Delayed pulmonary maturation in the fetus of the streptozotocin-diabetic rat

Pulmonary maturation was studied in fetuses in streptozotocin-diabetic rats on the final four days of gestation. Diabetes was induced prior to conception by the intravenous injection of streptozotocin. Fetuses were hyperglycemic but did not manifest hyperinsulinemia. Whole lung total phospholipid, phosphatidylcholine, and disaturated phosphatidylcholine were significantly decreased in the diabetic group on day 21 (term = 22 days), but not prior to or after that point in gestation. Morphologic analysis also revealed a decreased number of type II cells and lamellar bodies per alveolar lining cell in the diabetic group only on day 21, coincident with the changes in phospholipid analysis. Activities of enzymes involved in fetal pulmonary phospholipid synthesis were measured to see if differences could account for the observed developmental delay. No significant differences between diabetic and control lungs were noted in any of the enzymes studied from days 20-22, with the exception of an increase in cholinephosphate cytidylyltransferase activity in the diabetic fetuses on day 22. Immaturity in both biochemical and morphologic indices of lung development was present at a specific time late in the diabetic rat gestation. This maturational delay could not be accounted for by changes in the activities of enzymes involved in phospholipid synthesis. The fetus of the streptozotocin-diabetic rat provides a useful model to study the effects of hyperglycemia on fetal lung development.     

Reduction in brain serotonin synthesis rate in streptozotocin-diabetic rats

The rate of serotonin synthesis in brain was determined in streptozotocin-diabetic and normal rats using two methods. Both the rate of 5-hydroxytryptophan accumulation after aromatic amino acid decarboxylase inhibition, and the decline rate of 5-hydroxyindole acetic acid after pargyline treatment were significantly reduced in diabetic rats. The reduced rate of synthesis may be a direct result of significantly lowered brain tryptophan levels in diabetic rats.     

Hormonal regulation of the synthesis of lamellar body phosphatidylglycerol and phosphatidylinositol in fetal lung tissue

The influence of hormones on the synthesis of phospholipids of lung lamellar bodies was studied using lung tissue explants from 16- to 22-week gestational age human abortuses. Lung explants were incubated in a defined medium containing either no hormonal additions or insulin (2.5 micrograms/ml), cortisol (0.2 microgram/ml), or PRL (2.5 micrograms/ml), added alone or in various combinations. After 7 days of incubation, a purified lamellar body fraction was isolated from the explants. The effects of various hormone combinations on the relative rates of synthesis of lamellar body anionic glycerophospholipids during the last 24 h of culture were analyzed and compared to that of control explants. In control explants, 7.1% of the glycerophospholipid was synthesized as phosphatidylinositol, and 2.2% was synthesized as phosphatidylglycerol. Phosphatidylinositol synthesis was decreased significantly in explants incubated with cortisol alone, insulin plus cortisol, or insulin plus cortisol plus PRL (to 4.4%, 4.3%, and 3.7%, respectively), while phosphatidylglycerol synthesis was increased significantly in lamellar bodies from explants incubated with insulin plus cortisol or insulin plus cortisol plus PRL (to 5.5% and 5.7%, respectively). Although the relative rates of synthesis of lamellar body phosphatidylinositol and phosphatidylglycerol were significantly altered by hormones, the percentages of the total anionic glycerophospholipid were similar in all treatment groups (9.5%). The results of this study, therefore, are suggestive that lamellar body formation and glycerophospholipid composition are under hormonal control.     

Rapid reversal of a motor nerve conduction deficit in streptozotocin-diabetic rats by the angiotensin converting enzyme inhibitor lisinopril

The effect of treatment of rats with the angiotensin converting enzyme inhibitor lisinopril after 5 weeks of untreated streptozotocin-diabetes was examined by daily monitoring of sciatic motor conduction velocity to tibialis anterior muscle. Diabetes produced a 31.5% decrease in conduction velocity (P<0.001). Lisinopril treatment caused a progressive improvement which was significant after 3 days (P=0.002), full normalization being achieved by 6 days (P<0.0001). After 7 days of treatment there followed a 7-day washout period in which no lisinopril was given. During this time conduction velocity declined to untreated diabetic levels over 3 days. A subsequent treatment period resulted in complete normalization of conduction velocity within 2 days (P<0.0001). Thus, the marked functional effects seen for vasodilator treatment with lisinopril suggest that angiotension converting enzyme inhibitors may have potential therapeutic value in the treatment of diabetic neuropathy.     

Reduction in testicular function in rats. II. Reduction by dexamethasone in fetal and neonatal rats

Chronic administration of dexamethasone in drinking water to maternal rats from days 15 to 21 of gestation (1) reduced plasma testosterone concentrations in male fetuses between days 19 and 21 but not earlier on day 18 and abolished the prenatal peak of plasma testosterone which normally occurs on day 19 of gestation, and (2) suppressed the postnatal surge of plasma testosterone in male newborns 1.5 and 2 h after delivery at term by cesarean section. The administration of dexamethasone to male fetuses at birth induced 1 h later a slight but not significant increase in hypothalamic gonadotropin-releasing hormone (GnRH) and pituitary luteinizing hormone (LH) contents, reduced drastically plasma LH levels and completely prevented the postnatal surge of plasma testosterone which occurred normally in littermate controls. A rise in pituitary LH content, and a sharp reduction in plasma LH and testosterone concentrations were noted in 19-day-old male fetuses whose mothers were acutely treated with dexamethasone on day 18 of gestation. Similar evolutions for LH were observed in littermate females. These results suggest that the inhibitory effects of exogenous glucocorticoids on testosterone secretion could be mediated in both fetuses and newborns at least partially through suppression of the hypothalamic and pituitary secretion of GnRH and LH, respectively, and provide insight how stress or hormone imbalance may affect the development of this neuroendocrine system.     

In vivo insulin resistance in streptozotocin-diabetic rats — evidence for reversal following oral vanadate treatment

Summary Hepatic glucose production and peripheral glucose utilisation were measured in vivo with the euglycaemic-hyper-insulinaemic clamp technique in rats rendered severely diabetic with streptozotocin (45 mg/kg) and in control rats. The rats were studied in the post-absorptive state while anaesthetised. The basal glucose production and glucose utilisation were significantly higher (p<0.001) in diabetic rats 9 days after streptozotocin administration. During the clamp studies, suppression of glucose production by the liver induced by submaximal or maximal insulin levels was significantly less (p<0.01 and p<0.001 respectively) effective in diabetic rats as compared to control rats. Glucose utilisation was significantly lower following both submaximal (p<0.01) or maximal (p<0.001) hyperinsulinaemia as compared to control rats. Oral administration of vanadate (0.2mg/ml in drinking water) for a 20-day period in diabetic rats lowered their plasma glucose levels to normal near values within 4 days, normalised plasma insulin levels, and increased pancreatic insulin stores. The rate of glucose disappearance (K value) and in vivo glucose-induced insulin secretion as estimated during an i.v. glucose tolerance test were not significantly improved. In control rats, vanadate treatment did not significantly affect any of the above parameters. In vanadate treated diabetic rats, basal glucose production was normalised. Following submaximal or maximal hyperinsulinaemia, glucose production was suppressed normaly. Basal glucose utilisation was restored and returned to normal values during submaximal hyperinsulinaemia. However, during maximal hyperinsulinaemia, glucose utilisation still remained significantly lower (p<0.05) as compared to vanadate-treated control rats. Vanadate treatment in control rats did not affect significantly any of the above parameters. These results show an insulin-like effect of vanadate upon glucose metabolism in vivo in the liver and peripheral tissues of diabetic rats, leading to normalisation of glycaemia in the absence of any significant improvement of insulin secretion.     

Maternal side effects of prenatal dexamethasone therapy for fetal congenital adrenal hyperplasia.

Prenatal treatment of virilizing congenital adrenal hyperplasia in female fetuses via maternal dexamethasone (Dex) therapy (1-1.5 mg/day) from first trimester to birth was associated with excessive weight gain (47-56 pounds at 35-37 weeks gestation), Cushingoid facial features, severe striae resulting in permanent scarring, and hyperglycemic response (8-11.7 nmol/L) to oral glucose administration in all our experience (three cases). Other symptoms included hypertension, gastrointestinal intolerance, or extreme irritability. Previous pregnancies were uncomplicated by these problems. In each case, first or second trimester amniotic fluid 17-hydroxyprogesterone (17OHP, 17-41 nmol/L; normal less than 0.4 nmol/L), androstenedione (22-31 nmol/L, normal less than 5 nmol/L), and testosterone levels (0.54-0.7 nmol/L, normal less than 0.4 nmol/L) during Dex treatment were elevated regardless of the newborn genital outcome. Maternal serum estriol (E3) levels in one mother (normal newborn genitalia) were consistently low (less than 0.2 nmol/L) during the second and third trimester. In two mothers (partially virilized newborn genitalia) initial second trimester E3 levels were unsuppressed (11, 17.4 nmol/L) and suppressed (less than 1.4 nmol/L) following short-term increased dose. Conclusion: prenatal Dex treatment of virilizing congenital adrenal hyperplasia at a dose of 1-1.5 mg daily throughout gestation is associated with significant maternal side effects. Parents should be informed of these side effects before initiation of treatment. Careful monitoring for signs of side effects, medical intervention when necessary, and lowering of Dex dose during the second half of gestation would minimize the side effects. Maternal serum E3 levels appear useful for prediction of fetal outcome while amniotic fluid steroid levels may not.     

Delayed onset of persistent estrus in aged rats raised from parathyroidectomized mothers

Descendants of rats possessing lower responsiveness to the removal of the parathyroid gland [4] were examined for the aging process of the hypothalamic-pituitary-ovarian axis. The first generation rats of these descendants were born to mothers parathyroidectomized (Px) on the fifth day of gestation and subsequent generation rats were developed by brother-sister mating without any special treatment. More than 50% of the eighth to tenth generation (F₈-T₁₀) offsprings of the Px-rats showed regular 4-day estrous cycles at 15–16 months of age, while nearly 80% of normal F₈-F₁₀ rats developed persistent estrus at 13–14 months of age. In 14–15 month-old Px-offspring rats the LH and FSH surges occurred at 1630–1730 h of proestrus to a similar extent as those shown in 3–4 month-old normal rats. The release of LH and FSH following a single injection of luteinizing hormone-releasing hormone (LHRH) in 13 month-old Px-offspring rats was nearly normal, reaching a maximal level at 15 min as in young adult rats. In 13 month-old normal rats, serum LH measured after an injection of LHRH increased progressively until 60 min. The ovaries of the Px-offspring rats were heavier than those of age-matched normal rats and included well-developed corpora lutea and follicles in several sizes. The results suggest a delay in the aging process of the hypothalamic-pituitary-ovarian axis of the Px-offspring rats.     

Delayed onset of persistent estrus in aged rats raised from parathyroidectomized mothers

Descendants of rats possessing lower responsiveness to the removal of the parathyroid gland [4] were examined for the aging process of the hypothalamic-pituitary-ovarian axis. The first generation rats of these descendants were born to mothers parathyroidectomized (Px) on the fifth day of gestation and subsequent generation rats were developed by brother-sister mating without any special treatment. More than 50% of the eighth to tenth generation (F8-F10) offsprings of the Px-rats showed regular 4-day estrous cycles at 15-16 months of age, while nearly 80% of normal F8-F10 rats developed persistent estrus at 13-14 months of age. In 14-15 month-old Px-offspring rats the LH and FSH surges occurred at 1630-1730 h of proestrus to a similar extent as those shown in 3-4 month-old normal rats. The release of LH and FSH following a single injection of luteinizing hormone-releasing hormone (LHRH) in 13 month-old Px-offspring rats was nearly normal, reaching a maximal level at 15 min as in young adult rats. In 13 month-old normal rats, serum LH measured after an injection of LHRH increased progressively until 60 min. The ovaries of the Px-offspring rats were heavier than those of age-matched normal rats and included well-developed corpora lutea and follicles in several sizes. The results suggest a delay in the aging process of the hypothalamic-pituitary-ovarian axis of the Px-offspring rats.     

Glomerular basement membrane synthesis and serum concentration of type IV collagen in streptozotocin-diabetic rats

Summary Glomerular basement membrane synthesis was measured in vivo in diabetic rats at various times after streptozotocin injection. Simultaneously the type IV collagen concentration in serum was determined by a radioimmunoassay specific for the terminal cross-linking domain, 7S collagen. Basement membrane collagen synthesis and the 7S collagen levels were markedly raised in diabetic animals 18–34 days after streptozotocin injection and showed a significant correlation. The results suggest that the amount of serum 7S collagen reflects increased basement membrane synthesis in a diabetic situation. Both basement membrane collagen synthesis and serum 7S collagen concentration also show a positive correlation with the blood glucose levels of diabetic rats. This indicates that the degree of metabolic dysregulation influences basement membrane synthesis.     

Maternally administered dexamethasone transiently increases apoptosis in lungs of fetal rats

In late gestation, morphological maturation of fetal lung includes septal thinning of potential airspaces, a process accelerated by exogenous glucocorticoids. Apoptosis occurs in normal fetal lung. Glucocorticoids increase apoptosis in several tissues. The authors hypothesized that exogenous glucocorticoids would increase apoptosis in fetal lung, primarily in the interstitium. They administered dexamethasone (DEX), 1 mg/kg, or vehicle (Control) to pregnant rats at 19 days of gestation. Fetuses were delivered at 3, 7, 12, or 24 hours post injection. DEX decreased fetal body weight and lung weight, DNA, and protein 12 hours post injection. Using the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) reaction to label apoptotic cells in lung, they calculated an apoptotic index (AI, apoptotic cells/1000 total cells) for each fetus. Average DEX AI (3.6+/-2.6, mean+/-SD) was greater than Control (1.7+/-0.5) (P<.02). All DEX AIs were greater than Control AIs at 3, 7, and 12 hours, but were similar to Controls at 24 hours post injection. Apoptotic cells appeared to be interstitial, based on colocalization with vimentin staining. Presence of apoptotic cells was confirmed by electron microscopy and detection of the nucleosomal ladder pattern on DNA electrophoresis. The authors conclude that maternal administration of dexamethasone increases apoptosis in fetal lung, primarily in the interstitium. They speculate that apoptosis may contribute to morphological fetal lung maturation induced by endogenous glucocorticoids.     

Increased constriction of the ductus arteriosus by dexamethasone, indomethacin, and rofecoxib in fetal rats.

BACKGROUND: To find a better treatment for patent ductus arteriosus (PDA) in premature infants, the present study investigated the synergism of clinical doses of dexamethasone, indomethacin, and rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, on the fetal ductus arteriosus (DA) in rats. METHODS AND RESULTS: Dexamethasone (0.3 mg/kg), indomethacin (0.3 mg/kg), and rofecoxib (0.3 mg/kg), alone or in combination, were administered to preterm (d19) and near-term (d21) fetal rats. The ratio of the inner diameter of the DA to that of the main pulmonary artery (PA) (DA/PA) was studied at 2, 4 and 8 h after drug administration, using a rapid whole-body freezing method. In near-term rats, the combined administration of dexamethasone and indomethacin caused severe constriction, with a DA/PA ratio of 0.52+/-0.08 at 8 h, whereas the DA/PA ratios were 0.83+/-0.03 and 0.90+/-0.02 with dexamethasone and indomethacin, respectively. Combined administration of dexamethasone and rofecoxib also caused severe constriction, with a DA/PA ratio of 0.64+/-0.07 at 8 h, compared with the DA/PA ratio of 0.92+/-0.03 with rofecoxib alone. CONCLUSIONS: Combined therapy may be an option in the medical management of PDA in premature infants before considering surgical treatment.     

Effects of dexamethasone on fetal hemoglobin synthesis in peripheral blood erythroid burst-forming units

Colonies derived from erythroid burst-forming units (BFU-E) synthesize fetal hemoglobin (HbF) in amounts that far exceed in vivo levels. There is some evidence that HbF synthesis is controlled at the level of a primitive erythroid precursor cell. Dexamethasone may potentiate the development of BFU-E. Since a means of augmenting HbF production in sickle cell anemia or severe β-thalassemia would be of great therapeutic value, we studied the effects of dexamethasone on HbF and γ-globin chain synthesis in BFU-E from patients with sickle cell anemia and controls. HbF was measured by radioimmunoassay of BFU-E lysate and γ-chain synthesis by the incorporation of ³H-leucine into globin, which was then purified by gel filtration and column chromatography. Dexamethasone (10^?9 M) produced an increase in the number of BFU-E in 16 of 19 subjects when compared with numbers of BFU-E cultured with only erythropoietin. The individual BFU-E were larger and contained more subcolonies. Dexamethasone did not increase HbF or γ-chain synthesis, and there was no relationship between increased proliferation of BFU-E and augmented HbF production. Thus, although dexamethasone augmented the development of erythroid bursts, there was no increment in HbF.     

波生坦对实验性高原性肺动脉高压的逆转作用

目的 研究波生坦对实验性高原性肺动脉高压大鼠的逆转作用。方法 雄性SD大鼠随机分为5组:正常组，低压低氧3周组，，低压低氧6周组，安慰剂组和波生坦组。除正常组外，其它组置于模拟海拔5 000 m高原的减压舱中，8 h/d，分别持续3周，6周。自4周起，安慰剂组和波生坦组大鼠在低压低氧前分别给予生理盐水或波生坦灌胃。测定各组大鼠的肺血流动力学变化、右心室肥厚指数、肺系数；光镜观察直径小于100 μm肺动脉管壁厚度百分比和40~60 μm肺动脉的肌化度；分别测定血浆和肺组织中内皮素-1（ET-1）、一氧化氮（NO）的含量，肺组织中一氧化氮合酶（NOS）活性。结果 波生坦显著降低了高原性PH大鼠的肺动脉压和右心室收缩压，逆转了肺动脉的重构。波生坦减少了肺组织中的ET-1的含量，增加肺组织中结构性NOS(cNOS)和总NOS的活力，升高了血浆和肺组织中NO的水平。结论 波生坦可逆转已形成的高原性肺动脉高压，其机制可能与降低肺组织中ET-1的含量、增加机体内cNOS和总NOS的活性、升高体内NO的水平有关。波生坦对高原性肺动脉高压有积极的治疗意义。     

Interference of dexamethasone in the pulmonary cycle of Strongyloides venezuelensis in rats

The aim of this study was to investigate the interference of a daily treatment of dexamethasone in the pulmonary cycle of Strongyloides venezuelensis infection in rats. Three principal effects were found: 1) increased alveolar hemorrhagic inflammation provoked by the passage of larvae into alveolar spaces; 2) significant decrease of eosinophil and mast cell migration to the axial septum of the lungs; and 3) impaired formation of the reticular fiber network, interfering with granuloma organization. This study showed that the use of drugs with immunomodulatory actions, such as dexamethasone, in addition to interfering with the morbidity from the pulmonary cycle of S. venezuelensis infection, may contribute to showing the mechanisms involved in its pathogenesis.     

胎儿超声心动图诊断左心发育不良综合征13例报道

目的:探讨应用胎儿超声心动图对左心发育不良综合征(HLHS),诊断方法及诊断价值。方法:对胎儿超声心动图检出的13例HLHS胎儿的超声资料与病理解剖结果对照,分析胎儿超声心动图诊断要点。结果:经病理证实为HLHS 13例,均与超声诊断结果一致,超声诊断正确率100%。13例HLHS患儿中,Ⅰ型2例(15.4%),Ⅱ型5例(38.4%),Ⅲ型2例(15.4%),Ⅳ型4例(30.8%)。超声提示13例均显示左、右心系统比例极端不对称,左心室小、发育不良,右心系统比例增大,主肺动脉内径比例失调,主肺动脉血流方向呈反向。结论:产前胎儿超声心动图作为一种安全、便捷、经济及有效的检查方法,对胎儿左心发育不良综合征的检出具有重要的价值。     

Induction of gastric lesions and hypoglycemic response by food deprivation in streptozotocin-diabetic rats

Overnight fasting causes hemorrhagic lesions in the stomach of streptozotocin (STZ)-induced diabetic rats, but the pathogenetic mechanism remains unknown. The present study was performed to investigate the pathogenesis of such lesions developed in STZ-diabetic rats after starvation, mainly in relation to blood glucose changes. A single injection of STZ (70 mg/kg, intraperitoneally) induced hyperglycemic conditions one week after the administration, and high blood glucose levels (BGL: >350 mg%) remained up to three weeks later. The STZ-diabetic rats developed gastric lesions with the marked reduction of BGL after 18 hr of fasting, depending upon the duration of diabetes; the lesion score and BGL reduction in the 3-week-old STZ rats were 32.0±7.8 mm and >250 mg/100 ml, respectively. Acid secretion in the pylorus-ligated rats was not significantly changed in the STZ-induced diabetic conditions for the initial two weeks but slightly decreased at three weeks when compared with normal rats. Fasting of normal rats for 18 hr did not cause either BGL reduction or any lesion in the stomach. In the 3-week-old STZ animals, the severity of gastric lesions increased with the duration of fasting (4–18 hr) and was again closely associated with the degree of BGL reduction. These lesions induced by 18 hr of starvation in 3-week-old STZ rats were significantly inhibited by pretreatment with insulin (4 units/rat/day) for the last one week to maintain BGL within normal ranges or by intravenous infusion of 25% glucose during fasting period. Both of these treatments significantly prevented BGL reduction in response to fasting. These results suggest that gastric lesions induced in STZ-diabetic rats by fasting are insulin-sensitive and may be associated with a profound hypoglycemic response to food deprivation.     

The development of retinopathy in sucrose-fed and streptozotocin-diabetic rats

Summary Normal and streptozotocin-diabetic rats have been maintained for 6–11 months on completely balanced, reconstituted diets in which the sole source of carbohydrate was either 68% corn starch or 68% sucrose. The retinal vascular system was isolated by trypsin digestion and examined histologically for the presence of tortuosity and irregularity of capillary diameter, increased PAS-positive deposits, microaneurysms, loss of pericytes, endothelial proliferation, acellularity and strand formation. None of these pathological changes occurred in normal rats fed a starch-rich diet, but all developed to a similar extent in the sucrose-fed normal rats and the starch-fed diabetic group. The changes were more severe in sucrose-fed diabetic rats after 6 months. In all groups the retinopathy progressed with time. The possibility that a factor common to both the ingestion of a sucrose-rich diet and streptozotocin diabetes in rats has been considered since, histologically, the retinopathy observed was identical both with respect to severity and rate of development in normoglycaemic, sucrose-fed and hyperglycaemic, starch-fed diabetic rats.