摘要:

The effect of hyperglycemia on ischemic brain damage was investigated in a newborn dog model of hypothermic circulatory arrest. Newborn dogs were anesthetized with halothane, paralyzed, and artificially ventilated to maintain normoxia and acidbase balance. Animals were surface-cooled to 20°C, after which cardiac arrest was effected with i.v. KCl. Before surface cooling, one-half of the dogs (n= 12) received a bolus injection of 50% glucose to increase plasma glucose concentrations to approximately 33 mmol/L (600 mg/dL); control littermates (n= 12) received an equivalent volume of 1 N saline. The dogs remained asystolic for 1.75 h, after which cardiopulmonary resuscitation was accomplished. All animals survived, were allowed to recover from anesthesia at 37°C, and were maintained for 8 h of recovery, at which interval they underwent perfusion-fixation of their brains for pathologic analysis. Histologic grading of brain damage showed no statistically significant difference in the severity of neuronal necrosis within the cerebral cortex or caudate nucleus between hyperglycemic and normoglycemic littermates, with greater brain damage apparent in the amygdaloid nucleus of the hyperglycemic dogs (p< 0.02). Brainstem injury occurred more frequently in the hyperglycemic animals(p< 0.05). Correlation of coefficients analyses revealed a positive correlation between the severity of brain damage and plasma glucose concentration for both the caudate nucleus and amygdaloid nucleus but not for the cerebral cortex. The findings suggest that hyperglycemia superimposed upon hypothermic circulatory arrest in the newborn dog accentuates brain damage only in selected regions of the brain, especially the caudate and amygdaloid nuclei and brainstem, excluding the cerebral cortex.Abbreviations: MABP,mean arterial blood pressure;Paco2,partial pressure of arterial CO2;Pao2,partial pressure of arterial O2;pHa,arterial pH

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Transient cerebral ischemia in fetal sheep is followed by a period of delayed cerebral injury associated with cerebral vasodilation. As nitric oxide(NO) can mediate both vasodilation and neuronal death, this study investigated whether inhibition of NO synthesis would attenuate the vasodilation and decrease cerebral injury. Eleven late gestation (range 122-133 d) fetal sheep were subjected to 30 min of transient cerebral ischemiain utero. Two hours later, treatment group (n= 5) received a continuous infusion ofNG-nitro-L-arginine (L-NNA) at a dose of 50 mg·h-1for 4 h followed by 20 mg·h-1for the subsequent study period, a competitive inhibitor of NO synthase (NOS), whereas a control group (n= 6) received PBS. Inhibition of NOS activity was confirmed in the treatment group by1) suppression of the fall in mean arterial blood pressure (MAP) associated with acetylcholine (p< 0.01), and2) persistent increase in MAP after commencement of L-NNA (p< 0.05). Changes in cerebral blood volume (CBV) were observed for 3 d by measuring changes in concentration of total cerebral Hb([tHb]) using near infrared spectroscopy. The delayed increase in CBV commenced at 13.1 ± 1.0 h postischemia in the control and 12.7 ± 2.3 h in the treatment group. Maximum increase at 30-36 h was 0.5 ± 0.1 mL·100 g-1in the treatment group and 1.2 ± 0.2 mL·100 g-1in the control (p< 0.05). Final CBV was depressed below preischemic baseline in the treatment (-0.7 ± 0.2 mL·100 g-1) but not the control group (-0.1 ± 0.3 mL·100 g-1) (p< 0.05). Neuronal loss, quantified histologically 3 d postischemia, indicated that cerebral injury was increased in the treatment group (p< 0.05). The results indicate that after transient cerebral ischemia in fetal sheep, NOS inhibition attenuates the delayed rise in CBV but does not decrease the extent of cerebral injury.Abbreviations: NIRS,near infrared spectroscopy;CI,cortical impedance;ECoG,electrocorticographic activity;[tHb],total cerebral Hb;CBV,cerebral blood volume;NOS,nitric oxide synthase;NO,nitric oxide;L-NNA,NG-nitro-L-arginine;Sao2,arterial oxygen saturation;HbO2,oxyhemoglobin;MAP,mean arterial blood pressure;Ach,acetylcholine

