Abstract 13158: Impact of Enhancing Fetal Lung Vascular and Alveolar Development by Slow-release Novel Synthetic Prostacyclin Agonist for Treatment of Fetal Lung Hypoplasia

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Satoshi Umeda ◽  
Shigeru Miyagawa ◽  
Satsuki Fukushima ◽  
Akima Harada ◽  
Atsuhiro Saito ◽  
...  
Keyword(s):  
Placebo Group ◽  
Slow Release ◽  
Weight Ratio ◽  
Fetal Lung ◽  
Capillary Density ◽  
Maternal Blood ◽  
Lung Hypoplasia ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Medial Wall Thickness

Background: Lung hypoplasia and persistent pulmonary hypertension associated with critical pathologies, such as congenital diaphragmatic hernia (CDH), is the major cause of mortality in the neonates. Although prostaglandins pathway is known to play a pivotal role in the lung development, effectiveness of postnatal treatment by prostaglandin agonists was reported to be suboptimal. We hypothesized that prenatal treatment by ONO-1301SR, slow-release form of a novel synthetic prostacyclin agonist with thromboxane inhibitory activity, might promote development of lungs having hypoplasia in the fetal period. Methods: On embryonic day (E) 9.5, nitrofen was given to pregnant Sprague-Dawley rats to produce a CDH-relating lung hypoplasia model, while normal rats (n=4) received vehicle only. At the same day, either ONO-1301SR or placebo was randomly given to the nitrofen-treated rats (placebo; n=7, ONO; n=5). On E21.5, the normal fetuses, and the fetuses having CDH were analyzed. Results: Prenatal ONO-1301SR administration had no influence on incidence of nitrofen-induced CDH. One-seventh of maternal blood concentration of ONO-1301 was transferred to fetal blood at E21.5, warranting efficient placental permeability of this molecule. Prostacyclin receptor was expressed in pulmonary arterial smooth muscle cells in the fetus. Lung-to-body weight ratio (%) in the ONO group (1.88±0.07) was greater than that in the placebo group (1.60±0.04, p<0.01). Histologically, medial wall thickness in the ONO group was two-third thinner than that in the placebo group (p<0.01). In addition, the number of Ttf-1-positive cells and capillary density were 1.5 times or more greater in the ONO group than that in the placebo group (p<0.05), associated with a greater expression of VEGF and SDF-1 in the ONO group, suggesting enhanced development of the alveolar and capillary network. Conclusions: Prenatal ONO-1301SR administration promoted efficient development of hypoplastic lungs associated with CDH in the nitrofen-induced rat model, indicating potential of this treatment for pathologies having lung hypoplasia.

scholarly journals Notch signaling-modified mesenchymal stem cells improve tissue perfusion by induction of arteriogenesis in a rat hindlimb ischemia model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shusaku Maeda ◽  
Shigeru Miyagawa ◽  
Takuji Kawamura ◽  
Takashi Shibuya ◽  
Kenichi Watanabe ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Tissue Perfusion ◽  
Human Mesenchymal Stem Cell ◽  
Capillary Density ◽  
Adductor Muscle ◽  
Notch Signaling Pathway ◽  
Hindlimb Ischemia ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Whole Transcriptome Analysis

AbstractNotch signaling-modified human mesenchymal stem cell, SB623 cell, is a promising cell therapy product for ischemic stroke. With the aim to expand indications for their use for critical limb-threatening ischemia (CLTI), we hypothesized that SB623 cells improved tissue perfusion by inducing angiogenesis or arteriogenesis in a hindlimb ischemia model rat. In Sprague–Dawley rats, hindlimb ischemia was generated by femoral artery removal, then seven days after ischemic induction 1 × 105 SB623 cells or PBS was injected into the ischemic adductor muscle. As compared with the PBS group, tissue perfusion was significantly increased in the SB623 group. While capillary density did not vary between the groups, αSMA- and vWF-positive arterioles with a diameter  > 15 μm were significantly increased in the SB623 group. Whole transcriptome analysis of endothelial cells co-cultured with SB623 cells showed upregulation of the Notch signaling pathway as well as several other pathways potentially leading to arteriogenesis. Furthermore, rat muscle treated with SB623 cells showed a trend for higher ephrin-B2 and significantly higher EphB4 expression, which are known as arteriogenic markers. In the hindlimb ischemia model, SB623 cells improved tissue perfusion by inducing arteriogenesis, suggesting a promising cell source for treatment of CLTI.

Mineralocorticoid Receptor Activation by Aldosterone or Corticosterone Induces Hypertension, Myocardial Infarction and Proteinuria

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 723-723
Author(s):  
Qing-Feng Tao ◽  
Diego Martinez vasquez ◽  
Ricardo Rocha ◽  
Gordon H Williams ◽  
Gail K Adler
Keyword(s):  
Myocardial Infarction ◽  
Drinking Water ◽  
Mineralocorticoid Receptor ◽  
Critical Role ◽  
Weight Ratio ◽  
Myocardial Necrosis ◽  
Receptor Activation ◽  
Control Group ◽  
Sprague Dawley ◽  
Sprague Dawley Rats

P165 Aldosterone through its interaction with the mineralocorticoid receptor (MR) plays a critical role in the development of hypertension and cardiovascular injury (CVI). Normally, MR is protected by 11β-hydroxysteroid dehydrogenase (11β-HSD) which inactivates glucocorticoids preventing their binding to MR. We hypothesis that if activation of MR by either aldosterone or glucocorticoids induces hypertension and CVI, then the inhibition of 11β-HSD with glycyrrhizin (GA), a natural inhibitor of 11β-HSD, should induce damage similar to that observed with aldosterone. Sprague-Dawley rats were uninephrectomized, and treated for 4 weeks with 1% NaCl (in drinking water) for the control group, 1% NaCl + aldosterone infusion (0.75 μg/h), or 1% NaCl + GA (3.5 g/l in drinking water). After 4 weeks, aldosterone and GA caused significant increases in blood pressure compared to control rats ([mean ± SEM] 211± 9, 205 ± 12, 120 ± 9 mmHg, respectively, p<0.001). Both aldosterone- and GA-treated rats had a significant increase in proteinuria (152.2 ± 8.7 and 107.7 ± 19.5 mg/d, respectively) versus controls (51.2 ± 9.5 mg/d). There was a significant increase (p<0.001) in heart to body weight ratio in the rats treated with aldosterone or GA compared with control (3.92 ± 0.10, 3.98 ± 0.88, and 3.24 ± 0.92 mg/g, respectively). Hearts of GA and aldosterone treated rats showed similar histological changes consisting of biventricular myocardial necrosis and fibrinoid necrosis of small coronary arteries and arterioles. These data suggests that in rodents activation of MR by either aldosterone or corticosterone leads to severe hypertension, vascular injury, proteinuria and myocardial infarction. Thus, 11β-HSD plays an important role in protecting the organism from injury.

Abstract 114: K+ Rich Diet During Angiotensin II Hypertension Reduces Renal Na-Cl Cotransporter and Phosphorylation, but Not Blood Pressure

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Luciana C Veiras ◽  
Jiyang Han ◽  
Donna L Ralph ◽  
Alicia A McDonough
Keyword(s):  
Blood Pressure ◽  
Urine Volume ◽  
Weight Ratio ◽  
Distal Tubule ◽  
Reduce Blood Pressure ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
K Secretion ◽  
Pressure Natriuresis

During Ang II hypertension distal tubule Na-Cl Cotransporter (NCC) abundance and its activating phosphorylation (NCCp), as well as Epithelial Na+ channels (ENaC) abundance and activating cleavage are increased 1.5-3 fold. Fasting plasma [K+] is significantly lower in Ang II hypertension (3.3 ± 0.1 mM) versus controls (4.0 ± 0.1 mM), likely secondary to ENaC stimulation driving K+ secretion. The aim of this study was to test the hypothesis that doubling dietary K+ intake during Ang II infusion will lower NCC and NCCp abundance to increase Na+ delivery to ENaC to drive K+ excretion and reduce blood pressure. Methods: Male Sprague Dawley rats (225-250 g; n= 7-9/group) were treated over 2 weeks: 1) Control 1% K diet fed (C1K); 2) Ang II infused (400 ng/kg/min) 1% K diet fed (A1K); or 3) Ang II infused 2% K diet fed (A2K). Blood pressure (BP) was determined by tail cuff, electrolytes by flame photometry and transporters’ abundance by immunoblot of cortical homogenates. Results: As previously reported, Ang II infusion increased systolic BP (from 132 ± 5 to 197 ± 4 mmHg), urine volume (UV, 2.4 fold), urine Na+ (UNaV, 1.3 fold), heart /body weight ratio (1.23 fold) and clearance of endogenous Li+ (CLi, measures fluid volume leaving the proximal tubule, from 0.26 ± 0.02 to 0.51 ± 0.01 ml/min/kg) all evidence for pressure natriuresis. A2K rats exhibited normal plasma [K+] (4.6 ± 0.1 mM, unfasted), doubled urine K+ (UKV, from 0.20 to 0.44 mmol/hr), and increased CLi (to 0.8 ± 0.1 ml/min/kg) but UV, UNaV, cardiac hypertrophy and BP were unchanged versus the A1K group. As expected, NCC, NCCpS71 and NCCpT53 abundance increased in the A1K group to 1.5 ± 0.1, 2.9 ± 0.5 and 2.8 ± 0.4 fold versus C1K, respectively. As predicted by our hypothesis, when dietary K+ was doubled (A2K), Ang II infusion did not activate NCC, NCCpS71 nor NCCpT53 (0.91 ± 0.04, 1.3 ± 0.1 and 1.6 ± 0.2 fold versus C1K, respectively). ENaC subunit abundance and cleavage increased 1.5 to 3 fold in both A1K and A2K groups; ROMK was unaffected by Ang II or dietary K. In conclusion, evidence is presented that stimulation of NCC during Ang II hypertension is secondary to K+ deficiency driven by ENaC stimulation since doubling dietary K+ prevents the activation. The results also indicate that elevation in BP is independent of NCC activation

Exercise training and its effects with renal hypertensive rats

1985 ◽  
Vol 59 (5) ◽  
pp. 1410-1415 ◽  
Author(s):  
K. D. Marcus ◽  
C. M. Tipton
Keyword(s):  
Blood Pressure ◽  
Exercise Training ◽  
Capillary Density ◽  
Heart Weight ◽  
Sprague Dawley ◽  
Vo2 Max ◽  
Arterial Blood ◽  
Sprague Dawley Rats ◽  
Resting Blood Pressure ◽  
Renal Hypertensive Rats

The influence of endurance training on functional capacity [maximal O2 consumption (VO2 max)], caudal arterial blood pressure, and myocardial capillary density were investigated in normotensive rats and rats made hypertensive using the two-kidney one-clip approach (Goldblatt's hypertension). Male Sprague-Dawley rats were assigned to sham (N: 120–140 mmHg), moderately hypertensive (MH = 0.30-mm clips, 150–170 mmHg), or severely hypertensive (SH = 0.25-mm clips, 190–230 mmHg) groups. Rats designated to be runners (T) were exercised on a motor-driven treadmill equal to 50–70% of their VO2 max values for 8–12 wk. Compared with their nontrained (NT) controls, training was associated with significantly higher VO2 max values (12–15%) and muscle cytochrome-c oxidase activities (33–78%). Resting systolic blood pressure was not significantly changed in the N-and MH-T subgroups; however, it was 20–30 mmHg higher in the SH-T subgroup. Mean absolute heart weight for only the N-T group was significantly heavier than their NT controls. However, the mean predicted heart weights (heart wt = 0.639 X body wt of N-NT + 0.001 g) of the two SH groups were significantly higher than expected. The SH-T group had a lower (11%) subepicardial capillary density mean than its NT control and significantly fewer capillaries in the subendocardial region than the other five subgroups. It was concluded that moderate exercise training appeared to be detrimental to rats with severe hypertension because it increased resting blood pressure and decreased myocardial capillary density, even though it improved their functioning capacity.

Influence of protein deficiency in rats on hormonal status and cytoplasmic glucocorticoid receptors in maternal and fetal tissues

1982 ◽  
Vol 95 (1) ◽  
pp. 49-58 ◽  
Author(s):  
S. Mulay ◽  
D. R. Varma ◽  
S. Solomon
Keyword(s):  
Glucocorticoid Receptors ◽  
Fetal Liver ◽  
Fetal Lung ◽  
Maternal Plasma ◽  
Plasma Corticosterone ◽  
Protein Deficiency ◽  
Sprague Dawley ◽  
Pregnant Rats ◽  
Maternal Malnutrition ◽  
Sprague Dawley Rats

The influence of dietary protein deficiency on maternal plasma corticosterone and progesterone levels as well as on maternal and fetal liver and lung cytoplasmic glucocorti-coid receptors has been studied in Sprague–Dawley rats during the last 3 days of gestation. Plasma corticosterone levels of control but not protein-deficient rats increased on days 20 and 21 of gestation; corticosterone levels of protein-deficient rats decreased on day 21 of gestation. Maternal adrenalectomy caused only a moderate decrease in corticosterone levels in both groups of pregnant rats. Fetal corticosterone levels of the two groups of rats were similar. Progesterone levels were consistently lower in protein-deficient than in control animals from day 20 of gestation until 2–12 h after parturition. There were no differences in the binding of [3H]dexamethasone to liver cytosol of non-pregnant control and protein-deficient rats. However, receptor levels were lower in pregnant controls than in pregnant protein-deficient rats. Maternal protein deficiency led to an increase in fetal liver glucocorticoid receptor levels but exerted no significant effect on receptor levels in fetal lung. It is suggested that lower levels of plasma corticosterone and progesterone and high levels of liver glucocorticoid receptors in protein-deficient rats might be related to some of the adverse consequences of maternal malnutrition on fetal development.

scholarly journals Lactate as a Potential Biomarker of Sepsis in a Rat Cecal Ligation and Puncture Model

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Xiaozhu Zhai ◽  
Zhengfei Yang ◽  
Guanghui Zheng ◽  
Tao Yu ◽  
Peng Wang ◽  
...  
Keyword(s):  
Troponin I ◽  
Cecal Ligation ◽  
Weight Ratio ◽  
High Mobility ◽  
Dry Weight ◽  
Cecal Ligation And Puncture ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Potential Biomarker ◽  
Puncture Model

We attempted to investigate whether blood lactate is a useful biomarker for sepsis in a rat cecal ligation and puncture (CLP) model. Male Sprague-Dawley rats underwent approximately 75% cecum ligation and two punctures to induce high-grade sepsis. A lactate of 1.64 mmol/L (Youden score of 0.722) was selected as the best cutoff value to predict the onset of sepsis after CLP exposure; 46 of 50 rats who survived 24 hours after the CLP were divided into the L group (lactate < 1.64 mmol/L) and M group (lactate ≥ 1.64 mmol/L). In the M group, the animals had significantly higher murine sepsis scores and none survived 5 days post-CLP, and the rate of validated septic animals, serum procalcitonin, high mobility group box 1, blood urea nitrogen, alanine transaminase, cardiac troponin I, and the wet-to-dry weight ratio were significantly higher compared to the L group. Worsen PaO2/FiO2, microcirculations, and mean arterial pressure were observed in the M group. More severe damage in major organs was confirmed by histopathological scores in the M group compared with the L group. In conclusion, lactate ≥ 1.64 mmol/L might serve as a potential biomarker to identify the onset of sepsis in a rat CLP model.

scholarly journals Effect of diaspirin cross-linked hemoglobin on normal and postischemic microcirculation of the rat pancreas

1999 ◽  
Vol 276 (6) ◽  
pp. G1507-G1514 ◽  
Author(s):  
Ernst von Dobschuetz ◽  
Tomas Hoffmann ◽  
Clemens Engelschalk ◽  
Konrad Messmer
Keyword(s):  
Detrimental Effect ◽  
Oxygen Carrier ◽  
Capillary Density ◽  
Control Group ◽  
Leukocyte Adherence ◽  
Sprague Dawley ◽  
Rat Pancreas ◽  
Sprague Dawley Rats ◽  
Pancreatic Ischemia ◽  
Complete Restoration

Microcirculatory alterations with reduced nutritive supply to the pancreas could be the cause of hyperamylasemia, which occurs in some patients receiving the vasoactive oxygen carrier diaspirin cross-linked hemoglobin (DCLHb) in clinical studies. Therefore, the effects of DCLHb on rat pancreas microcirculation were evaluated. Anesthetized Sprague-Dawley rats received one of the following treatments during baseline conditions ( n = 7 rats/group): 10% hydroxyethyl starch (HAES) (0.4 ml/kg), DCLHb (400 mg/kg), or DCLHb (1,400 mg/kg). After 1 h of complete, reversible pancreatic ischemia, other animals received 10% HAES (0.4 ml/kg) or DCLHb (400 mg/kg) during the onset of reperfusion. The number of red blood cell-perfused capillaries (functional capillary density, FCD) and the level of leukocyte adherence in postcapillary venules in the pancreas were assessed by means of intravital microscopy during 2 h after treatment. In the nonischemic groups, FCD was 18% greater after DCLHb (1,400 mg/kg) than after 10% HAES treatment without any increase in leukocyte adherence. In the inschemia-reperfusion (I/R) 10% HAES group, FCD was significantly ( P < 0.05) lowered, leukocyte adherence enhanced, and mean arterial pressure (MAP) reduced by 31% compared with nonischemic animals. DCLHb treatment in the I/R group resulted in a slight increase in FCD, a significant ( P < 0.05) reduction of leukocyte adherence, and a complete restoration of MAP compared with the animals of the I/R control group. Thus our data provide no evidence for a detrimental effect on the pancreatic microcirculation or an enhanced risk of postischemic pancreatitis by DCLHb.

Abstract 10770: Curcumin Mitigates the Severity of Post-Resuscitation Myocardial Dysfunction Caused by Epinephrine in a Rat Cardiac Arrest Model

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Zhengfei Yang ◽  
Jiangang Wang ◽  
Lu Yin ◽  
Shen Zhao ◽  
Ziren Tang ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Placebo Group ◽  
Ventricular Fibrillation ◽  
Myocardial Function ◽  
Myocardial Dysfunction ◽  
Sprague Dawley ◽  
Successful Resuscitation ◽  
Sprague Dawley Rats ◽  
Group 3 ◽  
Group 2

Introduction: Epinephrine significantly increases the severity of post-resuscitation myocardial dysfunction (PRMD) and reduces the duration of survival. The cardioprotective effect of curcumin against catecholamine-induced cardiotoxicity has been established. In the present study, we investigated the effects of curcumin on PRMD caused by epinephrine in a rat model of cardiac arrest. Hypothesis: Curcumin reduces the severity of PRMD caused by epinephrine. Methods: Twenty-four male Sprague-Dawley rats weighing between 450-550g were randomized into three groups: 1) Placebo group; 2) Epinephrine (20ug/kg) group; 3) Curcumin (100 mg/kg) pretreatment + epinephrine (20ug/kg) group. Ventricular fibrillation (VF) was then induced. After 8 mins of VF, CPR was initiated for 8 mins, and defibrillation was then attempted. Myocardial function was measured by echocardiography at baseline and hourly for 4 hours following successful resuscitation. Results: All animals except for two in the placebo group were resuscitated. Post-resuscitation myocardial function was significantly impaired in all animals. Significantly worse myocardial function was observed in the Epinephrine group in comparison with the two other groups (Figure). However, myocardial function was significantly better in the animals treated with curcumin when compared with those in the two other groups (Figure). Conclusion: In a rat cardiac arrest model, curcumin reduced the severity of PRMD caused by epinephrine.

Impaired VEGF and nitric oxide signaling after nitrofen exposure in rat fetal lung explants

2008 ◽  
Vol 294 (1) ◽  
pp. L110-L120 ◽  
Author(s):  
Vincent Muehlethaler ◽  
Anette M. Kunig ◽  
Gregory Seedorf ◽  
Vivek Balasubramaniam ◽  
Steven H. Abman
Keyword(s):  
Nitric Oxide ◽  
Fetal Lung ◽  
Explant Culture ◽  
Vegf Receptor ◽  
Lung Growth ◽  
Sprague Dawley ◽  
Nitric Oxide Signaling ◽  
Sprague Dawley Rats ◽  
Lung Structure ◽  
Induced Changes

We hypothesized that abnormal fetal lung growth in experimental congenital diaphragmatic hernia after maternal nitrofen exposure alters lung structure due to impaired VEGF signaling, which can be reversed with VEGF or nitric oxide (NO) treatment. Timed-pregnant Sprague-Dawley rats were treated with nitrofen on embryonic day 9 (E9), and fetal lungs were harvested for explant culture on E15. Explants were maintained in 3% O2for 3 days and were treated with NO gas or recombinant human VEGF protein for 3 days. To determine the effects of VEGF inhibition on lung structure, normal fetal lung explants were treated with SU-5416, a VEGF receptor inhibitor, with or without exogenous NO or VEGF. We found that nitrofen treatment impaired lung structure, as evidenced by decreased branching at day 0, but lung structure was not different from controls after 3 days in culture. Nitrofen reduced lung VEGF but not endothelial NO synthase protein level. Treatment with NO enhanced lung growth in control and nitrofen-exposed lungs; however, the response to NO in the nitrofen-treated lungs was reduced when compared with controls. VEGF treatment did not cause a further increase in lung complexity after nitrofen exposure. SU-5416 treatment altered lung structure, which improved with NO but not VEGF treatment. Both nitrofen and SU-5416 treatment increased apoptosis in the mesenchyme of fetal lung explants. We conclude that nitrofen exposure increased apoptosis, decreased lung growth and reduced VEGF expression, and that exogenous NO but not VEGF treatment enhances lung growth. Disruption of lung architecture after VEGF receptor blockade was similar to nitrofen-induced changes but was more responsive to NO.

Sign in / Sign up

Export Citation Format

Share Document