高肺血流所致肺血管结构重建时内源性一氧化氮体系的研究

目的　探讨高肺血流所致肺血管结构重建时内源性一氧化氮 (NO)体系的变化。方法对大鼠行腹主动脉 下腔静脉分流术。 11周后以右心导管法测定肺动脉平均压 (mPAP) ,检测右心室 /左心室 +室间隔 [RV/(LV +S) ]的比值。观测肺血管显微及超微结构的变化 ,并且以分光光度计测定血浆NO含量 ,分别以原位杂交和免疫组织化学的方法检测肺动脉内皮型NO合酶 (eNOS)mRNA和蛋白的表达。结果　分流组大鼠mPAP明显高于对照组 [分别为 (2 2 5± 2 6)mmHg、(15 8± 2 8)mmHg,1mmHg =0 13 3kPa ,P <0 0 1],RV/(LV +S)比值也明显增加。光镜下 ,肺小血管肌化程度明显增强 ,肺中、小型肌型动脉相对中膜厚度明显增加。电镜下 ,肺腺泡内动脉内皮细胞增生、变性 ,内弹力层粗细不均 ,平滑肌细胞肥厚、向合成表型转化。并且分流组大鼠血浆NO含量明显高于对照组 [分别 (为3 0 2± 7 9) μmol/L、(19 7± 5 7) μmol/L ,P <0 0 1],肺动脉eNOSmRNA和蛋白表达均明显增强。 结论　NO体系 eNOSmRNA表达、eNOS蛋白表达及血浆NO含量上调在高肺血流所致肺动脉高压和肺血管结构重建的形成中起重要的调节作用     

出生后长期缺锌对大鼠生长发育及生长激素的影响

目的 研究出生后长期缺锌对大鼠生长发育的影响及其机制。方法 选取刚出生的SD大鼠3窝,每窝1只母鼠、10只仔鼠,3窝母鼠与仔鼠体重相近,仔鼠雌雄各半。随机分为3组,缺锌组（ZD）、配饲组（PF）、对照组（ZA）。实验期60 d。测定大鼠身长、股骨长度、直径、重量,血清生长激素（GH）含量。结果 ZD组身长[（16.15&#177;0.67）cm]明显低于PF组[（20.94&#177;0.98）cm]及ZA组[（23.08&#177;0.11）cm]（P〈0.01）;ZD组股骨长度[（2.61&#177;0.22）cm]明显低于PF组[（3.38&#177;0.10）cm]及ZA组[（3.54&#177;0.08）cm]（P〈0.01）;ZD组股骨直径[（0.30&#177;0.03）cm]明显低于PF组[（0.37&#177;0.33）cm]及ZA组[（0.42&#177;0.01）cm]（P〈0.01）;ZD组股骨重量[（0.65&#177;0.10）g]明显低于PF组[（1.07&#177;0.07）g]及ZA组[（1.28&#177;0.08）g]（P〈0.01）;ZD组血清生长激素水平[（0.47&#177;0.04）ng/ml]明显低于PF组[（0.66&#177;0.11）ng/ml]及ZA组[（0.75&#177;0.07）ng/ml]（P〈0.01）。结论 出生后长期缺锌可导致动物体内生长激素水平下降,是导致生长迟缓的原因之一。     

内源性一氧化氮调节大鼠低氧性肺血管结构的重建

目的 研究内源性一氧化氮对低氧性肺血管结构重建形成的调节作用。方法 大鼠随机分为４组;常氧组（ｎ＝８）、低氧组（ｎ＝８）、低氧＋Ｌ－精氨酸（Ｌ－Ａｒｇ）组（ｎ＝８）、低氧＋Ｎ＾ω－硝基－Ｌ－精氨酸甲酯（Ｌ－ＮＡＭＥ组）９ｎ＝６）。以光镜观测各组大鼠肺中、小肌型动脉的相对中膜厚度（ＲＭＴ）及相对中膜面积（ＲＭＡ）和三型肺小血管百分比。结果 低氧组大鼠肺中、小型动脉ＲＭＴ及ＲＭＡ和肺小血管肌型动脉百分     

Two cases suggesting a role for the L–arginine nitric oxide pathway in neonatal blood pressure regulation

Endogenous nitric oxide produced from L–arginine is a potent vasodilator that may be involved in blood pressure regulation. A male infant with argininosuccinate lyase deficiency, who could not synthesize L–arginine, was hypertensive prior to L–arginine replacement. The infusion of L–arginine resulted in a decrease in blood pressure. A three–fold increase in the dose of L–arginine further decreased blood pressure. On discontinuing the infusion of L–arginine, the patient's blood pressure increased. A female infant undergoing an L–arginine challenge test had a decrease in blood pressure during L–arginine infusion which resolved when the L–arginine infusion was discontinued. These two cases suggest that nitric oxide production from L–arginine may play a role in the normal regulation of systemic blood pressure.     