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Endothelium-derived nitric oxide (NO) regulates hemodynamics in the fetal kidney and modulates renal perfusion during postnatal maturation. We hypothesize that NO release by renal arteries increases with fetal maturation and contributes to the increased renal perfusion before and after birth. We tested the effect of maturation on relaxation to acetylcholine (ACh; 10-9M to 10-5M), the prototypic endothelium-dependent relaxing agent, and sodium nitroprusside (10-9M to 10-5M), an NO donor, on isolated main renal arteries obtained from anesthetized fetal guinea pigs of varying gestational age (0.5-0.8, 0.8-0.9, and 0.9-0.97 gestation), and neonatal (1-50 d) and reproductively mature adult guinea pigs. The effect of NO synthase inhibition by nitro-L-arginine (LNA; 10-4M) and cyclooxygenase inhibition by indomethacin (10-5M) on ACh relaxation was also measured. Ca2+-dependent NO synthase activity was measured in fetal (0.5-0.87 gestation), neonatal (1-10 d), and adult (mature) renal cortex by the conversion of [L-14C]arginine to [L-14C]citrulline and the time course compared with the relaxation responses. Sensitivity and maximal relaxation to ACh increased with fetal age. In neonatal renal arteries, maximal relaxation but not sensitivity to ACh increased relative to the fetal arteries. In adult renal arteries, both sensitivity and maximal relaxation increased compared with fetal arteries. Sensitivity but not maximal responses to sodium nitroprusside increased with age but exhibited a different maturational pattern than ACh relaxation. LNA inhibited ACh relaxation in arteries of all ages. Indomethacin reduced the sensitivity to ACh only in the fetal arteries. Ca2+-dependent NO synthase activity of the renal cortex increased during fetal development reaching levels at near term similar to those found in both the newborn and adult kidneys. These results suggest that endothelium-derived NO release by the renal artery and constitutive NO synthase activity in the renal microvasculature increases with fetal and postnatal maturation. Further, the sensitivity of vascular smooth muscle to NO also increases after birth. Thus, functional adaptations in both the endothelium and the vascular smooth muscle contribute to the maturational changes in mechanisms regulating renal hemodynamics before and after birth.Abbreviations: NO,nitric oxide;ACh,acetylcholine;SNP,sodium nitroprusside;LNA,nitro-L-arginine;NOS,nitric oxide synthase;PG,prostaglandin;ANOVA,analysis of variance

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Anatomical closure of the ductus arteriosus requires normally quiescent luminal endothelial cells and medial smooth muscle cells to migrate into the subendothelial space forming intimal mounds that eventually coalesce and occlude the vessel's lumen. The migration of endothelial cells and smooth muscle cells requires the presence of integrin receptors that interact with the surrounding matrix. We used immunohistochemical staining to examine the repertoires of integrins expressed by endothelial cells and smooth muscle cells during postnatal closure of the ductus arteriosus in full-term and preterm rhesus monkeys. In the fetal ductus, luminal endothelial cells have a limited repertoire of integrins. During postnatal ductus closure, luminal endothelial cells, of both term and preterm monkeys, change their phenotype and express the full repertoire of integrins found on growing capillary endothelial cells (α1β1,α2β1, α3β1,α6β1, αvβ1,α6β4, and αvβ5). Similarly, during ductus closure, smooth muscle cells of both term and preterm monkeys expand their integrin repertoire to include the α5β1and αvβ3integrins; these two integrins have been shown to be essential for smooth muscle cell migrationin vitro. These changes in integrin profile occur at the same time the endothelial and smooth muscle cells invade their neighboring compartments. In contrast, preterm monkeys with a persistently patent ductus lumen fail to develop these changes in integrin expression and fail to develop neointimal mounds. No evidence of intimal thickening occurs in the absence of changes in integrin expression. Therefore, endothelial cells and smooth muscle cells change phenotypes to produce the intimal thickening required for ductus closure.Abbreviations: EC,endothelial cell(s);SMC,smooth muscle cell(s);Fio2,fractional concentration of inspired oxygen;PECAM,platelet EC adhesion molecule

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Bilirubin encephalopathy results from the entry of bilirubin into the brain and is expressed by motor, sensory, and/or behavioral impairment. The jaundiced (jj) Gunn rat is a valuable animal model for studying the kinetics of bilirubin-induced neurotoxicity. This is often done by recording evoked potentials, which are also used as indices of brain damage in infants who develop neonatal jaundice, as is the case with the auditory nerve and brainstem evoked response (ABR). The present study describes the postnatal development of the somatosensory evoked potential (SEP) in Gunn rats. No effects of jaundice on the SEP were found in young jj rats (16-28 d). However, adult (3-4 mo) jj rats had prolonged latencies and decreased amplitudes of the P2 component of the SEP compared with adult nonjaundiced (Jj) rats. These changes in the SEP of jaundiced rats may reflect a synaptic lesion in these animals, possibly due to cumulative and/or progressive damage induced by bilirubin during the first 3 mo of life. After sulfadimethoxine administration, marked latency prolongations (2-6%) were observed in the early components of SEP in young (3-wk-old) jj (but not Jj) rats, as early as 2 h after injection. These changes, which became more severe (4-10%) with time, seem to be mostly peripheral. The present results suggest that the SEP may be a sensitive marker for the massive entry of bilirubin into the nervous system, and could serve as part of an evoked potential battery (in addition to visual evoked potential and ABR) in assessing bilirubin-induced neurotoxicity in jaundiced newborns and infants.Abbreviations: SEP,somatosensory evoked potential;VEP,visual evoked potential;ABR,auditory nerve and brainstem evoked response;jj,jaundiced Gunn rat;Jj,nonjaundiced Gunn rat;SDM,sulfadimethoxine

