ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We investigated the nitrous oxide-induced inactivation of methionine synthase and the concurrent homocysteine (Hey) export in mutant fibroblasts with defects in the homocysteine catabolizing enzyme, cystathionine β-synthase, or in methionine synthase, which carries out homocysteine remethylation. The fibroblasts were incubated in various concentrations of methionine to create conditions favoring methionine conservation or catabolism. In cystathionine β-synthase-deficient cells, high medium methionine partly protected the enzyme against inactivation, as previously found in normal fibroblasts. The Hey export rate at low methionine levels was low (0.2–0.6 nmol/ h/106cells), and increased 2–3-fold at high methionine levels. Nitrous oxide enhanced Hey export rate at low methionine, so that in the presence of nitrous oxide, the Hey export became less dependent of methionine. In cblG cells, the enzyme inactivation was moderate and independent of medium methionine. The Hey export rate was intermediate (0.5–0.8 nmol/h/106cells) at low methionine levels, and increased moderately (<2-fold) at high methionine levels or following nitrous oxide exposure. In cblE mutants, the enzyme activity was not affected by nitrous oxide, and the Hey export was high (0.8–1.6 nmol/h/106cells) and independent of methionine and nitrous oxide. These data suggest that Hey remethylation and cystathionine βsynthase activity are major determinants of Hey export at low and high methionine, respectively. The low susceptibility of methionine synthase to nitrous oxide in the presence of high methionine or in cblG or cblE mutants is probably related to low catalytic turnover.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We evaluated the neuroprotective effect of the nitric oxide synthesis inhibitor,NG-nitro-L-arginine in a neonatal hypoxic-ischemic rat model. Unilateral hypoxic-ischemic injury was produced in the brain of 7-d-old rats using a combination of a common carotid artery ligation and a hypoxic (8% oxygen) exposure for 2.5 h. In our experimental condition, rectal temperatures did not differ betweenNG-nitro-L-arginine-treated and saline-injected pups. We killed the animals 72 h later and assessed the hypoxic-ischemic brain damage histologically.NG-nitro-L-arginine (2 mg/kg) administered intraperitoneally 1.5 h before hypoxia resulted in 77% reduction of the infarcted hemispheric volume and 87% reduction of the infarcted striatal volume compared to saline injected controls.NG-nitro-L-arginine given 1.5 h before the insult also significantly prevented hypoxic-ischemic damage in the five hip-pocampal structures examined, dentate gyrus, CA4, CA3, CA1, and subiculum.NG-nitro-L-arginine administered immediately after hypoxia did not prevent hypoxic-ischemic brain damage. These results indicate that nitric oxide plays a key role in producing neonatal hypoxic-ischemic brain damage.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Inhaled nitric oxide has been reported to act as a specific pulmonary vasodilator. We used the newborn piglet to create acute hypoxic pulmonary hypertension and examined the effect of inhaled nitric oxide in this model. Six newborn piglets were instrumented in order to measure cardiac index, pulmonary arterial pressure, and systemic arterial pressure. Pulmonary hypertension was induced by reducing the fraction of inspired oxygen to 0.12 to 0.14. With hypoxia (arterial oxygen saturation between 35 and 45%), pulmonary arterial pressure increased by 48% (p< 0.01), pulmonary vascular resistance increased by 74% (p< 0.01), and both systemic arterial pressure and systemic vascular resistance decreased by 38 and 31%, respectively (p< 0.01). The animals were then giving varying concentrations of inhaled nitric oxide between 5 and 80 parts per million in random order. All concentrations of nitric oxide were associated with a rapid decrease in pulmonary arterial pressure and pulmonary vascular resistance (p< 0.001). Cardiac index increased (p< 0.001) and systemic vascular resistance significantly decreased (p= 0.01) with all doses of inhaled nitric oxide. The ratio of pulmonary to systemic vascular resistance decreased with all levels of inhaled nitric oxide (p< 0.001). For all of the above observations there was no significant difference noted between the varying doses of nitric oxide. The time course of the pulmonary arterial pressure response to nitric oxide was approximately twice as fast as that seen with the inhalation of 100% oxygen (10, 50, 90% responses of 4.1, 8.8, 88.6versus6.7, 51.9, 197 s, respectively;p< 0.01). Inhaled nitric oxide at levels of 5 parts per million or greater reverses hypoxia-induced pulmonary vasoconstriction in the newborn piglet model.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

To study the pulmonary vasodilator selectivity of low levels of inhaled nitric oxide (NO) in a model of neonatal pulmonary hypertension, we sequentially exposed anesthetized, spontaneously breathing neonatal pigs to each of four different inspired gas mixtures: room air, room air with 25 parts per million NO, hypoxia (14% O2in N2), and hypoxia with 25 parts per million NO. The room air, room air with NO, hypoxia, and hypoxia with NO exposures were of 15-min duration. The following measurements were made: mean systemic arterial, mean pulmonary arterial, and wedge pressures; thermodilution cardiac output; esophageal pressure; tracheal flow; and arterial Po2, Pco2, pH, hemoglobin, and methemoglobin. Inhalation of NO decreased pulmonary arterial pressure in both room air and hypoxia conditions (mean pulmonary arterial pressure 16 ± 1 torr room air, 13 ± 1 torr room air with NO,p< 0.005; and mean pulmonary arterial pressure 21 ± 2 torr hypoxia, 14 ± 1 torr hypoxia with NO,p< 0.005). NO had no significant effect on systemic arterial pressure, cardiac output, dynamic lung compliance, pulmonary resistance, or the measured blood variables during either control or hypoxic conditions. The results indicate that inhaled NO was a selective pulmonary vasodilator that could effectively reverse acute hypoxic pulmonary vasoconstriction. The normoxic vasodilation produced by NO inhalation also indicates the existence of basal vasomotor tone in the anesthetized, spontaneously breathing neonatal pig. The short-term exposures used produced no detectable manifestations of toxic side effects.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

To determine the vascular site(s) of action of hypoxia in the neonatal pig, isolated lungs were perfused at a constant flow rate and left atrial pressure; arterial, venous, and double occlusions were performed. The distribution of the total pulmonary vascular resistance and the total dynamic vascular compliance were calculated using a model of the pulmonary circulation consisting of upstream, central, and downstream compliances and resistances upstream and downstream of central compliance. In addition, the static vascular compliance was measured by venous followed by arterial occlusion, and the total vascular volume was measured by dye-dilution. In this preparation during control conditions alveolar Po2= 12 ± 2 kPa), total pulmonary vascular resistance was nearly evenly divided between resistance upstream and downstream of double occlusion pressure and total dynamic vascular compliance was concentrated mainly in the central compliance (7% upstream compliance, 82% central compliance, and 11% downstream compliance). Hypoxia (alveolar Po2= 4 ± 1 kPa) increased both resistance upstream of double occlusion pressure (p< 0.005) and resistance downstream of double occlusion pressure (p< 0.02) and decreased central compliance (p< 0.005). Hypoxia also decreased total pulmonary blood volume (p< 0.02). These results suggest that in the pulmonary vasculature of the neonatal pig, hypoxia results mainly in 7) arterial constriction as evidenced by a large increase in upstream resistance and a decrease in total pulmonary blood volume and 2) a smaller but significant venous constriction. This venous constriction may have implications in the pathogenesis and therapy of pulmonary vascular diseases associated with hypoxia such as postasphyxiai lung disease and bronchopulmonary dysplasia.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Treatment of nonhuman primate fetuses with epidermal growth factor (EGF) results in histologie and biochemical maturation of their lungs. To determine whether these effects improve lung function postnatally, we studied premature rhesus infants delivered at 78% of gestation afterin uterotreatment with EGF (n = 5) or placebo (n= 5). Indices of lung function during the 4 d of postnatal care included fractional concentration of inspired oxygen, peak inspiratory pressure, ventilator rate, mean airway pressure, arterial to alveolar oxygen tension ratio, and ventilation index. Statistically significant differences were noted in the time courses of these variables between EGF- and placebo-treated infants. The direction of the differences indicated that the EGF-treated infants had less severe lung disease. Surfactant apoprotein A concentration and lecithin to sphingomyelin ratio were both significantly higher in the amniotic fluid of the EGF-treated group, indicating advanced biochemical maturation in this group of animals. Whereas birth weight was not affected by EGF exposure, adrenal and gut weights, standardized for body weight, were increased significantly. Histologie studies showed advanced cellular maturation with increased parenchyma! airspace and decreased parenchyma! tissue space in the EGF-treated group compared with the control group. We conclude that prenatal exposure to EGF stimulates biochemical and histologie maturation of the lung and markedly attenuates the clinical severity of respiratory disease in this model of simian respiratory distress syndrome.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The effect of exogenous surfactant on the pharmacokinetics of intratracheally administered recombinant human superoxide dismutase (rhSOD) was studied. Five groups of rats received the following intratracheally: 1 mL/kg of saline; 5 or 25 mg/kg of rhSOD; or 4 mL/kg of exogenous surfactant followed in 30 min by 5 or 25 mg/ kg of rhSOD. Animals were killed at 24,48, and 72 h, and serum, bronchoalveolar lavage, and lung tissue were analyzed for rhSOD. rhSOD was not detected in the lungs of saline-treated animals or in serum from any animal. At 24 h, lung-tissue rhSOD was higher in rats treated with surfactant and rhSODversusrhSOD alone (5 mg/kg: 6.8 ± 2.5versus0 μg/whole lung,p< 0.05; 25 mg/kg: 29.9 ± 9.6versus0.1 ± 0.1 μg/whole lung,p< 0.05). Bronchoalveolar lavage fluid levels correlated well with lung tissue concentrations. By 48 h, lung tissue rhSOD concentrations were insignificant in all groups. rhSOD was still present in lavage fluid from rats treated with surfactant and rhSOD. No rhSOD was detected at 72 h. In separatein vitroexperiments, physical and biological drug-drug interaction studies were performed. When radiolabeled rhSOD was combined with exogenous surfactant and centrifuged at 10000 ×gfor 30 min, 81.3 ± 2.5% of rhSOD was found in the supernatantversus18.7 ± 2.5% in the surfactant pellet. Serial washing of the surfactant pellet removed virtually all remaining rhSOD. This finding suggests that the rhSOD and surfactant were only weakly associated. Combining rhSOD and exogenous surfactant did not alter the activity of either agent. Data suggest that exogenous surfactant prolongs the t½ of rhSOD in the lung. This finding may be important in determining future rhSOD administration strategies in preterm infants with respiratory distress syndrome who receive exogenous surfactant replacement therapy.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Manganese superoxide dismutase (MnSOD) is one of the main antioxidant enzymes in mammalian tissue. Previous studies have shown that the activity of MnSOD increases in the rat kidney during development. To define further the developmental change in MnSOD activity and better understand some of the steps involved in the control of MnSOD expression during kidney development, we measured MnSOD messenger RNA and enzyme activity in the ovine kidney cortex during fetal life, in the newborn period, and in adults. MnSOD mRNA and enzyme activity were detected at 0.65 gestation. Hybridization of the Northern blot with a human MnSOD cDNA probe showed evidence of two transcripts of 4.0 and 1.5 kb, respectively. There was a significant increase with age of MnSOD activity and MnSOD mRNA (p< 0.0001). The abundance of each MnSOD transcript significantly increased with age (p< 0.001). In the fetuses, both transcripts increase in parallel; in newborns and adults the 1.5-kb increase was significantly greater than the 4.0-kb increase. Enzyme activity and mRNA were strongly correlated (r = 0.89,p< 0.0001). These data indicate that the expression of MnSOD is developmentally regulated in the ovine kidney cortex. This increase seems to be dependent largely on pretranslational events.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID