组大鼠血清促甲状腺素释放激素(TRH)和促甲状腺激素(TSH)水平较常氧组显著降低(P＜0.05),血清总甲状腺素(TT4)、总三碘甲状腺原氨酸(TT3)、游离甲状腺素(FT4)和游离三碘甲状腺原氨酸(FT3)水平较常氧组显著增加(P＜0.05)。1和3 d低氧组大鼠肠道副拟杆菌属(Parabacteroides)、乳酸杆菌属(Lactobacillus)、丁酸球菌属(Butyricimonas)、拟杆菌属(Bacteroides)、臭味杆菌属(Odoribacter)和RC4-4菌属丰度较常氧组显著增加(P＜0.05),普氏菌属(Prevotella)丰度较常氧组显著降低(P＜0.05)。14、21和28 d低氧组大鼠副拟杆菌属、球毛菌属(Sphaerochaeta)、阿克曼氏菌属(Akkermansia)、迷踪菌属(Elusimicrobium)丰度较常氧组显著增加(P＜0.05),乳酸杆菌属、萨特氏菌属(Sutterella)丰度较常氧组显著降低(P＜0.05)。肠道菌群与HPT轴激素相关性分析表明,丁酸球菌属、迷踪菌属、萨特氏菌属与TRH、TSH显著负相关(P＜0.05),普氏菌属、拟杆菌属、臭味杆菌属、副拟杆菌属分别与TSH、TT4、TT3、FT4显著相关(P＜0.05),乳酸杆菌属与TRH、 TSH、FT4显著相关(P＜0.05),阿克曼氏菌属与TRH、FT4显著相关(P＜ 0.05),RC4-4菌属与TSH、TT3显著相关(P＜0.05)。结论: 模拟海拔5 500 m低氧应激显著改变SD大鼠肠道菌群的构成,这可能是甲状腺功能与低氧环境相适应的变化,变化程度与低氧应激时间有关;低氧环境下大鼠肠道菌群的变化与HPT轴激素水平显著相关。     

Adult carotid chemoafferent responses to hypoxia after 1, 2, and 4 wk of postnatal hyperoxia.

Exposing newborn rats to postnatal hyperoxia (60% O2) for 1-4 wk attenuates the ventilatory and phrenic nerve responses to acute hypoxia in adult rats. The goal of this research was to increase our understanding of the carotid chemoreceptor afferent neural input in this depressed response with different durations of postnatal hyperoxic exposure. Rats were exposed from a few days before birth to 1, 2, or 4 wk of 60% O2 and studied after 3-5 mo in normoxia. The rats were anesthetized with urethane. Whole carotid sinus nerve (CSN) responses to NaCN (40 microg/kg iv), 10 s of asphyxia and acute isocapnic hypoxia (arterial Po2 45 Torr) were determined. Mean CSN responses to stimuli after postnatal hyperoxia were reduced compared with controls. Responses in rats exposed to 1 wk of postnatal hyperoxia were less affected than those exposed to 2 and 4 wk of hyperoxia, which were equivalent to each other. These studies illustrate the importance of normoxia during the first 2 wk of life in development of carotid chemoreceptor afferent function.     

一氧化氮/内皮素在大鼠胃粘膜损伤中的作用及电针的调整效应

用酒精灌胃引起大鼠胃粘膜损伤模型,观察内皮衍生因子（ＮＯ／ＥＴ）的含量变化和电针对胃粘膜损伤调整作用,结果发现：酒精灌胃后,胃粘膜血流量（ＧＭＢＦ）、跨壁电位差,血ＮＯ含量降低（Ｐ〈０．０１）,血浆ＥＴ含量和胃粘膜损伤指数（ＬＩ）增高（Ｐ〈０．０１）。Ｌ－精氨酸（Ｌ－Ａｒｇ）或硝普钠（ＳＮＰ）灌注预处理后（ｉｖ）,ＮＯ含量和ＧＭＢＦ明显升高（Ｐ〈０．０１）,ＥＴ含量和ＬＩ指数下降（Ｐ〈０．０１）。     

Exogenous nitric oxide inhibits IRS-1 expression in rat hepatocytes and skeletal myocytes

Summary Accumulative evidence has supported the role of nitric oxide (NO) in a variety of normal physiological functions as well as many pathological conditions. In this study, we examined the possible diabetogenicity of NO by measuring the expression of the insulin receptor substrate (IRS)-1 in rat hepatocytes and skeletal myocytes. IRS-1 is important in the insulin-mediated signal transduction pathway in both liver and skeletal muscle. Exogenous NO donated by S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathione (GSNO) resulted in significant reduction in levels of IRS-1 in both cells, when compared to the insulin-stimulated control (p<0.001). Reversal to near normal levels was achieved using the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (carboxy-PTIO). SNAP was the more potent drug, and the skeletal myocytes were the more sensitive cells to the inhibitory effects of NO released from the drugs. These results provide further evidence that exogenous NO is a potent modulator of insulin-mediated signal transduction and may play a significant role in the pathogenesis of type 2 diabetes mellitus.     

Hypoxia enhances gene expression of inducible nitric oxide synthase and matrix metalloproteinase-9 in ras/myc-transformed serum-free mouse embryo cells under simulated inflammatory and infectious conditions

Ras/myc-transformed serum-free mouse embryo (ras/myc SFME) cells were treated with interferon-gamma (IFN-gamma; 100 U/ml) and/or lipopolysaccharide (LPS; 0.5 microg/ml) for 24 h to simulate inflammatory and infectious conditions and investigate their effects on the expression of inducible nitric oxide synthase (iNOS) mRNA, nitric oxide (NO) and matrix metalloproteinase-9 (MMP-9). In addition, aminoguanidine (AG; 1 mM), a NOS inhibitor, S-nitroso-N-acetyl-DL-penicillamine (SNAP; 10-200 microM), an NO donor or (+/-)-N-[(E)-4-ethyl-2-[(Z)-hydroxyimino]-5-nitro-3-hexene-1-yl]-3-pyridine carboxamide (NOR4; 10-200 microM), an NO donor, were added to analyze possible associations of NO with MMP-9. Tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 were also measured to analyze possible relationships of NO with the MMP-9/TIMP balance. Furthermore, the cells were treated with 1% O2 under the simulated inflammatory and infectious conditions and the mRNA expressions of iNOS and MMP-9 were analyzed to investigate the possible effects of hypoxia on the expression of genes involved in tumor malignant progression and distant metastasis. Co-treatment with IFN-gamma and LPS increased the expression levels of iNOS mRNA, NO and MMP-9, but NO may not be directly associated with MMP-9 or the MMP-9/TIMP balance. Treatment with 1% O2 markedly increased the gene expression levels of iNOS and MMP-9, indicating that ras/myc SFME cells alter the expression levels of tumor-associated genes and possibly enhance their malignancy as cancer cells under inflammatory, infectious and hypoxic conditions.