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

In 22 newborn piglets we studied the effect of hypovolemia or hypoxemia on hemodynamics and regional blood flow after instillation of porcine surfactant. Surfactant deficiency was obtained by repeated lung lavage, and blood flow measurements were carried out using radioactive microspheres. Three groups of piglets were studied, controls (n= 8), hypovolemia (n= 7), and hypoxemia (n= 7). Three to five minutes after instillation of surfactant, mean arterial blood pressure decreased significantly in all three groups with a mean decrease (±SD) of 31(±12), 33(±9), and 29(±9) mm Hg, respectively (p< 0.01 in all three groups). Systemic vascular resistance decreased significantly in all three groups immediately after surfactant instillation (p< 0.01) and returned to presurfactant level after 60 min. Blood flow did not change after surfactant instillation in any of the three groups, in neither skin, muscle, pancreas, brain, nor retina. In liver, kidney, intestine, and choroidea there was a decrease in blood flow immediately after instillation with return to presurfactant levels within 60 min. Hypoxemia or hypovolemia before surfactant instillation did not increase the hemodynamic instability. The decrease in mean arterial blood pressure was caused by a vasodilation and not by a reduced cardiac output.Abbreviations: a/A ratio,arterial/alveolar ratio of oxygen tension;ANOVA,analysis of variance;CBF,cerebral blood flow;CBFV,cerebral blood flow velocity;CBV,cerebral blood volume;CMRo2,cerebral metabolic rate for oxygen;CVP,central venous pressure;CVR,cerebral vascular resistance;Fio2,fraction of inspired oxygen;IVH,intraventricular hemorrhage;MABP,mean arterial blood pressure;Paco2,arterial tension of carbon dioxide;Pao2,arterial tension of oxygen;PIP,peak inspiratory pressure;presurf,presurfactant;PWM,periventricular white matter;RDS,respiratory distress syndrome;ROP,retinopathy of prematurity;SVR,systemic vascular resistance;Sao2,saturation of oxygen

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Since the description of bronchopulmonary dysplasia (BPD) in premature infants, the supplemental oxygen administered has been suspect in the etiology of BPD. This has prompted studies on the effect of hyperoxia on lung growth in neonatal animals. So far, these have not led to a treatment which either prevents or mitigates BPD. Another approach to investigate the effect of hyperoxia on the immature lung is to use lung explants from 12-d gestation mouse fetuses. Exposing explants to different concentrations of oxygen for 48 h, we found that exposures to oxygen both below (10%) and above (35% or greater) normoxia adversely affected branching morphogenesis and growth. The effect was irreversible at exposures of 50% oxygen and greater. To determine the role of reactive oxygen species (ROS) in the effect of hyperoxia, antioxidants and inhibitors of ROS formation were added to the incubating explants, and their influence on reducing the adverse effect of 50% oxygen was assessed. The combination of CuZn superoxide dismutase (SOD) and catalase, manganese SOD, manganese-3-tetrakis(1-methyl-4-pyridyl)porphorin, a low molecular weight SOD mimetic, and to a lesser extent, deferoximine, an antioxidant and inhibitor of hydroxyl radical formation, were successful in reducing the effect of 50% oxygen on morphogenesis. Not successful wereN-nitro-L-arginine methyl ester (an inhibitor of nitric oxide synthase); allopurinol (an inhibitor of xanthine oxidase);N-acetylcysteine and ebselen (a glutathione peroxidase mimetic); Trolox (a synthetic tocopherol); catalase, and CuZnSOD used alone. These results provide evidence that superoxide anion and possibly hydroxyl radical are the ROS most likely responsible for the growth effects of hyperoxia on mouse fetal lung morphogenesis.Abbreviations: ROS,reactive oxygen species;TMPYP,manganese-3-tetrakis[1-methyl-4-pyridyl]porphorin;SOD,superoxide dismutase;BPD,bronchopulmonary dysplasia;L-NAME,N-nitro-L-arginine methyl ester;ANOVA,analysis of variance;DMEM,Dulbecco's modified Eagle's medium