The influence of L-arginine on blood pressure, vascular nitric oxide and renal morphometry in the offspring from diabetic mothers

The present study was designed to evaluate the effects of L-arginine (L-arg) supplementation on blood pressure, vascular nitric oxide content, and renal morphometry in the adult offspring from diabetic mothers. Diabetes mellitus was induced in female rats with a single dose of streptozotocin (50 mg/kg), before mating. The offspring was divided into four groups: group C (controls); group DO (diabetic offspring); group CA (controls receiving 2% L-arg solution dissolved in 2% sucrose in the drinking water) and group DA (DO receiving the L-arg solution). Oral supplementation began after weaning and continued until the end of the experiments. In DO, hypertension was observed, from 3 mo on. In DA, pressure levels were not different from C and CA. In 6-mo-old animals, basal NO production (assessed by DAF-2) was significantly depressed in DO in comparison to controls. The NO production was significantly increased after stimulation with Ach or BK in all groups, the increase being greater in control than in DO rats. L-arg was able to improve the NO production and to prevent the glomerular hypertrophy in the DO. Our data suggest that the bioavailability of NO is reduced in the DO, because L-arg corrected both the hypertension and glomerular hypertrophy.     

一氧化氮的血管调节研究进展

20世纪80年代中期,气体信号分子NO引起科学界的广泛关注,被《Science》杂志评为“20世纪90年代的明星分子”.气体信号分子作为一个全新的概念出现在科学研究的各个领域,开创了科学研究的新局面.NO是体内的一种重要生理功能调节物质,在心血管系统中,NO可调节血管张力,调节血压,抑制血管平滑肌增生等.NO在高血压、动脉粥样硬化、高胆固醇血症、肺动脉高压的发病机制中具有重要病理生理学意义.     

Role of nitric oxide and cyclooxygenase pathway in lipopolysaccharide-induced intussusception

The etiology of intussusception (IN) remains largely obscure. In lipopolysaccharide (LPS)-induced IN, an experimental model in mice, IN is considered to be the consequence of altered intestinal motility as a result of increased nitric oxide (NO) along various inflammatory mediators. These could be decreased via cyclooxygenase (COX) inhibition by indomethacin. N--nitro-L-arginine methyl ester (L-NAME) inhibits nitric oxide synthase (NOS) and NO production. Indomethacin is known to prevent IN; however, the reason is unknown. In this study we aimed to determine the role of NO, the effects of inhibition of its production by L-NAME and indomethacin, and whether preventive effects of indomethacin on LPS-induced IN were related to NO inhibition. A total of 113 mice were divided into seven groups. In the control group (n=6), no procedure was done. In the sham group (n=6), 1 ml saline was given; in the indomethacin group (n=6), 10 mg/kg of indomethacin was given; and in the LPS group (n=30), 12 mg/kg of LPS was administered intraperitoneally (IP). In the LPS+indomethacin group (n=32), 10 mg/kg of indomethacin was administered IP simultaneously with 12 mg/kg of LPS. In the L-NAME group (n=6), 20 mg/kg of L-NAME was administered subcutaneously. In LPS+L-NAME group (n=27), 20 mg/kg of L-NAME was administered subcutaneously with 12 mg/kg of LPS IP. All animals were laparotomized 6 h following injections. Existence of IN was noted and blood specimens were obtained. NO was quantified by measurements of nitrite and nitrate, obtaining a total of NO metabolites (NOx). The results were compared using the Mann–Whitney U-test and Spearman correlation test. A value of p<0.05 was considered significant. A total of 17 mice (one in control, 10 in LPS, four in LPS+indomethacin, and two in LPS+L-NAME groups) were excluded from the study because of death or insufficient blood collection. LPS (12 mg/kg, IP) induced IN at a rate of 30% (n=6) in the LPS group. Mean NOx levels were statistically higher in the LPS group (186.67±20.06) compared with other groups (p<0.05). Mean NOx levels were significantly higher in the group of mice with IN than in those without in the LPS group of this study (295.46±16.42, 140.05±15.44, respectively, p<0.05). The mean NOx levels were statistically lower in the LPS+L-NAME(23.94±3.39) group than the LPS+indomethacin (106.77±24.54) group, with no IN detected in neither of these two groups. Increased NOx levels induced by LPS correlated well with the occurrence of IN, and decreasing these levels via COX inhibition by indomethacin or NOS inhibition by L-NAME totally prevented IN from forming in this study. By these observations, it could be concluded that NO is probably involved in the pathophysiology of IN in this experimental model of LPS-induced IN.     

Maternal and fetal influences on blood pressure.

To study maternal and fetal influences on blood pressure in childhood 405 children aged 4 years who were born and still resident in the Salisbury health district were visited at home for blood pressure and growth measurements. Information on the pregnancy, delivery, and baby was abstracted from the routine obstetric notes. Similar to recent findings in adults, the child's systolic pressure was inversely related to birth weight and positively related to placental weight. Systolic pressure at 4 years increased by 1.2 mm Hg for every SD decrease in the ratio of head circumference to length at birth, and by 1.1 mm Hg for every SD decrease in ponderal index at birth. Mothers whose haemoglobin concentrations fell below 100g/l during pregnancy had children whose systolic pressures were on average 2.9 mm Hg higher than the children of mothers with higher haemoglobin concentrations. Patterns of placental weight, birth weight, head circumference, and length that are associated with high blood pressure in adults are also associated with higher blood pressure in 4 year old children. Identification of the intrauterine influences that lead to these patterns of fetal growth could lead to the primary prevention of hypertension.     

Activation of the L-arginine nitric oxide pathway in severe sepsis

AIMS: To determine in children with sepsis syndrome and septic shock the time course of nitric oxide metabolites: nitrate and nitrite (nitrogen oxides). To determine whether serum concentrations of nitrogen oxides distinguished those children who died from sepsis from those who survived; those who required prolonged inotropic support compared with those who did not; and whether there was any relationship of the levels of nitrogen oxides to markers of tissue perfusion. METHODS: Nitrogen oxides were measured in 30 children with sepsis syndrome or septic shock at admission, 12, 24, and 48 hours. A non-septic control group had serum nitrogen oxides measured at admission. Markers of haemodynamics and tissue perfusion measured were mean arterial pressure, blood lactate, base deficit, gastric intramucosal pH, and deltaCO2 (DCO2: the difference between arterial and gastric intraluminal carbon dioxide tensions). Inotrope doses, number of organ systems failing at 48 hours, and outcome as survival were recorded. RESULTS: Children with sepsis had increased nitrogen oxide concentrations at presentation compared with a group of non-septic controls. Children with organ failure at 48 hours had higher serum nitrogen oxide concentrations than those with sepsis uncomplicated by organ failure at 48 hours. There was no difference in nitrogen oxide when patients were subgrouped according to the receipt of inotropes at 48 hours, and no association with markers of tissue perfusion, or survival. CONCLUSIONS: While this study shows that nitric oxide production is increased in sepsis in children, there was a limited relationship with clinically important markers of illness severity and no relationship to survival.     

Cerebral white matter blood flow and arterial blood pressure in preterm infants

It is generally assumed that one reason why white matter injury is common in preterm infants is the relatively poor vascular supply. Aim: To examine whether blood flow to the white matter is relatively more reduced at low blood pressure than is blood flow to the brain as a whole. Methods: Thirteen normoxic preterm infants had blood flow imaging on 16 occasions with single‐photon emission computed tomography (SPECT) using 99Tc labelled hexa‐methylpropylenamide oxime (HMPAO) as the tracer. Gestational age was 26–32 weeks. Transcutaneous carbon dioxide was between 4.7 and 8.5 kPa and mean arterial blood pressure between 22 and 55 mmHg. Results: There was no statistically significant direct relation between white matter blood flow percentage and any of the variables. Using non‐linear regression, however, assuming a plateau over a certain blood pressure threshold and a positive slope below this threshold, the relation to white matter flow percentage was statistically significant (p = 0.02). The threshold was 29 mmHg (95% confidence limits 26–33). Conclusion: Our analysis supports the concept of periventricular white matter as selectively vulnerable to ischaemia during episodes of low blood pressure.     

早产鼠高氧暴露后肺组织血管内皮生长因子和一氧化氮合酶的动态变化及相互关系

目的：最近研究表明,血管内皮生长因子（VEGF）及内皮型一氧化氮合酶(eNOS)功能的缺失,在支气管肺发育不良（BPD）发病机制中发挥了重要的作用。该文通过动态观察持续中浓度高氧暴露（60％O2）对早产大鼠肺内VGEF蛋白及mRNA和eNOS蛋白及mRNA表达的影响,探讨BPD的发病机制。方法：将21 d 孕早产鼠随机分为高氧暴露组(简称高氧组) 和空气对照组(简称空气组) ,分别置于常压高氧仓中（60％O2）和正常空气中暴露。分别于生后1,4,7,11,14 d每组各处死6只大鼠,留取肺组织标本。苏木精-伊红染色观察病理改变,免疫组化检测VEGF和eNOS蛋白表达,逆转录-聚合酶链反应方法检测VEGF和eNOS mRNA表达。结果：早产鼠高氧暴露4 d后出现肺泡间隔减少,微血管发育异常,间质纤维化,且病变随着高氧暴露时间的延长而加重。高氧组大鼠第4,7天时肺组织VEGF蛋白表达明显低于相应空气对照组(P< 0. 05), VEGF mRNA表达亦显著减少(P< 0. 05)。随着暴露时间的延长,VEGF蛋白和mRNA进行性降低。高氧组大鼠在高氧暴露过程中肺组织eNOS蛋白和mRNA表达亦随着暴露时间的延长而降低。结论：高氧暴露导致早产鼠肺组织VEGF和eNOS表达持续性减少,微血管发育异常和肺泡化受阻。这些由高氧暴露诱导产生的BPD样损害,可能与VEGF和eNOS的表达下调有关,且二者之间存在着密切的联系。［中国当代儿科杂志,2007,9（5）：473-478］     

Role of nitric oxide in hypoxia-induced changes in newborn rats

In order to investigate the role of nitric oxide (NO) in hypoxic tissue damage in newborns, we studied the effects of systemic administration of an inhibitor of NO synthase, N(G)-nitro-L-arginine (L-NNA), and the precursor for the synthesis of NO, L-arginine (L-ARG), on the biochemical and histological changes in brain, heart, lung, liver, kidney, intestine, and skeletal muscle tissues. Four groups of 1-day-old Wistar rat pups were used: control, hypoxic, L-ARG, and L-NNA groups. L-ARG 100 mg/kg or L-NNA 2 mg/kg was administered as a bolus intraperitoneally 1.5 h before hypoxia. Hypoxia increased lipid peroxidation in all tissues except muscle; this increase was prevented by L-NNA and L-ARG in brain, heart, lung, kidney, and liver tissues. L-NNA in intestine and L-ARG in muscle tissue increased lipid peroxidation. The tissue-associated myeloperoxidase activity was decreased in the liver by L-NNA and L-ARG. Histopathological changes in intestines were villous epithelial separation and hyperemia in hypoxic and L-NNA groups which were not observed in control and L-ARG groups. In lungs, pulmonary hemorrhage was observed only in the hypoxic group. These data suggest that NO acts both as a destructive and a protective agent in the pathogenesis of hypoxia-reoxygenation injuries.     

Mean arterial blood pressure and neonatal cerebral lesions.

Computerised continuous measurement of mean arterial blood pressure (MAP) and serial cranial ultrasonography in 33 infants of less than 31 weeks'' gestation showed that a MAP of less than 30 mm Hg for over an hour was significantly associated with severe haemorrhage, ischaemic cerebral lesions, or death within 48 hours. No severe lesions developed with a MAP greater than or equal to mm Hg.     

一氧化氮对缺氧性肺血管结构重建大鼠肺动脉血小板源生长因子表达的影响

目的 探讨一氧化氮对缺氧性肺血管结构重建大鼠肺动脉中血小板源生长因子 （ＰＤＧＦ）表达的影响。方法 将大鼠随机分为４组：常氧组（６只）、低氧组（６只）、低氧＋Ｌ－精氨酸组（低氧＋Ｌ－Ａｒｇ组）（７只）及低氧＋Ｎ＾ω－硝基－Ｌ－精氨酸甲酯组（低氧＋Ｌ－ＮＡＭＥ组）（６只）。以光学显微镜观测４组大鼠肺中、小肌型动脉的相对中膜厚度（ＲＭＴ）。应用ＰＤＧＦ的单克隆抗体经免疫组织化学技术对４组大鼠肺动脉ＰＤ     

一氧化碳对热性惊厥大鼠海马一氧化氮合酶/一氧化氮体系的影响

目的：反复热性惊厥(FS)后血红素氧合酶(HO)/一氧化碳(CO)系统和一氧化氮合酶(nNOS)/一氧化氮(NO)系统上调,但二者相互关系不清。本研究观察HO抑制剂锌原卟啉Ⅸ(ZnPPⅨ)对FS大鼠海马神经元型NOS(nNOS)mRNA和蛋白表达及NO含量的影响,以探讨CO对NOS/NO体系的调节作用。方法：采用热水浴诱导大鼠FS,隔日诱导1次,共诱导10次。发育期大鼠随机分为3组:对照组,FS组,FS+ZnPPⅨ组(均n=16)。分光光度计间接测定血浆CO和NO含量;核酸原位杂交法检测海马nNOSmRNA表达;Westernblot方法检测海马nNOS蛋白含量。结果：反复FS后海马nNOSmRNA和蛋白表达增高。用ZnPPⅨ进行干预后,血浆CO含量下降,海马nNOSmRNA和蛋白表达及血浆NO含量呈现一致性的显著。结论：反复FS时,外源性给予HO抑制剂ZnPPⅨ可可抑制HO/CO系统,降低血浆CO,增加神经元NOS的基因表达及NO含量,提示CO可能下调NOS/NO系统活性。