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Mouse models for cystic fibrosis (CF) with no CFTR function(Cftr-/-) have the disadvantage that most animals die of intestinal obstruction shortly after weaning. The objective of this research was to extend the lifespan of CF mice and characterize their phenotype. Weanlings were placed on a nutrient liquid diet, and histologic and functional aspects of organs implicated in the disease were subsequently examined. Approximately 90% ofCftr-/-mice survived to 60 d, the majority beyond 100 d.Cftr-/-mice were underweight and had markedly abnormal intestinal histology. The intestinal epithelia did not respond to challenges with agents that raised intracellular cAMP, consistent with the absence of functional CFTR. No lesions or functional abnormalities were evident in the lungs. Liquid-fedCftr-/-mice were infertile, although some males weaned to a solid diet were fertile before they died. Thus, we have succeeded in using dietary means to prolong the lives ofCftr-/-mice.Abbreviations: CF,cystic fibrosis;CFTR,cystic fibrosis transmembrane conductance regulator;Cftr,murine ortholog of the human gene defective in cystic fibrosis;Isc,short-circuit current

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

We investigated the development of the exocrine pancreas inCftr-/-mice in comparison with age-matched littermates(Cftr+/+,Cftr+/-) up to 100 d postnatally. Controls were weaned either to mouse chow or a liquid diet;Cftr-/-mice were weaned solely to a liquid diet. Solid-fed control mice gained weight and showed a progressive increase in pancreatic protein, DNA, amylase, lipase, trypsin, and chymotrypsin activities. Liquid-fed control mice showed similar postnatal somatic and pancreatic growth, except that amylase and lipase activities were lower than in the solid-fed controls.Cftr-/-mice exhibited significantly lower body and pancreatic weights than did controls. Pancreatic protein content and enzyme activities (notably amylase and lipase) were consistently lower than in the age-matched littermates fed either diet. The reduction in lipase activity inCftr-/-mice was noted before weaning. We concluded that the liquid diet influenced postnatal exocrine pancreatic development in mice. However, a further reduction in postnatal pancreatic growth and enzymatic activities in theCftr-/-mice was noted. These alterations could be due to the primary cystic fibrosis defect, although secondary factors, such as malnutrition induced by decreased dietary intake or abnormal absorptive capacity, may be responsible.Abbreviations: CF,cystic fibrosis;CFTR,CF transmembrane regulator;CCK,cholecystokinin

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Chronic lung disease (CLD) of prematurity is associated with an initial increase in pulmonary neutrophils followed by pulmonary fibrosis. We determined whether the proinflammatory cytokines, IL-1β and IL-6, were increased in the bronchoalveolar lavage fluid obtained from nine infants(median gestation 25 wk, birthweight 820 g) who developed CLD, seven (28 wk, 1110 g) who recovered from the respiratory distress syndrome (RDS), and four(38 wk, 2690 g) control infants. IL-1β and IL-6 protein were both increased in the bronchoalveolar lavage fluid from the CLD groups when compared with the RDS and control groups. This difference for both the cytokines was most marked on d 10 of age, when results from infants with and without CLD were compared (IL-1β, 4.6versus1.1 ng/mL,p< 0.05; and IL-6, 9.5versus1.5 ng/mL,p< 0.05). Immunocytochemistry of lavage cells for IL-1β, IL-6, and IL-8 protein showed alveolar macrophages to contain all three cytokines, with lesser staining evident in neutrophils, and in epithelial cells occasionally obtained by lavage. The contribution of alveolar macrophages and luminal cells to the increase in IL-6 and IL-1 was determined by performing semiquantitative reverse transcription-polymerase chain reactions on RNA extracted from lavage cells. IL-6 mRNA expression was increased in lavage cells from the CLD infants when compared with the RDS group. However, the expression for IL-1β and IL-8 mRNA was similar in both groups. These results suggest that IL-1β, IL-6, and IL-8 may contribute to the pathogenesis of CLD, and that, in CLD, IL-6 may be produced by cells within the air spaces.Abbreviations: CLD,chronic lung disease of prematurity;PCR,polymerase chain reaction;RDS,respiratory distress syndrome;RT,reverse transcription;ICAM,intercellular adhesion molecule-1;sICAM,soluble ICAM

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID