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Sample records for neonatal rat ventricular

  1. Calcium current in isolated neonatal rat ventricular myocytes.

    PubMed Central

    Cohen, N M; Lederer, W J

    1987-01-01

    1. Calcium currents (ICa) from neonatal rat ventricular heart muscle cells grown in primary culture were examined using the 'whole-cell' voltage-clamp technique (Hamill, Marty, Neher, Sakmann & Sigworth, 1981). Examination of ICa was limited to one calcium channel type, 'L' type (Nilius, Hess, Lansman & Tsien, 1985), by appropriate voltage protocols. 2. We measured transient and steady-state components of ICa, and could generally describe ICa in terms of the steady-state activation (d infinity) and inactivation (f infinity) parameters. 3. We observed that the reduction of ICa by the calcium channel antagonist D600 can be explained by both a shift of d infinity to more positive potentials as well as a slight reduction of ICa conductance. D600 did not significantly alter either the rate of inactivation of ICa or the voltage dependence of f infinity. 4. The calcium channel modulator BAY K8644 shifted both d infinity and f infinity to more negative potentials. Additionally, BAY K8644 increased the rate of inactivation at potentials between +5 and +55 mV. Furthermore, BAY K8644 also increased ICa conductance, a change consistent with a promotion of 'mode 2' calcium channel activity (Hess, Lansman & Tsien, 1984). 5. We conclude that, as predicted by d infinity and f infinity, there is a significant steady-state component of ICa ('window current') at plateau potentials in neonatal rat heart cells. Modulation of the steady-state and transient components of ICa by various agents can be attributed both to specific alterations in d infinity and f infinity and to more complicated alterations in the mode of calcium channel activity. PMID:2451004

  2. Characterization of nifedipine-resistant calcium current in neonatal rat ventricular cardiomyocytes.

    PubMed

    Pignier, C; Potreau, D

    2000-11-01

    Calcium current was recorded from ventricular cardiomyocytes of rats at various stages of postnatal development using the whole cell patch-clamp technique. In cultured 3-day-old neonatal cells, the current carried by Ca(2+) or Ba(2+) (5 mM) was not completely inhibited by 2 microM nifedipine. A residual current was activated in the same voltage range as the L-type, nifedipine-sensitive Ca(2+) current, but its steady-state inactivation was negatively shifted by 16 mV. This nifedipine-resistant calcium current was not further inhibited by other organic calcium current antagonists such as PN200-110, verapamil, and diltiazem nor by nickel, omega-conotoxin, or tetrodotoxin. It was completely blocked by cadmium and increased by isoproterenol and forskolin. This current was >20% of total calcium current in ventricular myocytes freshly isolated from neonatal rats, and it decreased during postnatal maturation, disappearing at the adult stage. This suggests that this current could be caused by an isoform of the L-type calcium channel expressed in a way that reflects the developmental stage of the rat heart.

  3. Anisotropic conduction block and reentry in neonatal rat ventricular myocyte monolayers

    PubMed Central

    de Diego, Carlos; Chen, Fuhua; Xie, Yuanfang; Pai, Rakesh K.; Slavin, Leonid; Parker, John; Lamp, Scott T.; Qu, Zhilin; Valderrábano, Miguel

    2011-01-01

    Anisotropy can lead to unidirectional conduction block that initiates reentry. We analyzed the mechanisms in patterned anisotropic neonatal rat ventricular myocyte monolayers. Voltage and intracellular Ca (Cai) were optically mapped under the following conditions: extrastimulus (S1S2) testing and/or tetrodotoxin (TTX) to suppress Na current availability; heptanol to reduce gap junction conductance; and incremental rapid pacing. In anisotropic monolayers paced at 2 Hz, conduction velocity (CV) was faster longitudinally than transversely, with an anisotropy ratio [AR = CVL/CVT, where CVL and CVT are CV in the longitudinal and transverse directions, respectively], averaging 2.1 ± 0.8. Interventions decreasing Na current availability, such as S1S2 pacing and TTX, slowed CVL and CVT proportionately, without changing the AR. Conduction block preferentially occurred longitudinal to fiber direction, commonly initiating reentry. Interventions that decreased gap junction conductance, such as heptanol, decreased CVT more than CVL, increasing the AR and causing preferential transverse conduction block and reentry. Rapid pacing resembled the latter, increasing the AR and promoting transverse conduction block and reentry, which was prevented by the Cai chelator 1,2-bis oaminophenoxy ethane-N,N,N′,N′-tetraacetic acid (BAPTA). In contrast to isotropic and uniformly anisotropic monolayers, in which reentrant rotors drifted and self-terminated, bidirectional anisotropy (i.e., an abrupt change in fiber direction exceeding 45°) caused reentry to anchor near the zone of fiber direction change in 77% of monolayers. In anisotropic monolayers, unidirectional conduction block initiating reentry can occur longitudinal or transverse to fiber direction, depending on whether the experimental intervention reduces Na current availability or decreases gap junction conductance, agreeing with theoretical predictions. PMID:21037233

  4. Protein kinase C-alpha-induced hypertrophy of neonatal rat ventricular myocytes.

    PubMed

    Vijayan, Kalpana; Szotek, Erika L; Martin, Jody L; Samarel, Allen M

    2004-12-01

    Protein kinase C (PKC) isoenzymes play a critical role in cardiomyocyte hypertrophy. At least three different phorbol ester-sensitive PKC isoenzymes are expressed in neonatal rat ventricular myocytes (NRVMs): PKC-alpha, -delta, and -epsilon. Using replication-defective adenoviruses (AdVs) that express wild-type (WT) and dominant-negative (DN) PKC-alpha together with phorbol myristate acetate (PMA), which is a hypertrophic agonist and activator of all three PKC isoenzymes, we studied the role of PKC-alpha in signaling-specific aspects of the hypertrophic phenotype. PMA induced nuclear translocation of endogenous and AdV-WT PKC-alpha in NRVMs. WT PKC-alpha overexpression increased protein synthesis and the protein-to-DNA (P/D) ratio but did not affect cell surface area (CSA) or cell shape compared with uninfected or control AdV beta-galactosidase (AdV betagal)-infected cells. PMA-treated uninfected cells displayed increased protein synthesis, P/D ratio, and CSA and elongated morphology. PMA did not further enhance protein synthesis or P/D ratio in AdV-WT PKC-alpha-infected cells. To assess the requirement of PKC-alpha for these PMA-induced changes, AdV-DN PKC-alpha or AdV betagal-infected NRVMs were stimulated with PMA. Without PMA, AdV-DN PKC-alpha had no effects on protein synthesis, P/D ratio, CSA, or shape vs. AdV betagal-infected NRVMs. PMA increased protein synthesis, P/D ratio, and CSA in AdV betagal-infected cells, but these parameters were significantly reduced in PMA-stimulated AdV-DN PKC-alpha-infected NRVMs. Overexpression of DN PKC-alpha enhanced PMA-induced cell elongation. Neither WT PKC-alpha nor DN PKC-alpha affected atrial natriuretic factor gene expression. Insulin-like growth factor-1 also induced nuclear translocation of endogenous PKC-alpha. PMA but not WT PKC-alpha overexpression induced ERK1/2 activation. However, AdV-DN PKC-alpha partially blocked PMA-induced ERK activation. Thus PKC-alpha is necessary for certain aspects of PMA-induced NRVM

  5. H2 and H3 relaxin inhibit high glucose-induced apoptosis in neonatal rat ventricular myocytes.

    PubMed

    Zhang, Xiaohui; Ma, Xiao; Zhao, Meng; Zhang, Bo; Chi, Jinyu; Liu, Wenxiu; Chen, Wenjia; Fu, Yu; Liu, Yue; Yin, Xinhua

    2015-01-01

    High concentrations of glucose induce cardiomyocyte apoptosis, and contribute to diabetic cardiomyopathy. Relaxin-2 and relaxin-3 are two members of the relaxin peptide family that are cardioprotective. However, it remains unknown whether relaxin-2 or relaxin-3 can regulate apoptosis in high glucose treated-neonatal rat ventricular myocytes (NRVMs). In cultured NRVMs, 33 mmol/l high glucose (HG) increased apoptosis in a time-dependent manner. HG-increased the protein expression of cleaved caspase-8 and -9, two initiators of the extrinsic and intrinsic pathways of apoptosis, Caspase-3 was attenuated by human recombinant relaxin-2 (H2 relaxin) or relaxin-3 (H3 relaxin), indicating that H2 and H3 relaxin inhibited HG-induced apoptosis. Furthermore, endoplasmic reticulum stress (ERS) markers CHOP and caspase-12 were markedly increased in HG-treated NRVMs, leading to apoptosis; this effect was also effectively attenuated by H2 relaxin or H3 relaxin. Treatment of NRVMs with HG reduced autophagy which cannot be adjusted by H2 relaxin or H3 relaxin. In conclusion, HG-induced apoptosis in NRVMs was mediated, in part, by the activation of the extrinsic and intrinsic pathways of apoptosis and ERS, all inhibited by H2 relaxin or H3 relaxin.

  6. Long-term cardiovascular effects of neonatal dexamethasone treatment: hemodynamic follow-up by left ventricular pressure-volume loops in rats.

    PubMed

    Bal, Miriam P; de Vries, Willem B; van Oosterhout, Matthijs F M; Baan, Jan; van der Wall, Ernst E; van Bel, Frank; Steendijk, Paul

    2008-02-01

    Dexamethasone is clinically applied in preterm infants to treat or prevent chronic lung disease. However, concern has emerged about adverse side effects. The cardiovascular short-term side effects of neonatal dexamethasone treatment are well documented, but long-term consequences are unknown. Previous studies showed suppressed mitosis during dexamethasone treatment, leading to reduced ventricular weight, depressed systolic function, and compensatory dilatation in prepubertal rats. In addition, recent data indicated a reduced life expectancy. Therefore, we investigated the long-term effects of neonatal dexamethasone treatment on cardiovascular function. Neonatal rats were treated with dexamethasone or received saline. Cardiac function was determined in 8-, 50-, and 80-wk-old animals, representing young adult, middle-aged, and elderly stages. A pressure-conductance catheter was introduced into the left ventricle to measure pressure-volume loops. Subsequently, the hearts were collected for histological examination. Our results showed reduced ventricular and body weights in dexamethasone-treated rats at 8 and 80 wk, but not at 50 wk. Cardiac output and diastolic function were unchanged, but systolic function was depressed at 50 and 80 wk, evidenced by reduced ejection fractions and rightward shifts of the end-systolic pressure-volume relationships. We concluded that previously demonstrated early adverse effects of neonatal dexamethasone treatment are transient but that reduced ventricular weight and systolic dysfunction become manifest again in elderly rats. Presumably, cellular hypertrophy initially compensates for the dexamethasone treatment-induced lower number of cardiomyocytes, but this mechanism falls short at a later stage, leading to systolic dysfunction. If applicable to humans, cardiac screening of a relatively large patient group to enable secondary prevention may be indicated.

  7. Antiarrhythmic effects of (-)-epicatechin-3-gallate, a novel sodium channel agonist in cultured neonatal rat ventricular myocytes.

    PubMed

    Wu, Adonis Zhi-Yang; Loh, Shih-Hurng; Cheng, Tzu-Hurng; Lu, Hsin-Hsiang; Lin, Cheng-I

    2013-01-01

    (-)-Epicatechin-3-gallate (ECG), a polyphenol extracted from green tea, has been proposed as an effective compound for improving cardiac contractility. However, the therapeutic potential of ECG on the treatment of arrhythmia remains unknown. We investigated the direct actions of ECG on the modulation of ion currents and cardiac cell excitability in the primary culture of neonatal rat ventricular myocyte (NRVM), which is considered a hypertrophic model for analysis of myocardial arrhythmias. By using the whole-cell patch-clamp configurations, we found ECG enhanced the slowly inactivating component of voltage-gated Na(+) currents (I(Na)) in a concentration-dependent manner (0.1-100 μM) with an EC(50) value of 3.8 μM. ECG not only shifted the current-voltage relationship of peak I(Na) to the hyperpolarizing direction but also accelerated I(Na) recovery kinetics. Working at a concentration level of I(Na) enhancement, ECG has no notable effect on voltage-gated K(+) currents and L-type Ca(2+) currents. With culture time increment, the firing rate of spontaneous action potential (sAP) in NRVMs was gradually decreased until spontaneous early after-depolarization (EAD) was observed after about one week culture. ECG increased the firing rate of normal sAP about two-fold without waveform alteration. Interestingly, the bradycardia-dependent EAD could be significantly restored by ECG in fast firing rate to normal sAP waveform. The expression of dominant cardiac sodium channel subunit, Nav1.5, was consistently detected throughout the culture periods. Our results reveal how ECG, the novel I(Na) agonist, may act as a promising candidate in clinical applications on cardiac arrhythmias. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Decorin and colchicine as potential treatments for post-haemorrhagic ventricular dilatation in a neonatal rat model.

    PubMed

    Hoque, Nicholas; Thoresen, Marianne; Aquilina, Kristian; Hogan, Sarah; Whitelaw, Andrew

    2011-01-01

    Post-haemorrhagic ventricular dilatation (PHVD) after intraventricular haemorrhage (IVH) remains a significant problem in preterm infants. Due to serious disadvantages of ventriculoperitoneal shunt dependence, there is an urgent need for non-surgical interventions. Considerable experimental and clinical evidence implicates transforming growth factor β (TGFβ) in the pathogenesis of PHVD. Colchicine and decorin are both compounds with anti-TGFβ properties. The former downregulates TGFβ production and is in clinical use for another fibrotic disease, and the latter inactivates TGFβ. We hypothesized that administration of decorin or colchicine, which both have anti-TGFβ properties, would reduce ventricular dilatation in a model of PHVD. 142 rat pups underwent intraventricular blood injection on postnatal days (PN) 7 and 8. Sixty-nine pups were randomized to colchicine 20 and 50 μg/kg/day or water by gavage for 13 days. Seventy were randomized to decorin 4 mg/kg or saline by intraventricular injection on PN8 and PN13. At PN21, the ventricular area was measured on coronal brain sections. Negative geotaxis was tested at PN14 in controls and in the decorin study group. Ventricular size was not different between animals receiving either drug or water/saline. Intraventricular blood impaired neuromotor performance, but decorin had no effect. Two drugs that block TGFβ by different mechanisms do not reduce ventricular dilatation in this model. Together with our previous work on losartan and pirfenidone, we conclude that blocking TGFβ alone does not prevent the development of PHVD. Copyright © 2011 S. Karger AG, Basel.

  9. Calcium-sensing receptor activation contributed to apoptosis stimulates TRPC6 channel in rat neonatal ventricular myocytes

    SciTech Connect

    Sun, Yi-hua; Li, Yong-quan; Feng, Shan-li; Li, Bao-xin; Pan, Zhen-wei; Xu, Chang-qing; Li, Ting-ting; Yang, Bao-feng

    2010-04-16

    Capacitative calcium entry (CCE) refers to the influx of calcium through plasma membrane channels activated on depletion of endoplasmic sarcoplasmic/reticulum (ER/SR) Ca{sup 2+} stores, which is performed mainly by the transient receptor potential (TRP) channels. TRP channels are expressed in cardiomyocytes. Calcium-sensing receptor (CaR) is also expressed in rat cardiac tissue and plays an important role in mediating cardiomyocyte apoptosis. However, there are no data regarding the link between CaR and TRP channels in rat heart. In this study, in rat neonatal myocytes, by Ca{sup 2+} imaging, we found that the depletion of ER/SR Ca{sup 2+} stores by thapsigargin (TG) elicited a transient rise in cytoplasmic Ca{sup 2+} ([Ca{sup 2+}]{sub i}), followed by sustained increase depending on extracellular Ca{sup 2+}. But, TRP channels inhibitor (SKF96365), not L-type channels or the Na{sup +}/Ca{sup 2+} exchanger inhibitors, inhibited [Ca{sup 2+}]{sub i} relatively high. Then, we found that the stimulation of CaR with its activator gadolinium chloride (GdCl{sub 3}) or by an increased extracellular Ca{sup 2+}([Ca{sup 2+}]{sub o}) increased the concentration of intracelluar Ca{sup 2+}, whereas, the sustained elevation of [Ca{sup 2+}]{sub i} was reduced in the presence of SKF96365. Similarly, the duration of [Ca{sup 2+}]{sub i} increase was also shortened in the absence of extracellular Ca{sup 2+}. Western blot analysis showed that GdCl{sub 3} increased the expression of TRPC6, which was reversed by SKF96365. Additionally, SKF96365 reduced cardiomyocyte apoptosis induced by GdCl{sub 3}. Our results suggested that CCE exhibited in rat neonatal myocytes and CaR activation induced Ca{sup 2+}-permeable cationic channels TRPCs to gate the CCE, for which TRPC6 was one of the most likely candidates. TRPC6 channel was functionally coupled with CaR to enhance the cardiomyocyte apoptosis.

  10. Carbon Nanohorns Promote Maturation of Neonatal Rat Ventricular Myocytes and Inhibit Proliferation of Cardiac Fibroblasts: a Promising Scaffold for Cardiac Tissue Engineering

    NASA Astrophysics Data System (ADS)

    Wu, Yujing; Shi, Xiaoli; Li, Yi; Tian, Lei; Bai, Rui; Wei, Yujie; Han, Dong; Liu, Huiliang; Xu, Jianxun

    2016-06-01

    Cardiac tissue engineering (CTE) has developed rapidly, but a great challenge remains in finding practical scaffold materials for the construction of engineered cardiac tissues. Carbon nanohorns (CNHs) may be a potential candidate due to their special structure and properties. The purpose of this study was to assess the effect of CNHs on the biological behavior of neonatal rat ventricular myocytes (NRVMs) for CTE applications. CNHs were incorporated into collagen to form growth substrates for NRVMs. Transmission electron microscopy (TEM) observations demonstrated that CNHs exhibited a good affinity to collagen. Moreover, it was found that CNH-embedded substrates enhanced adhesion and proliferation of NRVMs. Immunohistochemical staining, western blot analysis, and intracellular calcium transient measurements indicated that the addition of CNHs significantly increased the expression and maturation of electrical and mechanical proteins (connexin-43 and N-cadherin). Bromodeoxyuridine staining and a Cell Counting Kit-8 assay showed that CNHs have the ability to inhibit the proliferation of cardiac fibroblasts. These findings suggest that CNHs can have a valuable effect on the construction of engineered cardiac tissues and may be a promising scaffold for CTE.

  11. MicroRNA-27a Regulates Beta Cardiac Myosin Heavy Chain Gene Expression by Targeting Thyroid Hormone Receptor β1 in Neonatal Rat Ventricular Myocytes▿

    PubMed Central

    Nishi, Hitoo; Ono, Koh; Horie, Takahiro; Nagao, Kazuya; Kinoshita, Minako; Kuwabara, Yasuhide; Watanabe, Shin; Takaya, Tomohide; Tamaki, Yodo; Takanabe-Mori, Rieko; Wada, Hiromichi; Hasegawa, Koji; Iwanaga, Yoshitaka; Kawamura, Teruhisa; Kita, Toru; Kimura, Takeshi

    2011-01-01

    MicroRNAs (miRNAs), small noncoding RNAs, are negative regulators of gene expression and play important roles in gene regulation in the heart. To examine the role of miRNAs in the expression of the two isoforms of the cardiac myosin heavy chain (MHC) gene, α- and β-MHC, which regulate cardiac contractility, endogenous miRNAs were downregulated in neonatal rat ventricular myocytes (NRVMs) using lentivirus-mediated small interfering RNA (siRNA) against Dicer, an essential enzyme for miRNA biosynthesis, and MHC expression levels were examined. As a result, Dicer siRNA could downregulate endogenous miRNAs simultaneously and the β-MHC gene but not α-MHC, which implied that specific miRNAs could upregulate the β-MHC gene. Among 19 selected miRNAs, miR-27a was found to most strongly upregulate the β-MHC gene but not α-MHC. Moreover, β-MHC protein was downregulated by silencing of endogenous miR-27a. Through a bioinformatics screening using TargetScan, we identified thyroid hormone receptor β1 (TRβ1), which negatively regulates β-MHC transcription, as a target of miR-27a. Moreover, miR-27a was demonstrated to modulate β-MHC gene regulation via thyroid hormone signaling and to be upregulated during the differentiation of mouse embryonic stem (ES) cells or in hypertrophic hearts in association with β-MHC gene upregulation. These findings suggested that miR-27a regulates β-MHC gene expression by targeting TRβ1 in cardiomyocytes. PMID:21149577

  12. Isolation of cardiac myocytes and fibroblasts from neonatal rat pups.

    PubMed

    Golden, Honey B; Gollapudi, Deepika; Gerilechaogetu, Fnu; Li, Jieli; Cristales, Ricardo J; Peng, Xu; Dostal, David E

    2012-01-01

    Neonatal rat ventricular myocytes (NRVM) and fibroblasts (FBs) serve as in vitro models for studying fundamental mechanisms underlying cardiac pathologies, as well as identifying potential therapeutic targets. Both cell types are relatively easy to culture as monolayers and can be manipulated using molecular and pharmacological tools. Because NRVM cease to proliferate after birth, and FBs undergo phenotypic changes and senescence after a few passages in tissue culture, primary cultures of both cell types are required for experiments. Below we describe methods that provide good cell yield and viability of primary cultures of NRVM and FBs from 0 to 3-day-old neonatal rat pups.

  13. Isorhamnetin protects rat ventricular myocytes from ischemia and reperfusion injury.

    PubMed

    Zhang, Najuan; Pei, Fei; Wei, Huaying; Zhang, Tongtong; Yang, Chao; Ma, Gang; Yang, Chunlei

    2011-01-01

    Ischemia/reperfusion (I/R) has been known to cause damages to ventricular myocytes. Isorhamnetin, one member of flavonoid compounds, has cardioprotective effect, the effect that suggests a possible treatment for I/R damages. In the present investigation, we found that isorhamnetin could significantly promote the viability of neonatal rat ventricular myocytes that were exposed to ischemia/reperfusion (I/R) in vitro. Ventricular myocytes were obtained from neonatal SD rats, and then were divided randomly into three groups, namely I/R-/isor-, I/R+/isor- and I/R+/isor+ group. Before the whole experiment, the most appropriate concentration of isorhamnetin (4 μM) was determined by MTT assay. Our results showed that isorhamnetin could alleviate the damages of I/R to ventricular myocytes through inhibiting lactate dehydrogenase (LDH) activity, and repressing apoptosis. Compared with the counterpart of the I/R+/isor- group, LDH activity in the isorhamnetin-treated group weakened, halving from 24.1 ± 2.3 to 11.4 ± 1.2U/L. Additionally, flow cytometry showed the apparently increased apoptosis rate induced by I/R, the result that was further confirmed by transmission electron microscope. Administration of isorhamnetin, however, assuaged the apoptosis induced by I/R. Corresponding to the reduced apoptosis rate in the I/R+/isor+ group, western blotting assay showed increased amount of Bcl-2 and p53, decreased amount of Bax, and nuclear accumulation of NF-κB/p65.

  14. Outcomes of neonatal Ebstein's anomaly without right ventricular forward flow.

    PubMed

    Baek, Jae Suk; Yu, Jeong Jin; Im, Yu Mi; Yun, Tae-Jin

    2016-08-01

    In neonates with Ebstein's anomaly and absent right ventricular forward flow, pulmonary valve morphology is normal or abnormal. Although initial postnatal presentations of these 2 conditions are similar, clinical courses and therapeutic strategies for each category differ greatly. Among 29 neonates with Ebstein's anomaly without right ventricular forward flow on initial postnatal echocardiography, 16 had a normal pulmonary valve and 13 had an abnormal pulmonary valve. During the postnatal follow-up of the normal pulmonary valve group, right ventricular forward flow commenced approximately 10 days after birth (1-15 days). The ductus arteriosus was surgically ligated in 3 neonates to facilitate right ventricular forward flow. Biventricular or 1 1/2 ventricular physiology was eventually achieved in 14 patients in the normal pulmonary valve group (14/16, 88%) and 2 patients in the abnormal pulmonary valve group (2/13, 15.3%). With respect to the preoperative echocardiographic findings, the normal pulmonary valve group had a significantly larger pulmonary valve annulus (8.2 ± 1.4 mm in the normal pulmonary valve group and 6.4 ± 1.8 mm in the abnormal pulmonary valve group, P = .002) and smaller cardiothoracic ratio (0.79 ± 0.05 in the normal pulmonary valve group and 0.85 ± 0.07 in the abnormal pulmonary valve group, P = .03). Mild to moderate pulmonary regurgitation was present in all patients (16/16, 100%) in the normal pulmonary valve group, but 3 patients (3/13, 23%) in the abnormal pulmonary valve group also had pulmonary regurgitation. On logistic regression analysis, only pulmonary valve annulus size remained as an indicator of a normal pulmonary valve (P = .03). In patients with Ebstein's anomaly and absent right ventricular forward flow, large pulmonary valve annulus size indicated a normal pulmonary valve. Patients with a normal pulmonary valve showed better survival and had a higher probability of achieving biventricular hemodynamics

  15. Abnormal ventricular development in preterm neonates with visually normal MRIs

    NASA Astrophysics Data System (ADS)

    Shi, Jie; Wang, Yalin; Lao, Yi; Ceschin, Rafael; Mi, Liang; Nelson, Marvin D.; Panigrahy, Ashok; Leporé, Natasha

    2015-12-01

    Children born preterm are at risk for a wide range of neurocognitive and neurobehavioral disorders. Some of these may stem from early brain abnormalities at the neonatal age. Hence, a precise characterization of neonatal neuroanatomy may help inform treatment strategies. In particular, the ventricles are often enlarged in neurocognitive disorders, due to atrophy of surrounding tissues. Here we present a new pipeline for the detection of morphological and relative pose differences in the ventricles of premature neonates compared to controls. To this end, we use a new hyperbolic Ricci flow based mapping of the ventricular surfaces of each subjects to the Poincaré disk. Resulting surfaces are then registered to a template, and a between group comparison is performed using multivariate tensor-based morphometry. We also statistically compare the relative pose of the ventricles within the brain between the two groups, by performing a Procrustes alignment between each subject's ventricles and an average shape. For both types of analyses, differences were found in the left ventricles between the two groups.

  16. Echodense spinal subarachnoid space in neonates with progressive ventricular dilatation: a marker of noncommunicating hydrocephalus.

    PubMed

    Rudas, G; Almássy, Z; Papp, B; Varga, E; Méder, U; Taylor, G A

    1998-10-01

    Our purpose was to evaluate the frequency and clinical significance of echogenic debris in the spinal subarachnoid space of neonates at risk for progressive ventricular dilatation. Spinal sonography was performed on 15 neonates with severe intracranial hemorrhage (n = 10) or bacterial meningitis (n = 5). Spinal sonography also was performed on 16 control neonates. Images were analyzed for the presence and location of echogeric debris within the thoracolumbar subarachnoid space. Lumbar punctures were performed on all 31 neonates, and CSF was analyzed for cell count and protein content. Ten of 15 neonates required ventricular drainage procedures. Progressive ventricular dilatation occurred in 11 of 15 neonates with intracranial hemorrhage or meningitis. Echogenic debris was present in the thoracolumbar subarachnoid space on spinal sonography in every neonate with progressive ventricular dilatation compared with none of the 16 control neonates (p < .0001 by chi-square analysis). In addition, the 11 neonates with echogenic subarachnoid space had significantly higher protein and RBC contents in the lumbar CSF (p < .04). Echogenic subarachnoid space revealed by sonography is associated with progressive ventricular dilatation after severe intracranial hemorrhage or bacterial meningitis and is caused by high protein and RBC contents in the subarachnoid space. This finding may be helpful in identifying neonates who will not benefit from serial lumbar punctures for treatment of hydrocephalus.

  17. Internal right ventricular band for multiple ventricular septal defects in a neonate undergoing arterial switch and aortic arch repair.

    PubMed

    Carroll, William W; Shirali, Girish S; Bradley, Scott M

    2011-01-01

    A neonate presented with d-transposition of the great arteries, aortic arch hypoplasia, aortic coarctation, and multiple ventricular septal defects. During the arterial switch procedure and the aortic arch repair, a fenestrated Gore-Tex disk (W.L. Gore & Assoc, Flagstaff, AZ) was sewn into the right ventricular outflow tract to restrict pulmonary blood flow. The internal right ventricular band successfully controlled the pulmonary blood flow, maintaining a systemic oxygen saturation of 88% to 92%, and allowing growth from 3.5 to 10.5 kg. At 8 months of age, the internal band in the patient was removed, and the ventricular septal defects were successfully closed.

  18. Ventricular Parasystole in a Neonatal Rhesus Macaque (Macaca mulatta).

    PubMed

    Collins, Dalis E; Dozier, Brandy L; Stanton, Jeffrey J; Colgin, Lois Ma; MacAllister, Rhonda

    2016-12-01

    A 6-d-old Indian-origin female rhesus macaque (Macaca mulatta) presented with bradycardia shortly after sedation with ketamine. No other cardiac abnormalities were apparent. Approximately 2 wk after the initial presentation, the macaque was again bradycardic and exhibited a regularly irregular arrhythmia on a prestudy examination. ECG, echocardiography, blood pressure measurement, SpO2 assessment, and a CBC analysis were performed. The echocardiogram and bloodwork were normal, but the infant was hypotensive at the time of echocardiogram. The ECG revealed ventricular parasystole. Ventricular parasystole is considered a benign arrhythmia caused by an ectopic pacemaker that is insulated from impulses from the sinus node. Given this abnormality, the macaque was transferred to a short-term study protocol, according to veterinary recommendation. On the final veterinary exam, a grade 3 systolic murmur and a decrease in arrhythmia frequency were noted. Gross cardiac lesions were not identified at necropsy the following day. Cardiac tissue sections were essentially normal on microscopic examination. This infant did not display signs of cardiovascular insufficiency, and a review of the medical record indicated normal growth, feed intake and activity levels. This case demonstrates the importance of appropriate screening of potential neonatal and juvenile research candidates for occult cardiovascular abnormalities. Whether the arrhythmia diagnosed in this case was truly innocuous is unclear, given the documented hypotension and the development of a systolic heart murmur.

  19. Ventricular Zone Disruption in Human Neonates With Intraventricular Hemorrhage.

    PubMed

    McAllister, James P; Guerra, Maria Montserrat; Ruiz, Leandro Castaneyra; Jimenez, Antonio J; Dominguez-Pinos, Dolores; Sival, Deborah; den Dunnen, Wilfred; Morales, Diego M; Schmidt, Robert E; Rodriguez, Esteban M; Limbrick, David D

    2017-05-01

    To determine if ventricular zone (VZ) and subventricular zone (SVZ) alterations are associated with intraventricular hemorrhage (IVH) and posthemorrhagic hydrocephalus, we compared postmortem frontal and subcortical brain samples from 12 infants with IVH and 3 nonneurological disease controls without hemorrhages or ventriculomegaly. Birth and expiration estimated gestational ages were 23.0-39.1 and 23.7-44.1 weeks, respectively; survival ranges were 0-42 days (median, 2.0 days). Routine histology and immunohistochemistry for neural stem cells (NSCs), neural progenitors (NPs), multiciliated ependymal cells (ECs), astrocytes (AS), and cell adhesion molecules were performed. Controls exhibited monociliated NSCs and multiciliated ECs lining the ventricles, abundant NPs in the SVZ, and medial vs. lateral wall differences with a complex mosaic organization in the latter. In IVH cases, normal VZ/SVZ areas were mixed with foci of NSC and EC loss, eruption of cells into the ventricle, cytoplasmic transposition of N-cadherin, subependymal rosettes, and periventricular heterotopia. Mature AS populated areas believed to be sites of VZ disruption. The cytopathology and extension of the VZ disruption correlated with developmental age but not with brain hemorrhage grade or location. These results corroborate similar findings in congenital hydrocephalus in animals and humans and indicate that VZ disruption occurs consistently in premature neonates with IVH. © 2017 American Association of Neuropathologists, Inc. All rights reserved.

  20. Left ventricular volumetric conductance catheter for rats.

    PubMed

    Ito, H; Takaki, M; Yamaguchi, H; Tachibana, H; Suga, H

    1996-04-01

    Left ventricular (LV) volume (V) is an essential parameter for assessment of the cardiac pump function. Measurement of LVV in situ by a conductance catheter method has been widely used in dogs and humans but not yet in small experimental animals such as rats. We instituted a miniaturized six-electrode conductance catheter (3-F) for rat LVV measurement and its signal processing apparatus. We compared stroke volumes (SVs) simultaneously measured with this conductance catheter introduced into the LV through the apex and an electromagnetic flow probe placed on the ascending aorta during gradual decreases in LVV by an inferior vena caval occlusion. A high and linear correlation (r = 0.982) was obtained between these differently measured by SVs pooled from six rats. In another group of three rats, LV pressure was simultaneously measured with a 3-F catheter-tip micromanometer introduced into the LV through the apex. We obtained the slope of the end-systolic pressure-volume (P-V) relationship (Emax) by a gradual ascending aortic occlusion. After administration of propranolol, Emax obviously decreased with no change in volume intercept of the P-V relationship. The conductance volumetry proved to be useful in rats.

  1. Transcatheter pulmonary valve perforation and balloon dilatation in neonates with pulmonary atresia and intact ventricular septum

    PubMed Central

    Gerestein, C.G.; Berger, R.M.F.; Dalinghaus, M.; Bogers, A.J.J.C.; Witsenburg, M.

    2003-01-01

    Background Pulmonary atresia and intact ventricular septum is characterised by a great morphological variety. Treatment is not uniform. Objective To evaluate our experience with transcatheter valvotomy and balloon dilatation in neonates with pulmonary atresia and intact ventricular septum. Design Retrospective. Methods Between January 1997 and September 2000 five neonates with pulmonary atresia and intact ventricular septum underwent transcatheter valvotomy and balloon dilatation. Results The catheter intervention was performed at a mean age of 27 days (range 3-95 days). The atretic pulmonary valve was successfully perforated in all neonates. Subsequent balloon dilatation was successful in four neonates. Balloon dilatation was unsuccessful in one patient, who underwent an elective surgical valvotomy of the pulmonary valve after five days. Three patients needed a modified Blalock-Taussig shunt after a mean of 23 days. Four patients required repeated balloon dilatation after a mean of 227 days. Mean follow-up was 2.7 years (range 1-5 years). Conclusions Transcatheter perforation of the pulmonary valve membrane and balloon dilatation is a good, safe initial therapy in selected neonates with pulmonary atresia and intact ventricular septum. This procedure can prevent open-heart surgery in these patients in the first months of life. ImagesFigure 1Figure 2 PMID:25696158

  2. Impaired acclimatization to chronic hypoxia in adult male and female rats following neonatal hypoxia.

    PubMed

    Lumbroso, Delphine; Joseph, Vincent

    2009-08-01

    We tested the hypothesis that neonatal exposure to hypoxia alters acclimatization to chronic hypoxia later in life. Rat pups were exposed to normobaric hypoxia (12% O(2); nHx group) in a sealed chamber, or to normoxia (21% O(2); nNx group) from the day before birth to postnatal day 10. The animals were then raised in normal conditions until reaching 12 wk of age. At this age, we assessed ventilatory and hematological acclimatization to chronic hypoxia by exposing male and female nHx and nNx rats for 2 wk to 10% O(2). Minute ventilation, metabolic rate, hypoxic ventilatory response, hematocrit, and hemoglobin levels were measured both before and after acclimatization. We also quantified right ventricular hypertrophy as an index of pulmonary hypertension both before and after acclimatization. There was a significant effect of neonatal hypoxia that decreases ventilatory response (relative to metabolic rate, VE/VCO(2)) to acute hypoxia before acclimatization in males but not in females. nHx rats had an impaired acclimatization to chronic hypoxia characterized by altered respiratory pattern and elevated hematocrit and hemoglobin levels after acclimatization, in both males and females. Right ventricular hypertrophy was present before and after acclimatization in nHx rats, indicating that neonatal hypoxia results in pulmonary hypertension in adults. We conclude that neonatal hypoxia impairs acclimatization to chronic hypoxia in adults and may be a factor contributing to the establishment of chronic mountain sickness in humans living at high altitude.

  3. An improved technique for repeated gavage administration to rat neonates.

    PubMed

    Watanabe, Chiaki; Kuwagata, Makiko; Yoshimura, Shinsuke; Azegami, Jiro; Kojima, Kouichi; Ono, Hiroshi; Nagao, Tetsuji

    2003-09-01

    The technique for gavage administration to rat nurslings was improved to allow determination of the direct effects of chemical substances in the nurslings. Rat neonates were treated with distilled water from postnatal day 1 through 20 using this technique. The viability of neonates during the administration period was comparable to that of untreated neonates. No adverse effects of this technique on the development of neonates were found, and no histological alterations of the esophagus or pharynx. Therefore, we conclude that use of our improved gavage administration method will contribute to ensuring successful neonatal development and thus allowing accurate assessment of the toxicological effects of test compounds on rat nurslings.

  4. Metformin attenuates hyperoxia-induced lung injury in neonatal rats by reducing the inflammatory response.

    PubMed

    Chen, Xueyu; Walther, Frans J; Sengers, Rozemarijn M A; Laghmani, El Houari; Salam, Asma; Folkerts, Gert; Pera, Tonio; Wagenaar, Gerry T M

    2015-08-01

    Because therapeutic options are lacking for bronchopulmonary dysplasia (BPD), there is an urgent medical need to discover novel targets/drugs to treat this neonatal chronic lung disease. Metformin, a drug commonly used to lower blood glucose in type 2 diabetes patients, may be a novel therapeutic option for BPD by reducing pulmonary inflammation and fibrosis and improving vascularization. We investigated the therapeutic potential of daily treatment with 25 and 100 mg/kg metformin, injected subcutaneously in neonatal Wistar rats with severe experimental BPD, induced by continuous exposure to 100% oxygen for 10 days. Parameters investigated included survival, lung and heart histopathology, pulmonary fibrin and collagen deposition, vascular leakage, right ventricular hypertrophy, and differential mRNA expression in the lungs of key genes involved in BPD pathogenesis, including inflammation, coagulation, and alveolar development. After daily metformin treatment rat pups with experimental BPD had reduced mortality, alveolar septum thickness, lung inflammation, and fibrosis, demonstrated by a reduced influx of macrophages and neutrophils and hyperoxia-induced collagen III and fibrin deposition (25 mg/kg), as well as improved vascularization (100 mg/kg) compared with control treatment. However, metformin did not ameliorate alveolar enlargement, small arteriole wall thickening, vascular alveolar leakage, and right ventricular hypertrophy. In conclusion metformin prolongs survival and attenuates pulmonary injury by reducing pulmonary inflammation, coagulation, and fibrosis but does not affect alveolar development or prevent pulmonary arterial hypertension and right ventricular hypertrophy in neonatal rats with severe hyperoxia-induced experimental BPD.

  5. Metformin attenuates hyperoxia-induced lung injury in neonatal rats by reducing the inflammatory response

    PubMed Central

    Chen, Xueyu; Walther, Frans J.; Sengers, Rozemarijn M. A.; Laghmani, El Houari; Salam, Asma; Folkerts, Gert; Pera, Tonio

    2015-01-01

    Because therapeutic options are lacking for bronchopulmonary dysplasia (BPD), there is an urgent medical need to discover novel targets/drugs to treat this neonatal chronic lung disease. Metformin, a drug commonly used to lower blood glucose in type 2 diabetes patients, may be a novel therapeutic option for BPD by reducing pulmonary inflammation and fibrosis and improving vascularization. We investigated the therapeutic potential of daily treatment with 25 and 100 mg/kg metformin, injected subcutaneously in neonatal Wistar rats with severe experimental BPD, induced by continuous exposure to 100% oxygen for 10 days. Parameters investigated included survival, lung and heart histopathology, pulmonary fibrin and collagen deposition, vascular leakage, right ventricular hypertrophy, and differential mRNA expression in the lungs of key genes involved in BPD pathogenesis, including inflammation, coagulation, and alveolar development. After daily metformin treatment rat pups with experimental BPD had reduced mortality, alveolar septum thickness, lung inflammation, and fibrosis, demonstrated by a reduced influx of macrophages and neutrophils and hyperoxia-induced collagen III and fibrin deposition (25 mg/kg), as well as improved vascularization (100 mg/kg) compared with control treatment. However, metformin did not ameliorate alveolar enlargement, small arteriole wall thickening, vascular alveolar leakage, and right ventricular hypertrophy. In conclusion metformin prolongs survival and attenuates pulmonary injury by reducing pulmonary inflammation, coagulation, and fibrosis but does not affect alveolar development or prevent pulmonary arterial hypertension and right ventricular hypertrophy in neonatal rats with severe hyperoxia-induced experimental BPD. PMID:26047641

  6. Neurobehavioral Deficits in Progressive Experimental Hydrocephalus in Neonatal Rats.

    PubMed

    Olopade, F E; Shokunbi, M T

    2017-03-06

    Hydrocephalus is usually associated with functional deficits which can be assessed by neurobehavioral tests. This study characterizes the neurobehavioral deficits occurring with increasing duration and severity of ventriculomegaly in an experimental neonatal hydrocephalic rat model. Hydrocephalus was induced in three weeks old albino rats by intracisternal injection of kaolin while controls received sterile water injection. They were sacrificed in batches at one, four and eight weeks post-injection after neurobehavioral tests (forelimb grip strength, open field and Morris water maze tests) were performed. The hydrocephalic rats were also categorized into mild, moderate and severe hydrocephalus based on ventricular size. The indices of muscular strength and vertical movements in severely hydrocephalic rats were 28.05 ± 5.19 seconds and 7.29 ± 2.71 rearings respectively, compared to controls (75.68 ± 8.58 seconds and 17.09 ± 1.25 rearings respectively). At eight weeks, vertical movements were significantly reduced in hydrocephalic rats compared to controls (3.14 ± 1.3 vs 13 ± 4.11 rearings). At one week, indices of learning and memory were significantly reduced in hydrocephalic rats, compared to controls (0.89±0.31 vs 3.88±1.01 crossings), but at 8 weeks, the indices were similar (2.56 ± 0.41 vs 3.33 ± 0.71 crossings). Untreated hydrocephalus is accompanied by decline in motor functions which increase with duration and severity of ventriculomegaly. However, cognitive deficits appear to partially recover.

  7. Stimulation of the p38 Mitogen-activated Protein Kinase Pathway in Neonatal Rat Ventricular Myocytes by the G Protein–coupled Receptor Agonists, Endothelin-1 and Phenylephrine: A Role in Cardiac Myocyte Hypertrophy?

    PubMed Central

    Clerk, Angela; Michael, Ashour; Sugden, Peter H.

    1998-01-01

    We examined the activation of the p38 mitogen-activated protein kinase (p38-MAPK) pathway by the G protein–coupled receptor agonists, endothelin-1 and phenylephrine in primary cultures of cardiac myocytes from neonatal rat hearts. Both agonists increased the phosphorylation (activation) of p38-MAPK by ∼12-fold. A p38-MAPK substrate, MAPK-activated protein kinase 2 (MAPKAPK2), was activated approximately fourfold and 10 μM SB203580, a p38-MAPK inhibitor, abolished this activation. Phosphorylation of the MAPKAPK2 substrate, heat shock protein 25/27, was also increased. Using selective inhibitors, activation of the p38-MAPK pathway by endothelin-1 was shown to involve protein kinase C but not Gi/Go nor the extracellularly responsive kinase (ERK) pathway. SB203580 failed to inhibit the morphological changes associated with cardiac myocyte hypertrophy induced by endothelin-1 or phenylephrine between 4 and 24 h. However, it decreased the myofibrillar organization and cell profile at 48 h. In contrast, inhibition of the ERK cascade with PD98059 prevented the increase in myofibrillar organization but not cell profile. These data are not consistent with a role for the p38-MAPK pathway in the immediate induction of the morphological changes of hypertrophy but suggest that it may be necessary over a longer period to maintain the response. PMID:9679149

  8. Stem cell factor improves lung recovery in rats following neonatal hyperoxia-induced lung injury

    PubMed Central

    Miranda, Luis F.; Rodrigues, Claudia O.; Ramachandran, Shalini; Torres, Eneida; Huang, Jian; Klim, Jammie; Hehre, Dorothy; McNiece, Ian; Hare, Joshua M.; Suguihara, Cleide Y.; Young, Karen C.

    2016-01-01

    BACKGROUND Stem cell factor (SCF) and its receptor, c-kit, are modulators of angiogenesis. Neonatal hyperoxia-induced lung injury (HILI) is characterized by disordered angiogenesis. The objective of this study was to determine whether exogenous SCF improves recovery from neonatal HILI by improving angiogenesis. METHODS Newborn rats assigned to normoxia (RA: 20.9% O2) or hyperoxia (90% O2) from postnatal day (P) 2 to 15, received daily injections of SCF 100 µg/kg or placebo (PL) from P15 to P21. Lung morphometry was performed at P28. Capillary tube formation in SCF-treated hyperoxia-exposed pulmonary microvascular endothelial cells (HPMECs) was determined by Matrigel assay. RESULTS As compared with RA, hyperoxic-PL pups had decrease in alveolarization and in lung vascular density, and this was associated with increased right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and vascular remodeling. In contrast, SCF-treated hyperoxic pups had increased angiogenesis, improved alveolarization, and attenuation of pulmonary hypertension as evidenced by decreased RVSP, right ventricular hypertrophy, and vascular remodeling. Moreover, in an in vitro model, SCF increased capillary tube formation in hyperoxia-exposed HPMECs. CONCLUSION Exogenous SCF restores alveolar and vascular structure in neonatal rats with HILI by promoting neoangiogenesis. These findings suggest a new strategy to treat lung diseases characterized by dysangiogenesis. PMID:24153399

  9. Cerebral microbleeds in a neonatal rat model

    PubMed Central

    Carusillo Theriault, Brianna; Woo, Seung Kyoon; Karimy, Jason K.; Keledjian, Kaspar; Stokum, Jesse A.; Sarkar, Amrita; Coksaygan, Turhan; Ivanova, Svetlana; Gerzanich, Volodymyr

    2017-01-01

    Background In adult humans, cerebral microbleeds play important roles in neurodegenerative diseases but in neonates, the consequences of cerebral microbleeds are unknown. In rats, a single pro-angiogenic stimulus in utero predisposes to cerebral microbleeds after birth at term, a time when late oligodendrocyte progenitors (pre-oligodendrocytes) dominate in the rat brain. We hypothesized that two independent pro-angiogenic stimuli in utero would be associated with a high likelihood of perinatal microbleeds that would be severely damaging to white matter. Methods Pregnant Wistar rats were subjected to intrauterine ischemia (IUI) and low-dose maternal lipopolysaccharide (mLPS) at embryonic day (E) 19. Pups were born vaginally or abdominally at E21-22. Brains were evaluated for angiogenic markers, microhemorrhages, myelination and axonal development. Neurological function was assessed out to 6 weeks. Results mRNA (Vegf, Cd31, Mmp2, Mmp9, Timp1, Timp2) and protein (CD31, MMP2, MMP9) for angiogenic markers, in situ proteolytic activity, and collagen IV immunoreactivity were altered, consistent with an angiogenic response. Vaginally delivered pups exposed to prenatal IUI+mLPS had spontaneous cerebral microbleeds, abnormal neurological function, and dysmorphic, hypomyelinated white matter and axonopathy. Pups exposed to the same pro-angiogenic stimuli in utero but delivered abdominally had minimal cerebral microbleeds, preserved myelination and axonal development, and neurological function similar to naïve controls. Conclusions In rats, pro-angiogenic stimuli in utero can predispose to vascular fragility and lead to cerebral microbleeds. The study of microbleeds in the neonatal rat brain at full gestation may give insights into the consequences of microbleeds in human preterm infants during critical periods of white matter development. PMID:28158198

  10. Hydrostatic forces limit swelling of rat ventricular myocardium.

    PubMed

    Pine, M B; Brooks, W W; Nosta, J J; Abelmann, W H

    1981-11-01

    To study ventricular cellular volume regulation when cell membranes and ion pumps cannot prevent swelling, rat ventricular sections were incubated in modified Krebs-Henseleit solutions in which 1) potassium was substituted for sodium, ion for ion; or 2) sodium chloride was reduced to decrease osmolarity to 228, 171, or 114 mosM. Ventricular water, [3H]inulin and [3H]mannitol spaces, potassium, sodium, chloride, and protein contents, and resting transmembrane potentials were measured. Increases in ventricular cellular volume were less than 30% in potassium-substituted and extremely dilute media (114 mosM), in contrast to increases of over 100% in identically treated renal cortical slices. In potassium-substituted solution, the fluid gained by ventricular cells during incubation was hypertonic with respect to the bathing medium. In dilute solution (171 and 114 mosM), ventricular, cellular, and extracellular osmolarities equilibrated only after substantial losses of cellular ions had occurred. These findings support the existence of mechanical limitations to ventricular cellular swelling, which may be caused by a unique network of interstitial collagen present in ventricular myocardium.

  11. Developmental features of the neonatal brain: MR imaging. Part II. Ventricular size and extracerebral space.

    PubMed

    McArdle, C B; Richardson, C J; Nicholas, D A; Mirfakhraee, M; Hayden, C K; Amparo, E G

    1987-01-01

    Magnetic resonance (MR) imaging with a 0.6-T magnet was performed on 51 neonates, aged 29-42 weeks postconception. In 45 neonates, the ventricular/brain ratio (V/B) at the level of the frontal horns and midbody of the lateral ventricles ranged from 0.26 to 0.34. In six other infants a V/B of 0.36 or greater was associated with either cerebral atrophy or obstructive hydrocephalus. The width of the extracerebral space measured along specified points varied little in the neonatal period and ranged from 0 to 4 mm in 48 infants. Extracerebral space widths of 5-6 mm were seen in three other infants with severe asphyxia. Prominence of the subarachnoid space overlying the posterior parietal lobes is normal in neonates and should not be confused with cerebral atrophy. The authors conclude that V/B ratios of 0.26-0.34 and extracerebral space widths of 0-4 mm represent the normal range, and that neonates whose measurements exceed these values should be followed up.

  12. Computational tool for morphological analysis of cultured neonatal rat cardiomyocytes.

    PubMed

    Leite, Maria Ruth C R; Cestari, Idágene A; Cestari, Ismar N

    2015-08-01

    This study describes the development and evaluation of a semiautomatic myocyte edge-detector using digital image processing. The algorithm was developed in Matlab 6.0 using the SDC Morphology Toolbox. Its conceptual basis is the mathematical morphology theory together with the watershed and Euclidean distance transformations. The algorithm enables the user to select cells within an image for automatic detection of their borders and calculation of their surface areas; these areas are determined by adding the pixels within each myocyte's boundaries. The algorithm was applied to images of cultured ventricular myocytes from neonatal rats. The edge-detector allowed the identification and quantification of morphometric alterations in cultured isolated myocytes induced by 72 hours of exposure to a hypertrophic agent (50 μM phenylephrine). There was a significant increase in the mean surface area of the phenylephrine-treated cells compared with the control cells (p<;0.05), corresponding to cellular hypertrophy of approximately 50%. In conclusion, this edge-detector provides a rapid, repeatable and accurate measurement of cell surface areas in a standardized manner. Other possible applications include morphologic measurement of other types of cultured cells and analysis of time-related morphometric changes in adult cardiac myocytes.

  13. Renal inflammatory response to urinary tract infection in rat neonates.

    PubMed

    Zarepour, M; Moradpoor, H; Emamghorashi, F; Owji, S M; Roodaki, M; Khamoushi, M

    2015-09-01

    Urinary tract infection (UTI) is one of the most common bacterial infections. Maternal UTI is a risk factor for neonatal UTI. The aim of the present study was to determine the severity of renal inflammation in neonate rats born from mothers with induced UTI. Twelve pregnant rats (Sprague-Dawley) were included in study. The rats were divided into two groups (six rats in each group). In the first group, pyelonephritis was induced in the third trimester of pregnancy and the second group was used as a control group. After delivery, the neonates were divided into three groups based on days after birth (the 1 st, 3 rd and 7 th days after birth). In each group, two neonates of each mother were killed and a midline abdominal incision was made and both kidneys were aseptically removed. On the 7 th day, rat mothers were killed and their kidneys were removed. The preparations were evaluated with a bright field microscope for inflammatory response. Renal pathology showed inflammation in all UTI-induced mothers, but only two cases of neonates (2.1%) showed inflammation in the renal parenchyma. There was no relation between the positive renal culture and the pathological changes. We conclude that neonates with UTI born to UTI-induced mothers showed a lesser inflammatory response.

  14. [Echocardiographic study of left ventricular geometry in spontaneously hypertensive rats].

    PubMed

    Escudero, Eduardo M; Pinilla, Oscar A; Carranza, Verónica B

    2009-01-01

    The purpose of this study was to analyze by echocardiogram left ventricular (LV) geometry in spontaneously hypertensive rats (SHR). Echocardiographic study, systolic blood pressure and heart rate were obtained in 114 male, 4-month old rats, 73 SHR and 41 Wistar (W). Left ventricular mass index (LVMI), relative wall thickness (RWT), stroke volume, and mid ventricular shortening were calculated with echocardiographic parameters. Normal LV was defined considering the mean plus 2 SD of LVMI and RWT in W. Patterns of abnormal LV geometry were: LV concentric remodeling, LVMI < 2.06 mg/g - RWT > 0.71; eccentric, left ventricular hypertrophy (LVH), LVMI > 2.06 mg/g - RWT < 0.71; and concentric LVH, LVMI > 2.06 mg/g - RWT > 0.71. Systolic blood pressure (SBP) and cardiac output (CO) were used to obtain total peripheral resistance (TPR). twelve % of SHR had normal LV geometry; 18% LV concentric remodeling; 33% concentric LVH and 37% eccentric LVH. LV concentric remodeling showed the smallest CO and highest TPR of any group. Eccentric LVH presented similar SBP as the other SHR groups and high CO with lower TPR. Our findings in SHR exhibit different patterns of LV geometry like in humans. These results strengthen the similarities between SHR and human essential hypertension.

  15. [Effects of neuroendocrine obesity induction on systemic hemodynamics and left ventricular function of normotensive rats].

    PubMed

    Voltera, Alina F; Cesaretti, Mário L R; Ginoza, Milton; Kohlmann, Osvaldo

    2008-02-01

    The aim of this study was to evaluate the effects of obesity induced by neonatal Monosodium Glutamate (MSG) administration upon body weight, tail blood pressure, systemic hemodynamics and left ventricular function of Wistar rats. Two groups of Wistar rats were prepared: a) 18 animals made obese through the administration of 2 mg/Kg/SC of MSG during the first 11 days of the neonatal period and b)16 control animals (vehicle treated for the same period). Adults animals were followed from the 3rd up the 6th month of life with blood pressure and body weight being measured twice a week. At the end of this period, in part of animals from both groups, we evaluated the left ventricular function through the Langendorff isolated heart preparation whereas the remainders were used to evaluate the systemic hemodynamics through a termodilution method. MSG animals showed significant increases in heart rate (WST=235.0+/-35.1; MSG=312.0+/-90.8 bpm), total peripheral resistance (WST=0.312+/-0.100; MSG=0.535+/-0.195 mmHg.ml(-1).min) and in relative epididymal adipose tissue content (WST=2.076+/-0.622; MSG=2.731+/-0.722 g/100 g) and a reduction of systolic volume (WST=1.020+/-0.364; MSG=0.748+/-0.455 microl/bat). An increase in mean arterial pressure was also detected in obese animals during the hemodynamic evaluation. The increases in HR and TPR and the reduction in SV suggest an augmentation in the sympathetic activation of those obese normotensive rats associated with an increased visceral fat deposition.

  16. Left Ventricular Dysfunction Following Neonatal Pulmonary Valve Balloon Dilation for Pulmonary Atresia or Critical Pulmonary Stenosis.

    PubMed

    Ronai, Christina; Rathod, Rahul H; Marshall, Audrey C; Oduor, Rebecca; Gauvreau, Kimberlee; Colan, Steven D; Brown, David W

    2015-08-01

    Pulmonary valve (PV) balloon dilation (BD) is the primary therapy for infants born with critical pulmonary stenosis (PS) or membranous pulmonary atresia with intact ventricular septum (PAIVS). We observed left ventricular (LV) dysfunction in patients following BD and sought to determine its incidence, clinical course and associated risk factors. Clinical, echocardiographic and catheterization data for all patients who underwent neonatal (<2 weeks age) PV BD for critical PS or PAIVS between January 2000 and February 2014 were retrospectively analyzed (n = 129). Post-procedure LV dysfunction was defined as ejection fraction (EF) <54 %. Median age at PV BD was 1 day. Most (71 %) patients had critical PS. Median PV diameter pre-BD was 6.0 mm with PV z-scores -4.1 to 0.9, median LV EF pre-BD was 58 %. Post-BD LV dysfunction developed in 45 patients (35 %); 15 patients had LV EF ≤40 %. Median time to normalization of LV EF was 10 days (range 2-72). In univariate analysis, diagnosis (critical PS or PAIVS), right ventricle to LV pressure ratio pre-BD, acute procedural complication and post-BD inotropic support were not associated with post-BD LV dysfunction. In multivariable analysis, the predictors of post-procedure LV dysfunction were lower PV z-score (OR 1.81, p 0.04), tricuspid regurgitation pre-BD ≥ moderate (OR 3.73, p 0.008) and larger right ventricular apical area (OR 1.99, p 0.04). LV dysfunction post-neonatal PV BD develops in a significant number of patients (35 %) and can be severe, but resolves. The risk of developing LV dysfunction post-PV BD is highest in patients with larger right ventricles.

  17. The neurological effects of brevetoxin on neonatal rats

    SciTech Connect

    Tapley, S.R.; Ramsdell, J.S.; Xi, D.

    1994-12-31

    We have investigated the neuroexcitatory and neurodegenerative effects of brevetoxin on neonatal rats. Brevetoxin, a marine-biotoxin that has been implicated in several seafood poisoning incidents, is produced by the dinoflagellate Gymnodinium brevis. Four studies were done: dose response, northern analysis, immunohistochemistry and neurodegeneration. We found that neonatal rats are much more sensitive to brevetoxin than adult rats. The effectiveness of c-fos as a biomarker is being investigated, because of the high basal expression in young animals. The neurodegeneration, although not available yet, should provide valuable information.

  18. Acute and chronic morphine alters formalin pain in neonatal rats.

    PubMed

    Zissen, Maurice H; Zhang, Guohua; Kendig, Joan J; Sweitzer, Sarah M

    2006-05-29

    The present study tested the hypothesis that morphine exposure during the human developmental equivalent of the third trimester would alter inflammatory pain. This study examined whether acute or continuous opioid exposure in the neonatal rat alters formalin-induced nociception after 4 days of abstinence. Rats were exposed to a single acute administration of morphine on postnatal day 7 or 72 h of opioid infusion from postnatal days 5-7 via osmotic pump. When challenged with intraplantar formalin on postnatal day 11, rats exposed to acute or chronic morphine had increased phase II pain-associated behaviors. These findings suggest that neonatal morphine exposure may have unintended consequences on inflammatory pain.

  19. Experimental hyperleptinemia in neonatal rats leads to selective leptin responsiveness, hypertension, and altered myocardial function.

    PubMed

    Samuelsson, Anne-Maj; Clark, James; Rudyk, Olena; Shattock, Michael J; Bae, Sung Eun; South, Timothy; Pombo, Joaquim; Redington, Kathrine; Uppal, Esna; Coen, Clive W; Poston, Lucilla; Taylor, Paul D

    2013-09-01

    The prevalence of obesity among pregnant women is increasing. Evidence from human cohort studies and experimental animals suggests that offspring cardiovascular and metabolic function is compromised through early life exposure to maternal obesity. Previously, we reported that juvenile offspring of obese rats develop sympathetically mediated hypertension associated with neonatal hyperleptinemia. We have now addressed the hypothesis that neonatal exposure to raised leptin in the immediate postnatal period plays a causal role. Pups from lean Sprague-Dawley rats were treated either with leptin (3 mg/kg IP) or with saline twice daily from postnatal day 9 to 15 to mimic the exaggerated postnatal leptin surge observed in offspring of obese dams. Cardiovascular function was assessed by radiotelemetry at 30 days, and 2 and 12 months. In juvenile (30 days) leptin-treated rats, hearts were heavier and night-time (active period) systolic blood pressure was raised (mm Hg; mean ± SEM: male leptin-treated, 132 ± 1 versus saline-treated, 119 ± 1, n=6, P<0.05; female leptin-treated, 132 ± 2 versus saline-treated, 119 ± 1, n=6, P<0.01), and the pressor response to restraint stress and leptin challenge increased compared with saline-treated rats. Heart rate variability demonstrated an increased low:high frequency ratio in 30-day leptin-treated animals, indicative of heightened sympathetic efferent tone. Echocardiography showed altered left ventricular structure and systolic function in 30-day female leptin versus saline-treated rats. These disorders persisted to adulthood. In isolated hearts, contractile function was impaired at 5 months in male leptin-treated rats. Exogenously imposed hyperleptinemia in neonatal rats permanently influences blood pressure and cardiac structure and function.

  20. Dexmedetomidine reduces cranial temperature in hypothermic neonatal rats.

    PubMed

    McAdams, Ryan M; McPherson, Ronald J; Kapur, Raj; Phillips, Brian; Shen, Danny D; Juul, Sandra E

    2015-06-01

    The α2-adrenergic agonist dexmedetomidine (DEX) is increasingly used for prolonged sedation of critically ill neonates, but there are currently no data evaluating possible consequences of prolonged neonatal DEX exposure. We evaluated the pharmacokinetics and histological consequences of neonatal DEX exposure. DEX was administered (s.c.) to naive (uninjured) neonatal Lewis rats to provide acute (25 µg/kg, ×1) or prolonged (25 µg/kg three times daily, ×2 or ×4 d) exposure. Therapeutic hypothermia was simulated using a water-cooled blanket. Cranial temperatures were measured using an infrared thermometer. DEX concentrations were measured by LC-MS in plasma and homogenized brainstem tissue for pharmacokinetic analysis. Cortex, cerebellum, and brainstem were evaluated for evidence of inflammation or injury. Prolonged neonatal DEX exposure was not associated with renal or brain pathology or indices of gliosis, macrophage activation, or apoptosis in either hypothermic or control rats. Plasma and brain DEX concentrations were tightly correlated. DEX peaked within 15 min in brain and reduced cranial temperature from 32 to 30 °C within 30 min after injection in cooled rats. Prolonged DEX treatment in neonatal rats was not associated with abnormal brain histology. These data provide reassuring preliminary results for using DEX with therapeutic hypothermia to treat near-term brain injury.

  1. Cardiac Muscle Studies with Rat Ventricular Strips

    ERIC Educational Resources Information Center

    Whitten, Bert K.; Faleschini, Richard J.

    1977-01-01

    Details undergraduate physiology laboratory experiments that demonstrate mechanical properties of cardiac muscle, using strips from the ventricle of a rat heart. Includes procedures for obtaining length-tension curves, demonstrating the role of calcium in excitation-contraction coupling, and showing effects of several cardiovascular drugs…

  2. Cardiac Muscle Studies with Rat Ventricular Strips

    ERIC Educational Resources Information Center

    Whitten, Bert K.; Faleschini, Richard J.

    1977-01-01

    Details undergraduate physiology laboratory experiments that demonstrate mechanical properties of cardiac muscle, using strips from the ventricle of a rat heart. Includes procedures for obtaining length-tension curves, demonstrating the role of calcium in excitation-contraction coupling, and showing effects of several cardiovascular drugs…

  3. Right ventricular hypertrophy causes impairment of left ventricular diastolic function in the rat.

    PubMed

    Lamberts, Regis R; Vaessen, Rob J; Westerhof, Nico; Stienen, Ger J M

    2007-01-01

    Right ventricular (RV) pressure overload causes right ventricular hypertrophy in several types of pulmonary and congenital heart diseases. The associated cardiac dysfunction has generally been attributed to alterations in RV function. However, due to global neurohormonal adaptations and mechanical ventricular interaction left ventricular (LV) function could be affected as well.Therefore,LV function, RV function and their interaction were studied in rats with monocrotaline (MCT)-induced RV hypertrophy and control rats. MCT (30 mg/kg) was used to induce pulmonary hypertension, which resulted, after 28 days, in marked RV hypertrophy (RV-weight: control 220 +/- 15,MCT 437 +/- 34mg,p < 0.05). In Langendorff-perfused hearts with balloons inserted in both the LV and the RV, the diastolic pressure-volume relations showed increased stiffness, and relaxation was prolonged in the LV and RV in the MCT group compared to controls. In the MCT group, developed pressures were increased only in the RV. An increase of LV volume increased RV diastolic pressure to a similar extent in both groups. However, an increase in RV volume did not affect LV diastolic pressure in controls, but significantly increased LV diastolic pressure in the MCT group. LV and RV developed pressure-volume relations were not affected. Calculated circumferential end-diastolic wall stresses (sigma) were larger in the MCT group (LV-sigma: 0.55 +/- 0.02, RV-sigma: 1.94 +/- 0.30 kN/m(2), both p< 0.05 to control) compared to controls (LV-sigma: 0.34 +/- 0.06,RV-sigma: 1.23 +/- 0.46 kN/m2). In the MCT group, collagen content was increased in the LV, septum and RV compared to controls. In conclusion, structural changes of the RV and LV result in depressed LV diastolic function during RV hypertrophy.

  4. Comparison of the offset distance of the tricuspid septal leaflet in neonates with Ebstein's anomaly and neonates with pulmonary atresia with intact ventricular septum.

    PubMed

    Kim, Min Jeong; Yu, Jeong Jin; Kang, So Yeon; Seo, Chang Deok; Baek, Jae Suk; Kim, Young-Hwue; Ko, Jae-Kon

    2015-01-01

    An indexed offset distance of the tricuspid septal leaflet ⩾8 mm/m2 is a quantitative criterion for the diagnosis of Ebstein's anomaly. The purpose of this study was to investigate the validity of this criterion for the discrimination of Ebstein's anomaly from pulmonary atresia with intact ventricular septum in neonatal patients. A total of 122 neonatal patients, 56 with Ebstein's anomaly and 66 with pulmonary atresia with intact ventricular septum, were enrolled. Diagnosis of each anomaly was based on typical morphologic features. Echocardiographic variables, including the offset distance of the tricuspid septal leaflet, were measured via an offline analysis of images recorded before 1 month of age. The offset distance of the tricuspid septal leaflet was indexed by the body surface area, and the indexed offset distances in the Ebstein's anomaly and pulmonary atresia with intact ventricular septum groups were 34.2 mm/m2 (7.1-119.1 mm/m2) and 7.2 mm/m2 (0.0-25.6 mm/m2), respectively. The indexed offset distance was ⩾8 mm/m2 in 29 (43.9%) of the patients with pulmonary atresia with intact ventricular septum; clinical and echocardiographic characteristics were comparable between these 29 patients and the remaining 37 patients with pulmonary atresia with intact ventricular septum. When an indexed offset distance ⩾8 mm/m2 was applied as a cut-off for the diagnosis of Ebstein's anomaly, the sensitivity was 0.963 and the specificity was 0.561. In conclusion, indexed offset distance ⩾8 mm/m2 cannot be used as a cut-off for the diagnosis of complicated Ebstein's anomaly in neonatal patients with pulmonary atresia with intact ventricular septum.

  5. Resveratrol reduces intracellular free calcium concentration in rat ventricular myocytes.

    PubMed

    Liu, Zheng; Zhang, Li-Ping; Ma, Hui-Jie; Wang, Chuan; Li, Ming; Wang, Qing-Shan

    2005-10-25

    Resveratrol (trans-3, 4', 5-trihydroxy stilbene), a phytoalexin found in grape skins and red wine, has been reported to have a wide range of biological and pharmacological properties. It has been speculated that resveratrol may have cardioprotective activity. The objective of our study was to investigate the effects of resveratrol on intracellular calcium concentration ([Ca(2+)](i)) in rat ventricular myocytes. [Ca(2+)](i) was detected by laser scanning confocal microscopy. The results showed that resveratrol (15~60 mumol/L) reduced [Ca(2+)](i) in normal and Ca(2+)-free Tyrode's solution in a concentration-dependent manner. The effects of resveratrol on [Ca(2+)](i) in normal Tyrode's solution was partially inhibited by pretreatment with sodium orthovanadate (Na3VO4, 1.0 mmol/L, P<0.01), an inhibitor of protein tyrosine phosphatase, or L-type Ca(2+) channel agonist Bay K8644 (10 mumol/L, P<0.05), but could not be antagonized by NO synthase inhibitor L-NAME (1.0 mmol/L). Resveratrol also markedly inhibited the ryanodine-induced [Ca(2+)](i) increase in Ca(2+)-free Tyrode's solution (P<0.01). When Ca(2+) waves were produced by increasing extracellular Ca(2+) concentration from 1 to 10 mmol/L, resveratrol (60 mumol/L) could reduce the velocity and duration of propagating waves, and block the propagating waves of elevated [Ca(2+)](i). These results suggest that resveratrol may reduce the [Ca(2+)](i) in isolated rat ventricular myocytes. The inhibition of voltage-dependent Ca(2+) channel and tyrosine kinase, and alleviation of Ca(2+) release from sarcoplasmic reticulum (SR) are possibly involved in the effects of resveratrol on rat ventricular myocytes. These findings could help explain the protective activity of resveratrol against cardiovascular disease.

  6. Cellular engineering of ventricular adult rat cardiomyocytes.

    PubMed

    Weikert, Christian; Eppenberger-Eberhardt, Monika; Eppenberger, Hans M

    2003-10-01

    Preparation of viable cultured adult cardiomyocytes (vARCs) is a prerequisite for cell-based transplantation and tissue engineering. Ectopic gene expression is important in this context. Here, we present an in vitro cell replating strategy using Accutase for cultured vARCs, allowing ectopic gene expression. Cultured vARCs from 6- to 8-week-old rats were used. Transfections with EGFP (enhanced green fluorescent protein) constructs, Mlc-3f-EGFP or alpha-actinin-EGFP were performed using adenovirus-enhanced transferrin-mediated infection (AVET). Accutase (PAA Laboratories, Linz, Austria) was used for the detachment of cultured cells. Immunohistochemical analysis, together with confocal laser microscopy was used for structural analysis of the cells. Cultured vARCs could be detached with a high yield (40 to 60%) from primary cultures using Accutase. The cultivation period plays an important role in the yield of viable cells. Resultant replated vARCs (rep-vARCs) rapidly (1-2 h) acquired a rounded up shape without degradation of their contractile apparatus, which is in contrast to the rod-shaped freshly isolated vARCs (fi-vARCs). The detached cells survived passage through a narrow syringe needle. After seeding, detached cells rapidly attached to various substrates, increased their content of the contractile apparatus, and formed cell-cell contacts within 3 days after reseeding. The detached cells survived passage through a narrow syringe needle. The high recovery of cells after replating enabled the use of the AVET system for gene delivery. AVET is free of infectious particles and does not lead to expression of viral proteins. Transfection of vARCs prior to detachment had a small effect on cell recovery and ectopically synthesized proteins were properly localized after replating. Detachment of cultured vARCs using Accutase is well compatible with ectopic gene expression and yields a viable transgenic population of vARCs that eventually may be suitable as transgenic

  7. Melatonin potentiates the anticonvulsant action of phenobarbital in neonatal rats

    PubMed Central

    Forcelli, Patrick A.; Soper, Colin; Duckles, Anne; Gale, Karen; Kondratyev, Alexei

    2013-01-01

    Phenobarbital is the most commonly utilized drug for neonatal seizures. However, questions regarding safety and efficacy of this drug make it particularly compelling to identify adjunct therapies that could boost therapeutic benefit. One potential adjunct therapy is melatonin. Melatonin is used clinically in neonatal and pediatric populations, and moreover, it exerts anticonvulsant actions in adult rats. However, it has not been previously evaluated for anticonvulsant effects in neonatal rats. Here, we tested the hypothesis that melatonin would exert anticonvulsant effects, either alone, or in combination with phenobarbital, the most commonly utilized anticonvulsant in neonatal medicine. Postnatal day (P)7 rats were treated with phenobarbital (0–40 mg/kg) and/or melatonin (0–80 mg/kg) prior to chemoconvulsant challenge with pentylenetetrazole (100 mg/kg). We found that melatonin significantly potentiated the anticonvulsant efficacy of phenobarbital, but did not exert anticonvulsant effects on its own. These data provide additional evidence for the further examination of melatonin as an adjunct therapy in neonatal/pediatric epilepsy. PMID:24206906

  8. Domoic acid is a potent neurotoxin to neonatal rats.

    PubMed

    Xi, D; Peng, Y G; Ramsdell, J S

    1997-01-01

    Domoic acid induces a time-dependent neuroexcitotoxic effect in neonatal rats characterized by hyperactivity, stereotypic scratching, convulsions, and death with observable behaviors occurring at exposures 40 times lower by body weight in neonates than reported in adults. Low doses of domoic acid (0.1 mg/kg) induced c-fos in the central nervous system which was inhibited in part by 2-amino-5-phosphonovaleric acid, an NMDA receptor antagonist. Domoic acid caused no evidence of structural alteration in the brain of neonates as assessed by Nissel staining and cupric silver histochemistry. Domoic acid induced reproducible behavioral effects at doses as low as 0.05 mg/kg and induced seizures doses as low as 0.2 mg/kg. Determination of serum domoic acid levels after 60 min exposure indicated that serum levels of domoic acid in the neonates corresponded closely to the serum levels that induce similar symptoms in adult rats and mice. We conclude that neonatal rats are highly sensitive to the neuroexcitatory and lethal effects of domoic acid and that the increased sensitivity results from higher than expected serum levels of domoic acid. These findings are consistent with other findings that reduced serum clearance of domoic acid is a predisposing factor to domoic acid toxicity.

  9. The impact of left ventricular stretching in model cultivations with neonatal cardiomyocytes in a whole-heart bioreactor.

    PubMed

    Hülsmann, Jörn; Aubin, Hug; Wehrmann, Alexander; Lichtenberg, Artur; Akhyari, Payam

    2017-05-01

    Here, we investigate the impact of integrated three-dimensional (3D) left ventricular (LV) stretching on myocardial maturation in a whole-heart bioreactor setting. Therefore, decellularized rat hearts were selectively repopulated with rodent neonatal cardiomyocytes (5 · 10(6) cells per heart) and cultured over 5 days. Continuous medium perfusion was maintained through the coronary artery system in a customized whole-heart bioreactor system with or without integrated biomechanical stimulation of LV. 3D repopulation effectiveness and cellular vitality were evaluated by repetitive metabolic WST-1 assays and 3D confocal microscopy analysis through fluorescent staining, also assessing cellular organization. Moreover, specific myocardial vitality was verified by detecting spontaneous electrophysiological activity using a multielectrode assay. Western blot analysis of cardiac myosin heavychain (MHC) and quantitative RT-PCR for Connexin 43 was used to analyze cardiomyocyte maturation. Decellularized whole-heart constructs repopulated with neonatal cardiomyocytes (repopWHC) showed vital 3D cell populations throughout the repopulation sites within the LV with a significant increase in metabolic activity (326 ± 113% for stimulated constructs vs. 162 ± 32% for non-stimulated controls after 96 h of continuous cultivation as compared to their state 24 h after injection, directly prior to bioreactor cultivation). Further, bioreactor cultivation under integrated mechanical LV stimulation not only led to a higher degree of cellular organization and an increased MHC content, but also to a significant increase of Cx43 gene expression resulting in a regain of 60 ± 19% of native neonatal hearts expression level in contrast to 20 ± 9% for non-stimulated controls (P = 0.03). Therefore, our study suggests that the integration of LV stretching into whole-heart bioreactor cultivation may enhance cardiac maturation not only by promoting cellular organization

  10. Regulatory Effect of Connexin 43 on Basal Ca2+ Signaling in Rat Ventricular Myocytes

    PubMed Central

    Li, Chen; Yu, Xinfeng; Jing, Xian; Xu, Pingxiang; Luo, Dali

    2012-01-01

    Background It has been found that gap junction-associated intracellular Ca2+ [Ca2+]i disturbance contributes to the arrhythmogenesis and hyperconstriction in diseased heart. However, whether functional gaps are also involved in the regulation of normal Ca2+ signaling, in particular the basal [Ca2+]i activities, is unclear. Methods and Results Global and local Ca2+ signaling and gap permeability were monitored in cultured neonatal rat ventricular myocytes (NRVMs) and freshly isolated mouse ventricular myocytes by Fluo4/AM and Lucifer yellow (LY), respectively. The results showed that inhibition of gap communication by heptanol, Gap 27 and flufenamic acid or interference of connexin 43 (Cx43) with siRNA led to a significant suppression of LY uptake and, importantly, attenuations of global Ca2+ transients and local Ca2+ sparks in monolayer NRVMs and Ca2+ sparks in adult ventricular myocytes. In contrast, overexpression of rat-Cx43 in NRVMs induced enhancements in the above measurements, and so did in HEK293 cells expressing rat Cx43. Additionally, membrane-permeable inositol 1,4,5-trisphosphate (IP3 butyryloxymethyl ester) and phenylephrine, an agonist of adrenergic receptor, could relieve the inhibited Ca2+ signal and LY uptake by gap uncouplers, whereas blockade of IP3 receptor with xestospongin C or 2-aminoethoxydiphenylborate mimicked the effects of gap inhibitors. More importantly, all these gap-associated effects on Ca2+ signaling were also found in single NRVMs that only have hemichannels instead of gap junctions. Further immunostaining/immunoblotting single myocytes with antibody against Cx43 demonstrated apparent increases in membrane labeling of Cx43 and non-junctional Cx43 in overexpressed cells, suggesting functional hemichannels exist and also contribute to the Ca2+ signaling regulation in cardiomyocytes. Conclusions These data demonstrate that Cx43-associated gap coupling plays a role in the regulation of resting Ca2+ signaling in normal ventricular

  11. Ceftriaxone attenuates hypoxic-ischemic brain injury in neonatal rats

    PubMed Central

    2011-01-01

    Background Perinatal brain injury is the leading cause of subsequent neurological disability in both term and preterm baby. Glutamate excitotoxicity is one of the major factors involved in perinatal hypoxic-ischemic encephalopathy (HIE). Glutamate transporter GLT1, expressed mainly in mature astrocytes, is the major glutamate transporter in the brain. HIE induced excessive glutamate release which is not reuptaked by immature astrocytes may induce neuronal damage. Compounds, such as ceftriaxone, that enhance the expression of GLT1 may exert neuroprotective effect in HIE. Methods We used a neonatal rat model of HIE by unilateral ligation of carotid artery and subsequent exposure to 8% oxygen for 2 hrs on postnatal day 7 (P7) rats. Neonatal rats were administered three dosages of an antibiotic, ceftriaxone, 48 hrs prior to experimental HIE. Neurobehavioral tests of treated rats were assessed. Brain sections from P14 rats were examined with Nissl and immunohistochemical stain, and TUNEL assay. GLT1 protein expression was evaluated by Western blot and immunohistochemistry. Results Pre-treatment with 200 mg/kg ceftriaxone significantly reduced the brain injury scores and apoptotic cells in the hippocampus, restored myelination in the external capsule of P14 rats, and improved the hypoxia-ischemia induced learning and memory deficit of P23-24 rats. GLT1 expression was observed in the cortical neurons of ceftriaxone treated rats. Conclusion These results suggest that pre-treatment of infants at risk for HIE with ceftriaxone may reduce subsequent brain injury. PMID:21933448

  12. Melatonin potentiates the anticonvulsant action of phenobarbital in neonatal rats.

    PubMed

    Forcelli, Patrick A; Soper, Colin; Duckles, Anne; Gale, Karen; Kondratyev, Alexei

    2013-12-01

    Phenobarbital is the most commonly utilized drug for neonatal seizures. However, questions regarding safety and efficacy of this drug make it particularly compelling to identify adjunct therapies that could boost therapeutic benefit. One potential adjunct therapy is melatonin. Melatonin is used clinically in neonatal and pediatric populations, and moreover, it exerts anticonvulsant actions in adult rats. However, it has not been previously evaluated for anticonvulsant effects in neonatal rats. Here, we tested the hypothesis that melatonin would exert anticonvulsant effects, either alone, or in combination with phenobarbital. Postnatal day (P)7 rats were treated with phenobarbital (0-40mg/kg) and/or melatonin (0-80mg/kg) prior to chemoconvulsant challenge with pentylenetetrazole (100mg/kg). We found that melatonin significantly potentiated the anticonvulsant efficacy of phenobarbital, but did not exert anticonvulsant effects on its own. These data provide additional evidence for the further examination of melatonin as an adjunct therapy in neonatal/pediatric epilepsy. Copyright © 2013 Elsevier B.V. All rights reserved.

  13. Right ventricular cyclic nucleotide signaling is decreased in hyperoxia-induced pulmonary hypertension in neonatal mice.

    PubMed

    Heilman, Rachel P; Lagoski, Megan B; Lee, Keng Jin; Taylor, Joann M; Kim, Gina A; Berkelhamer, Sara K; Steinhorn, Robin H; Farrow, Kathryn N

    2015-06-15

    Pulmonary hypertension (PH) and right ventricular hypertrophy (RVH) affect 25-35% of premature infants with significant bronchopulmonary dysplasia (BPD), increasing morbidity and mortality. We sought to determine the role of phosphodiesterase 5 (PDE5) in the right ventricle (RV) and left ventricle (LV) in a hyperoxia-induced neonatal mouse model of PH and RVH. After birth, C57BL/6 mice were placed in room air (RA) or 75% O2 (CH) for 14 days to induce PH and RVH. Mice were euthanized at 14 days or recovered in RA for 14 days or 42 days prior to euthanasia at 28 or 56 days of age. Some pups received sildenafil or vehicle (3 mg·kg(-1)·dose(-1) sc) every other day from P0. RVH was assessed by Fulton's index [RV wt/(LV + septum) wt]. PDE5 protein expression was analyzed via Western blot, PDE5 activity was measured by commercially available assay, and cGMP was measured by enzyme-linked immunoassay. Hyperoxia induced RVH in mice after 14 days, and RVH did not resolve until 56 days of age. Hyperoxia increased PDE5 expression and activity in RV, but not LV + S, after 14 days. PDE5 expression normalized by 28 days of age, but PDE5 activity did not normalize until 56 days of age. Sildenafil given during hyperoxia prevented RVH, decreased RV PDE5 activity, and increased RV cGMP levels. Mice with cardiac-specific overexpression of PDE5 had increased RVH in RA. These findings suggest normal RV PDE5 function is disrupted by hyperoxia, and elevated PDE5 contributes to RVH and remodeling. Therefore, in addition to impacting the pulmonary vasculature, sildenafil also targets PDE5 in the neonatal mouse RV and decreases RVH.

  14. A Neonate with Susceptibility to Long QT Syndrome Type 6 who Presented with Ventricular Fibrillation and Sudden Unexpected Infant Death

    PubMed Central

    Sauer, Charles W.; Marc-Aurele, Krishelle L.

    2016-01-01

    Patient: Female, 19-day Final Diagnosis: 19 day old neonate with susceptibility to Long QT syndrome • ventricular fibrillation Symptoms: Cardiac arrest • cardiac arrhythmia • encephalopathy Medication: — Clinical Procedure: Cardioversion Specialty: Pediatrics and Neonatology Objective: Rare disease Background: This is a case of a neonate with susceptibility to long QT syndrome (LQTS) who presented with a sudden unexpected infant death. Experts continue to debate whether universal electrocardiogram (ECG) screening of all newborns is feasible, practical, and cost-effective. Case Report: A 19-day-old neonate was found unresponsive by her mother. ECG showed ventricular fibrillation and a combination of a lidocaine drip plus multiple defibrillations converted the rhythm to normal sinus. Unfortunately, MRI brain imaging showed multiple infarcts and EEG showed burst suppression pattern with frequent seizures; life supportive treatment was stopped and the infant died. Genetic testing revealed two mutations in the KCNE2 gene consistent with susceptibility to LQTS type 6. Conclusions: We believe this case is the first to demonstrate both a precipitating electrocardiographic and genetic cause of death for an infant with LQTS, showing a cause-and-effect relationship between LQTS mutation, ventricular arrhythmia, and death. We wonder whether universal ECG newborn screening to prevent LQTS death could have saved this baby. PMID:27465075

  15. Neonatal morphine enhances nociception and decreases analgesia in young rats.

    PubMed

    Zhang, Guo Hua; Sweitzer, Sarah M

    2008-03-14

    The recognition of the impact of neonatal pain experience on subsequent sensory processing has led to the increased advocacy for the use of opioids for pain relief in infants. However, following long-term opioid exposure in intensive care units more than 48% of infants exhibited behaviors indicative of opioid abstinence syndrome, a developmentally equivalent set of behaviors to opioid withdrawal as seen in adults. Little is known about the long-term influence of repeated neonatal morphine exposure on nociception and analgesia. To investigate this, we examined mechanical and thermal nociception on postnatal days 11, 13, 15, 19, 24, 29, 39 and 48 following subcutaneous administration of morphine (3 mg/kg) once daily on postnatal days 1-9. The cumulative morphine dose-response was assessed on postnatal days 20 and 49, and stress-induced analgesia was assessed on postnatal days 29 and 49. Both basal mechanical and thermal nociception in neonatal, morphine-exposed rats were significantly lower than those in saline-exposed, handled-control rats and naive rats until P29. A rightward-shift of cumulative dose-response curves for morphine analgesia upon chronic neonatal morphine was observed both on P20 and P49. The swim stress-induced analgesia was significantly decreased in neonatal morphine-exposed rats on P29, but not on P49. These data indicate that morphine exposure equivalent to the third trimester of gestation produced prolonged pain hypersensitivity, decreased morphine antinociception, and decreased stress-induced analgesia. The present study illustrates the need to examine the long-term influence of prenatal morphine exposure on pain and analgesia in the human pediatric population.

  16. Sexually dimorphic brain and behavioral asymmetries in the neonatal rat.

    PubMed Central

    Ross, D A; Glick, S D; Meibach, R C

    1981-01-01

    The 2-deoxy-D-glucose method was used to study asymmetries in cerebral metabolic activity in neonatal rats. Left-right asymmetries in 2-deoxy-D-glucose uptake were observed in hippocampus, diencephalon, cortex, and medulla-pons: 2-deoxy-D-glucose incorporation was greater in right hippocampus, right diencephalon, left cortex, and left medulla-pons. These asymmetries occurred only in females. We also observed neonatal asymmetries in tail position that, in both sexes, were predictive of adult turning preferences; females had right-sided biases in both neonatal and adult characteristics. Collectively these data indicate that cerebral lateralization is sexually dimorphic and is present at birth. Images PMID:6940200

  17. Ventricular arrhythmia incidence in the rat is reduced by naloxone.

    PubMed

    Pugsley, M K; Hayes, E S; Wang, W Q; Walker, M J A

    2015-07-01

    This study characterized the antiarrhythmic effects of the opioid receptor antagonist naloxone in rats subject to electrically induced and ischemic arrhythmias. Naloxone (2, 8 and 32 μmol/kg/min) was examined on heart rate, blood pressure, and the electrocardiogram (EKG) as well as for effectiveness against arrhythmias produced by occlusion of the left anterior descending coronary artery or electrical stimulation of the left ventricle. Naloxone reduced blood pressure at the highest dose tested while heart rate was dose-dependently reduced. Naloxone dose-dependently prolonged the P-R and QRS intervals and increased the RSh amplitude indicative of effects on cardiac sodium (Na) channels. Naloxone prolonged the Q-T interval suggesting a delay in repolarization. Naloxone effects were comparable to the comparator quinidine. Naloxone (32 μmol/kg/min) reduced ventricular fibrillation (VF) incidence to 38% (from 100% in controls). This same dose significantly increased the threshold for induction of ventricular fibrillation (VFt), prolonged the effective refractory period (ERP) and reduced the maximal following frequency (MFF). The patterns of ECG changes, reduction in ischemic arrhythmia (VF) incidence and changes in electrically induced arrhythmia parameters at high doses of naloxone suggest that it directly blocks cardiac Na and potassium (K) ion channels.

  18. Altered ovarian responsiveness to gonadotropins in neonatally irradiated immature rats

    SciTech Connect

    Freud, A.; Sod-Moriah, U.A.

    1988-01-01

    Female rats which were exposed to a single low dose of gamma irradiation (6R or 15R) at the age of 8 days produce smaller litters when mature than untreated controls. In order to study the possibility that such an impaired reproductive performance could result from a reduced ovulation rate, neonatally irradiated females were treated with PMSG (12 iu/rat) at the age of 26 days. Another group of rats, similarly treated, was further injected with hCG (5 iu/rat) 48 hours later. Animals were killed 48, 55, 60 and 72 hours after PMSG treatment or 72 and 120 after hCG injection. The results indicated that PMSG treatment increased the ovarian weight of non-irradiated controls as well as of irradiated rats and in all animals induced a proestrus like profile of LH. Only a combined treatment of PMSG and hCG resulted in ovulation and corpora lutea formation with significantly increased numbers of corpora lutea in the ovaries of the irradiated rats. The latter was associated with higher progesterone plasma levels not correlated to the number of corpora lutea. The gradual decrease in the number of ovarian binding sites for hCG with increased radiation dose and the increased association constant in the 15R group could not explain the increased sensitivity of the ovary to exogenous gonadotropins which results from neonatal exposure to low doses of gamma irradiation.

  19. Brief neonatal handling alters sexually dimorphic behaviors in adult rats.

    PubMed

    Fujimoto, Tetsuya; Kubo, Kazuhiko; Nishikawa, Yasuo; Aou, Shuji

    2014-03-01

    Several effects of neonatal handling on brain and behavior have been reported. We investigated the effects of neonatal handling on behaviors that have been shown to be sexually dimorphic in rats using an open-field test. "Gender differences" were observed in locomotor activity, exploratory behavior and grooming in the handled group. However, clear gender differences in these behaviors were not observed in the non-handled group. Our findings show that brief daily handling sessions (~ 1 min) in the first 2 weeks of postnatal life increased locomotor activity and exploratory behavior, and that these effects were more pronounced in females. Moreover, many rats in the non-handling group exhibited an increase in defecation relative to the handling group during the 10-min observation period. This suggests that the non-handling group experienced more stress in response to the novel open-field arena, and that this resulted in the absence of gender differences. Notably, this anxiety-related response was attenuated by neonatal handling. Our study underscores the impact of brief neonatal handling on sexually dimorphic behaviors, and indicates that caution should be exercised in controlling for the effects of handling between experimental groups, particularly in neurotoxicological studies that evaluate gender differences.

  20. Acoustic hypersensitivity in adult rats after neonatal ventral hippocampus lesions.

    PubMed

    Macedo, Carlos Eduardo; Angst, Marie-Josée; Guiberteau, Thierry; Brasse, David; O'Brien, Terence John; Sandner, Guy

    2010-02-11

    Rats with a bilateral neonatal ventral hippocampus lesion (NVHL) are used as models of neurobiological aspects of schizophrenia. In view of their decreased number of GABAergic interneurons, we hypothesized that they would show increased reactivity to acoustic stimuli. We systematically characterized the acoustic reactivity of NVHL rats and sham operated controls. They were behaviourally observed during a loud white noise. A first cohort of 7 months' old rats was studied. Then the observations were reproduced in a second cohort of the same age after characterizing the reactivity of the same rats to dopaminergic drugs. A third cohort of rats was studied at 2, 3, 4, 5 and 6 months. In subsets of lesioned and control rats, inferior colliculus auditory evoked potentials were recorded. A significant proportion of rats (50-62%) showed aberrant audiogenic responses with explosive wild running resembling the initial phase of audiogenic seizures. This was not correlated with their well-known enhanced reactivity to dopaminergic drugs. The proportion of rats showing this strong reaction increased with rats' age. After the cessation of the noise, NVHL rats showed a long freezing period that did neither depend on the size of the lesion nor on the rats' age. The initial negative deflection of the auditory evoked potential was enhanced in the inferior colliculus of only NVHL rats that displayed wild running. Complementary anatomical investigations using X-ray scans in the living animal, and alizarin red staining of brain slices, revealed a thin layer of calcium deposit close to the medial geniculate nuclei in post-NVHL rats, raising the possibility that this may contribute to the hyper-reactivity to sounds seen in these animals. The findings of this study provide complementary information with potential relevance for the hyper-reactivity noted in patients with schizophrenia, and therefore a tool to investigate the underlying biology of this endophenotype.

  1. Abdominal expiratory muscle activity in anesthetized vagotomized neonatal rats.

    PubMed

    Iizuka, Makito

    2009-05-01

    The pattern of respiratory activity in abdominal muscles was studied in anesthetized, spontaneously breathing, vagotomized neonatal rats at postnatal days 0-3. Anesthesia (2.0% isoflurane, 50% O(2)) depressed breathing and resulted in hypercapnia. Under this condition, abdominal muscles showed discharge late in the expiratory phase (E2 activity) in most rats. As the depth of anesthesia decreased, the amplitude of discharges in the diaphragm and abdominal muscles increased. A small additional burst frequently occurred in abdominal muscles just after the termination of diaphragmatic inspiratory activity (E1 or postinspiratory activity). Since this E1 activity is not often observed in adult rats, the abdominal respiratory pattern likely changes during postnatal development. Anoxia-induced gasping after periodic expiratory activity without inspiratory activity, and in most rats, abdominal expiratory activity disappeared before terminal apnea. These results suggest that a biphasic abdominal motor pattern (a combination of E2 and E1 activity) is a characteristic of vagotomized neonatal rats during normal respiration.

  2. Carnitine promotes heat shock protein synthesis in adriamycin-induced cardiomyopathy in a neonatal rat experimental model.

    PubMed

    Strauss, M; Anselmi, G; Hermoso, T; Tejero, F

    1998-11-01

    In order to evaluate carnitine protective strategy and its relationship with heat shock protein induction, female Sprague-Dawley neonatal rats, body weight 40 g, were randomized into four groups: control, adriamycin, carnitine and carnitine-adriamycin. Adriamycin was injected i.v. at a dose of 27 mg/kg (0.1 ml). Carnitine was administered i.v. (20 mg/0.1 ml) before each subdose of adriamycin and then per os (180 mg/kg) daily for 12 weeks. Body weight was recorded weekly. Ventricular wall thickness and cellular damage percentage were morphometrically and ultrastructurally determined, respectively. The determinations were realized monthly until the third month after treatment. The heat shock protein 25 content in the supernatant of the homogenized heart tissue was determined by Western blot analysis. Eight and 12 weeks after treatment, body weight and ventricular wall thickness decreased much more in adriamycin groups than in control and carnitine ones. At the same time, electron microscopic analysis of adriamycin left ventricular wall samples showed loss of myofibrils, swollen mitochondria and vacuoles. Carnitine-adriamycin treated rats resemble control groups more than adriamycin treated samples. Moreover, de-novo synthesis of heat shock protein was three times more induced in carnitine-adriamycin rats than in adriamycin ones. Carnitine may enhance the cell-protecting mechanism based on an induction of shock protein, and this first cellular response could reduce the severity of late adriamycin-cardiomiopathy.

  3. Homeostatic control of manganese excretion in the neonatal rat

    SciTech Connect

    Ballatori, N.; Miles, E.; Clarkson, T.W.

    1987-05-01

    Previous studies in neonatal and suckling animals showed that immature animals have a greatly diminished capacity to excrete manganese and therefore were considered to be unable to regulate tissue manganese concentrations. In contrast, the present studies indicate that suckling rats have the capacity to excrete excess manganese at rates nearly comparable to those of adults. Eight- to 10-day-old rats given a tracer dose of /sup 54/MnCl/sub 2/ (essentially carrier free), either via gavage or by intraperitoneal injection showed little elimination of the /sup 54/Mn until the 18-19th day of life, when there was an abrupt increase in the rate of the metal's excretion. However, when manganese was given in doses of 1 and 10 mg/kg, the young animals excreted from 30-70% of the dose in only 4 days, at which time a new rate of excretion was achieved. This enhanced rate of excretion remained constant until the 18-19th day of life, when it was again accelerated. Biliary excretion of manganese, the primary route for the elimination of the metal, was only 30-60% lower in 14-day-old rats compared with adults at doses ranging from tracer to 10 mg /sup 54/Mn/kg. For both the 14-day-old and adult rats, an apparent biliary transport maximum was reached at a dose of 10 mg Mn/kg. These studies indicate that the excretory pathways for manganese are well developed in the neonatal rat. The avid retention of tracer quantities of manganese by the neonate may be a consequence of the scarcity of this essential trace metal in its diet.

  4. Evidence of ventricular contamination of the optical signal in preterm neonates with post hemorrhagic ventricle dilation

    NASA Astrophysics Data System (ADS)

    Kishimoto, J.; Diop, M.; McLachlan, P.; de Ribaupierre, S.; Lee, D. S. C.; St. Lawrence, K.

    2015-03-01

    Dilation of the cerebral ventricles is a common condition in preterm neonates with intraventricular hemorrhage (IVH). This post hemorrhagic ventricle dilation (PHVD) can lead to lifelong neurological impairment through ischemic injury due to increased intracranial pressure (ICP). Interventions, such as ventricular tapping to remove cerebrospinal fluid (CSF), are used to prevent injury, but determining the optimal time for treatment is difficult as clinical signs of increased ICP lack sensitivity. There is a growing interest in using near-infrared spectroscopy (NIRS) because of its ability to monitor cerebral oxygen saturation (StO2) at the bedside. However, the accuracy of NIRS may be affected by signal contamination from enlarged ventricles, especially if there are blood breakdown products (bbp) in CSF following IVH. To investigate this, serial NIR spectra from the head and from CSF samples were acquired over a month from seven IVH patients undergoing treatment for PHVD. Over time, the visual appearance of the CSF samples progressed from dark brown ("tea color") to clear yellow, reflecting the reduction in bbp concentration as confirmed by the stronger absorption around 760 nm at the earlier time points. All CSF samples contained strong absorption at 960 nm due to water. More importantly the same trend in these absorption features was observed in the in vivo spectra, and Monte Carlo simulations confirmed the potential for signal contamination from enlarged ventricles. These findings highlight the challenges of accurately measuring StO2 in this patient population and the necessity of using a hyperspectral NIRS system to resolve the additional chromophores.

  5. Isolation and characterization of intact mitochondria from neonatal rat brain.

    PubMed

    Rajapakse, N; Shimizu, K; Payne, M; Busija, D

    2001-12-01

    Poor outcome after neonatal brain injury may be associated with alterations in mitochondrial function. Thus, isolated mitochondria have been a useful tool in understanding the underlying mechanisms of mitochondrial dysfunction. However, isolation and characterization of mitochondria from neonatal rat brain are not fully described. Thus, the aim of this study was to develop a rapid method for the isolation and characterization of functional mitochondria from neonatal rat brain. Mitochondria were isolated from 7-day-old rat brain weighing approximately 500 mg using a discontinuous Percoll density gradient. Brains were homogenized in 12% Percoll/sucrose buffer and layered onto a 26% Percoll/40% Percoll gradient followed by centrifugation. Four methods were used for assessing mitochondrial integrity and function: (1) electron microscopy to assess the morphology of the mitochondria and to determine the relative purity of the preparation; (2) fluorescence of chloromethyl-X-rosamine (Mito Tracker Red) in mitochondria as an indicator of mitochondrial membrane potential (Delta psi(m)); (3) state 3 and 4 respiration; and (4) protein import into mitochondria using an in vitro-synthesized mitochondrial malate dehydrogenase (mMDH). These studies demonstrated that the morphology of mitochondria is maintained with intact outer membranes and well-developed cristae, and Delta psi(m) is preserved. Respiration measurements revealed tightly coupled mitochondria with a respiration control ratio (RCR) of 4.1+/-0.18 (n=6). Import of precursor mMDH into mitochondria increased in a time-dependent manner maximizing at 15 min. The results indicate that neonatal brain mitochondria isolated using this method are well coupled, morphologically intact and are capable of protein import across the outer and inner mitochondrial membranes.

  6. User-guided segmentation of preterm neonate ventricular system from 3-D ultrasound images using convex optimization.

    PubMed

    Qiu, Wu; Yuan, Jing; Kishimoto, Jessica; McLeod, Jonathan; Chen, Yimin; de Ribaupierre, Sandrine; Fenster, Aaron

    2015-02-01

    A three-dimensional (3-D) ultrasound (US) system has been developed to monitor the intracranial ventricular system of preterm neonates with intraventricular hemorrhage (IVH) and the resultant dilation of the ventricles (ventriculomegaly). To measure ventricular volume from 3-D US images, a semi-automatic convex optimization-based approach is proposed for segmentation of the cerebral ventricular system in preterm neonates with IVH from 3-D US images. The proposed semi-automatic segmentation method makes use of the convex optimization technique supervised by user-initialized information. Experiments using 58 patient 3-D US images reveal that our proposed approach yielded a mean Dice similarity coefficient of 78.2% compared with the surfaces that were manually contoured, suggesting good agreement between these two segmentations. Additional metrics, the mean absolute distance of 0.65 mm and the maximum absolute distance of 3.2 mm, indicated small distance errors for a voxel spacing of 0.22 × 0.22 × 0.22 mm(3). The Pearson correlation coefficient (r = 0.97, p < 0.001) indicated a significant correlation of algorithm-generated ventricular system volume (VSV) with the manually generated VSV. The calculated minimal detectable difference in ventricular volume change indicated that the proposed segmentation approach with 3-D US images is capable of detecting a VSV difference of 6.5 cm(3) with 95% confidence, suggesting that this approach might be used for monitoring IVH patients' ventricular changes using 3-D US imaging. The mean segmentation times of the graphics processing unit (GPU)- and central processing unit-implemented algorithms were 50 ± 2 and 205 ± 5 s for one 3-D US image, respectively, in addition to 120 ± 10 s for initialization, less than the approximately 35 min required by manual segmentation. In addition, repeatability experiments indicated that the intra-observer variability ranges from 6.5% to 7.5%, and the inter-observer variability is 8.5% in terms

  7. Rutaecarpine attenuates hypoxia-induced right ventricular remodeling in rats.

    PubMed

    Li, Wen-Qun; Li, Xiao-Hui; Du, Jie; Zhang, Wang; Li, Dai; Xiong, Xiao-Ming; Li, Yuan-Jian

    2016-07-01

    Rutaecarpine has been shown to exhibit wide pharmacological effects in the cardiovascular system via stimulation of calcitonin gene-related peptide (CGRP) release. In the present study, the effect of rutaecarpine on hypoxia-induced right ventricular (RV) remodeling and the underlying mechanisms were evaluated. RV remodeling was induced by hypoxia (10 % O2, 3 weeks) in rats. Rats were treated with rutaecarpine (20 or 40 mg/kg) by intragastric administration. Proliferation of cardiac fibroblasts was induced by TGF-β1 (5 ng/mL) and determined by MTS and EdU incorporation method. Cardiac fibroblasts were treated with exogenous CGRP (10 or 100 nM). The concentrations of CGRP and TGF-β1 in plasma were measured by ELISA. The expression of eIF3a, p27, α-SMA, collagen-I/III, ANP, and BNP were measured by real-time PCR or western blot. Hypoxia induced an increase of right ventricle systolic pressure (RVSP), ration of RV/LV+S, and RV/tibial length in rats, while cardiac hypertrophy, apoptosis, and fibrosis were detected. The expression of ANP, BNP, α-SMA, collagen-I, collagen-III, eIF3a, and TGF-β1 was up-regulated, and the expression of p27 was down-regulated in the right ventricle of hypoxia-treated rats. The plasma concentration of CGRP was decreased and TGF-β1 was increased in hypoxia-treated rats. All of these effects induced by hypoxia were attenuated by rutaecarpine in a dose-dependent manner. In cultured cardiac fibroblasts, TGF-β1 significantly promoted the proliferation and up-regulated the expression of α-SMA and collagen-I/III, while the expression of eIF3a was up-regulated and the expression of p27 was down-regulated. The effects of TGF-β1 were attenuated by CGRP. CGRP8-37, a selective CGRP receptor antagonist, abolished the effects of CGRP. Rutaecarpine attenuates hypoxia-induced RV remodeling via stimulation of CGRP release, and the effects of rutaecarpine involve the eIF3a/p27 pathway.

  8. Neonatal inflammatory pain increases hippocampal neurogenesis in rat pups.

    PubMed

    Leslie, Ana Teresa F S; Akers, Katherine G; Martinez-Canabal, Alonso; Mello, Luís Eugênio de Araújo; Covolan, Luciene; Guinsburg, Ruth

    2011-08-26

    Preterm infants undergo several painful procedures during their stay in neonatal intensive care units. Previous studies suggest that early painful experiences may have an impact on brain development. Here, we used an animal model to investigate the effect of neonatal pain on the generation of new neurons in the dentate gyrus region of the hippocampus. Rat pups received intraplantar injections of complete Freund's adjuvant (CFA), a painful inflammatory agent, on either P1 or P8 and were sacrificed on P22. We found that rat pups injected with CFA on P8 had more BrdU-labeled cells and a higher density of cells expressing doublecortin (DCX) in the subgranular zone of the dentate gyrus. No change in BrdU-labeling or DCX expression was observed in pups injected with CFA on P1. These findings indicate that neonatal pain can increase hippocampal neurogenesis, suggesting that early painful experiences may shape brain development and thereby influence behavioral outcome. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  9. [Eukaryotic expression vector pcDNA3-HERG transfection inhibits angiotensin II induced neonatal rabbit ventricular myocyte hypertrophy in vitro].

    PubMed

    Zhao, Yong-hui; Cui, Chang-cong; Li, Yu; Huang, Chen

    2009-10-01

    To explore the effects of eukaryotic expression vector pcDNA3-HERG transfection on angiotensin II (Ang II) induced myocyte hypertrophy in cultured neonatal rabbit ventricular myocytes. Neonatal rabbit ventricular myocytes and eukaryotic expression vector pcDNA3-HERG transfected ventricular myocytes were cultured in Dulbecco's-modified Eagle medium (DMEM), containing 1% fetal bovine serum (FBS) for 6 h, then stimulated with Ang II (10(-7) mol/L) for 48 h. Control ventricular myocytes were cultured in Dulbecco's-modified Eagle medium (DMEM), containing 1% fetal bovine serum (FBS) for 54 h. At 6 and 54 h, myocyte hypertrophic parameters including myocyte volume, total protein content and membrane capacitance, action potential duration (APD) and Calcineurin (CaN) activity were measured. Compared to control myocytes, APD at 90% repolarization (APD(90)) was prolonged by 19.8% (P < 0.01), without signs of myocyte hypertrophy at 6 h post Ang II stimulation, APD(90) was prolonged by 22.1% (P < 0.01), myocyte volume, total protein content and membrane capacitance and CaN activity were significantly increased by 40.4%, 40.4%, 38.2% and 114.7% respectively (all P < 0.01) at 48 h after Ang II stimulation. HERG gene transfection upregulated I(HERG) tail current (3.6-fold higher than I(Kr)-rapidly activating delayed rectifier potassium current, P < 0.01). HERG gene transfection also accelerated and repolarization and a shortened APD(90) and inhibited myocyte hypertrophy and CaN activation induced by Ang II. Ang II induced prolongation of APD(90) is directly associated with myocyte hypertrophy by increasing the Ca(2+) influx and resulting in the increment of intracellular Ca(2+) and activation of CaN reaction pathway.

  10. Dual role of GABA in the neonatal rat hippocampus.

    PubMed

    Khalilov, I; Dzhala, V; Ben-Ari, Y; Khazipov, R

    1999-11-01

    The effects of modulators of GABA-A receptors on neuronal network activity were studied in the neonatal (postnatal days 0-5) rat hippocampus in vitro. Under control conditions, the physiological pattern of activity of the neonatal hippocampal network was characterized by spontaneous network-driven giant depolarizing potentials (GDPs). The GABA-A receptor agonist isoguvacine (1-2 microM) and the allosteric modulator diazepam (2 microM) induced biphasic responses: initially the frequency of GDPs increased 3 to 4 fold followed by blockade of GDPs and desynchronization of the network activity. The GABA-A receptor antagonists bicuculline (10 microM) and picrotoxin (100 microM) blocked GDPs and induced glutamate (AMPA and NMDA)-receptor-mediated interictal- and ictal-like activities in the hippocampal slices and the intact hippocampus. These data suggest that at early postnatal ages GABA can exert a dual - both excitatory and inhibitory - action on the network activity.

  11. Left ventricular remodeling after experimental myocardial cryoinjury in rats.

    PubMed

    Ciulla, Michele M; Paliotti, Roberta; Ferrero, Stefano; Braidotti, Paola; Esposito, Arturo; Gianelli, Umberto; Busca, Giuseppe; Cioffi, Ugo; Bulfamante, Gaetano; Magrini, Fabio

    2004-01-01

    The standard coronary ligation, the most studied model of experimental myocardial infarction in rats, is limited by high mortality and produces unpredictable areas of necrosis. To standardize the location and size of the infarct and to elucidate the mechanisms of myocardial remodeling and its progression to heart failure, we studied the functional, structural, and ultrastructural changes of myocardial infarction produced by experimental myocardial cryoinjury. The cryoinjury was successful in 24 (80%) of 30 male adult CD rats. A subepicardial infarct was documented on echocardiograms, with an average size of about 21%. Macroscopic examination reflected closely the stamp of the instrument used, without transition zones to viable myocardium. Histological examination, during the acute setting, revealed an extensive area of coagulation necrosis and hemorrhage in the subepicardium. An inflammatory infiltrate was evident since the 7th hour, whereas the reparative phase started within the first week, with proliferation of fibroblasts, endothelial cells, and myocytes. From the 7th day, deposition of collagen fibers was reported with a reparative scar completed at the 30th day. Ultrastructural study revealed vascular capillary damage and irreversible alterations of the myocytes in the acute setting and confirmed the histological findings of the later phases. The damage was associated with a progressive left ventricular (LV) remodeling, including thinning of the infarcted area, hypertrophy of the noninfarcted myocardium, and significant LV dilation. This process started from the 60th day and progressed over the subsequent 120 days period; at 180 days, a significant increase in LV filling pressure, indicative of heart failure, was found. In conclusion, myocardial cryodamage, although different in respect to ischemic damage, causes a standardized injury reproducing the cellular patterns of coagulation necrosis, early microvascular reperfusion, hemorrhage, inflammation

  12. [The rat ventricular myocardium in chronic hypercapnia. Electron microscopic study].

    PubMed

    Reichart, E; Moravec, J; Moravec, M; Marotte, F; Hatt, P Y

    1975-11-01

    An electron microscope study of the left ventricular myocardium from rat acclimatized to chronic hypercapnia was done in order to complete the preceding work concerning general effects of respiratory acidosis. After 15 and 30 days of the acclimatation to 8% CO2 no lesions of the myocardium could be found. The results of the morphometric analysis indicated, however, discrete modifications of heart ultrastructure similar to those found before in hypoxic and failing hearts: namely a decrease of mitochondrial mean diameter and a non significant decrease of mitochondrial fractional volume. The latter was accompanied by a significant decrease of myofibrillar mass. The presence of cellular oedema seems to be suggested by an increase of fractional volume of the cytosol. The mechanism of these changes is not easy to explain. Further work will be necessary to make a choice between two possibilities: (1) depressed contractility related to some direct effect of high pCO2 and (2) tissue hypoxia secondary to local effects of the former.

  13. Neonatal inhalatory anesthetic exposure: reproductive changes in male rats.

    PubMed

    Arena, A C; Pereira, O C M

    2002-12-01

    We investigated the effects of an inhalatory anesthetic (ethyl ether) during the neonatal period of brain sexual differentiation on the later fertility and sexual behavior of male rats. Animals were exposed to ethyl ether immediately after birth. At adulthood, body weight, testes wet weight, and plasma testosterone levels were not affected; however, neonatal exposure to ether showed alterations on male fertility: a decrease in the number of spermatids and spermatozoa, an increase in the transit time of cauda epididymal spermatozoa and a decrease in daily sperm production. An alteration of sexual behavior was also observed: decreased male sexual behavior and appearance of homosexual behavior when the male rats were castrated and pretreated with exogenous estrogen. Probably, the ether delayed or reduced the testosterone peak of the sexual differentiation period, altering the processes of masculinization and defeminization of the hypothalamus. Our results indicate that perinatal exposure to ethyl ether during the critical period of male brain sexual differentiation, acting as endocrine disruptors, has a long-term effect on the fertility and sexual behavior of male rats, suggesting endocrine disruption through incomplete masculinization and defeminization of the central nervous system.

  14. Development of a Vascularized Heterotopic Neonatal Rat Heart Transplantation Model.

    PubMed

    Shimada, Shogo; Del Nido, Pedro J; Friehs, Ingeborg

    2016-01-01

    Rodent adult-to-adult heterotopic heart transplantation is a well-established animal model, and the detailed surgical technique with several modifications has been previously described. In immature donor organ transplantation, however, the surgical technique needs to be revised given the smaller size and fragility of the donor graft. Here, we report our surgical technique for heterotopic abdominal (AHTx) and femoral (FHTx) neonatal rat heart transplantation based on an experience of over 300 cases. Heterotopic heart transplantation was conducted in syngeneic Lewis rats. Neonatal rats (postnatal day 2-4) served as donors. AHTx was performed by utilizing the conventional adult-to-adult transplant method with specific modifications for optimal aortotomy and venous anastomosis. In the FHTx, the donor heart was vascularized by connecting the donor's aorta and pulmonary artery to the recipient's right femoral artery and vein, respectively, in an end-to-end manner. A specifically fashioned butterfly-shaped rubber sheet was used to align the target vessels properly. The transplanted graft was visually assessed for its viability and was accepted as a technical success when the viability met specific criteria. Successfully transplanted grafts were subject to further postoperative evaluation. Forty cases (AHTx and FHTx; n = 20 each) were compared regarding perioperative parameters and outcomes. Both models were technically feasible (success rate: AHTx 75% vs. FHTx 70%) by refining the conventional heterotopic transplant technique. Injury to the fragile donor aorta and congestion of the graft due to suboptimal venous connection were predominant causes of failure, leading to refractory bleeding and poor graft viability. Although the FHTx required significantly longer operation time and graft ischemic time, the in situ graft viabilities were comparable. The FHTx provided better postoperative monitoring as it enabled daily graft palpation and better echocardiographic

  15. The effect of sildenafil on right ventricular remodeling in a rat model of monocrotaline-induced right ventricular failure

    PubMed Central

    Bae, Hyun Kyung; Lee, Hyeryon; Kim, Kwan Chang

    2016-01-01

    Purpose Pulmonary arterial hypertension (PAH) leads to right ventricular failure (RVF) as well as an increase in pulmonary vascular resistance. Our purpose was to study the effect of sildenafil on right ventricular remodeling in a rat model of monocrotaline (MCT)-induced RVF. Methods The rats were distributed randomly into 3 groups. The control (C) group, the monocrotaline (M) group (MCT 60 mg/kg) and the sildenafil (S) group (MCT 60 mg/kg+ sildenafil 30 mg/kg/day for 28 days). Masson Trichrome staining was used for heart tissues. Western blot analysis and immunohistochemical staining were performed. Results The mean right ventricular pressure (RVP) was significantly lower in the S group at weeks 1, 2, and 4. The number of intra-acinar arteries and the medial wall thickness of the pulmonary arterioles significantly lessened in the S group at week 4. The collagen content also decreased in heart tissues in the S group at week 4. Protein expression levels of B-cell lymphoma-2 (Bcl-2)-associated X, caspase-3, Bcl-2, interleukin (IL)-6, matrix metalloproteinase (MMP)-2, endothelial nitric oxide synthase (eNOS), endothelin (ET)-1 and ET receptor A (ERA) in lung tissues greatly decreased in the S group at week 4 according to immunohistochemical staining. According to Western blotting, protein expression levels of troponin I, brain natriuretic peptide, caspase-3, Bcl-2, tumor necrosis factor-α, IL-6, MMP-2, eNOS, ET-1, and ERA in heart tissues greatly diminished in the S group at week 4. Conclusion Sildenafil alleviated right ventricular hypertrophy and mean RVP. These data suggest that sildenafil improves right ventricular function. PMID:27462355

  16. Antioxidant effects of hydrogen sulfide on left ventricular remodeling in smoking rats are mediated via PI3K/Akt-dependent activation of Nrf2.

    PubMed

    Zhou, Xiang; Zhao, Liangping; Mao, Jinning; Huang, Jian; Chen, Jianchang

    2015-03-01

    There is growing evidence that oxidative stress plays critical roles in the pathogenesis of cardiac remodeling. In the present study, we established a rat model of passive smoking and investigated the antioxidant effects of hydrogen sulfide (H2S) on smoking-induced left ventricular remodeling. Cardiac structure and function were evaluated using 2-dimensional echocardiography. Myocardial fibrosis was detected by Masson's trichrome staining and immunohistochemistry. Oxidative stress was assessed by measuring malondialdehyde levels, superoxide dismutase and glutathione peroxidase activities, and reactive oxygen species generation in the myocardium. Neonatal rat cardiomyocytes transfected with specific siRNA and exposed to cigarette smoke condensate and H2S donor sodium hydrosulfide were used to confirm the involvement of Nrf2 and PI3K/Akt signaling in the antioxidant effects of H2S. Our results indicated that H2S could protect against left ventricular remodeling in smoking rats via attenuation of oxidative stress. Moreover, H2S was also found to increase the phosphorylation of Akt and GSK3β and decrease the nuclear expression of Fyn, which consequently leads to nuclear translocation of Nrf2 and elevated expression of HO-1 and NQO1. In conclusion, H2S may exert antioxidant effects on left ventricular remodeling in smoking rats via PI3K/Akt-dependent activation of Nrf2 signaling.

  17. A novel approach to the management of critically ill neonatal Ebstein's anomaly: Veno-venous extracorporeal membrane oxygenation to promote right ventricular recovery.

    PubMed

    Bauser-Heaton, Holly; Nguyen, Charles; Tacy, Theresa; Axelrod, David

    2015-01-01

    This is the first report of the use of veno-venous extracorporeal membrane oxygenation in a neonate with severe Ebstein's anomaly. The report suggests the use of veno-venous extracorporeal membrane oxygenation in the immediate neonatal period may be a useful therapy in severe Ebstein's anomaly. By providing adequate oxygenation independent of the patient's native pulmonary blood flow, veno-venous extracorporeal membrane oxygenation allows the pulmonary vascular resistance to decrease and may promote right ventricular recovery.

  18. A Neonate with Susceptibility to Long QT Syndrome Type 6 who Presented with Ventricular Fibrillation and Sudden Unexpected Infant Death.

    PubMed

    Sauer, Charles W; Marc-Aurele, Krishelle L

    2016-07-28

    BACKGROUND This is a case of a neonate with susceptibility to long QT syndrome (LQTS) who presented with a sudden unexpected infant death. Experts continue to debate whether universal electrocardiogram (ECG) screening of all newborns is feasible, practical, and cost-effective. CASE REPORT A 19-day-old neonate was found unresponsive by her mother. ECG showed ventricular fibrillation and a combination of a lidocaine drip plus multiple defibrillations converted the rhythm to normal sinus. Unfortunately, MRI brain imaging showed multiple infarcts and EEG showed burst suppression pattern with frequent seizures; life supportive treatment was stopped and the infant died. Genetic testing revealed two mutations in the KCNE2 gene consistent with susceptibility to LQTS type 6. CONCLUSIONS We believe this case is the first to demonstrate both a precipitating electrocardiographic and genetic cause of death for an infant with LQTS, showing a cause-and-effect relationship between LQTS mutation, ventricular arrhythmia, and death. We wonder whether universal ECG newborn screening to prevent LQTS death could have saved this baby.

  19. Progesterone and estradiol plasma levels in neonatally irradiated cycling rats

    SciTech Connect

    Freud, A.; Sod-Moriah, U.A. )

    1990-01-01

    Female rats which were exposed to a single low dose of gamma irradiation (6R or 15R) at the age of 8 days produce smaller litters when mature than untreated controls. The possibility that the impaired fertility resulted from altered ovarian activity as reflected by changes in plasma levels of progesterone or estardiol was investigated. Plasma levels of both steroids were determined throughout the day of proestrus. Progesterone level was also determined in 6R animals on the day of weaning. The maturity of such irradiated rats was assessed by observing the time of vaginal opening. The results indicated that the preovulatory peak of progesterone was delayed in the 6R rats whereas in the 15R group its levels were significantly lower. On the other hand no differences in estradiol plasma levels were noticed between the groups. The higher level of progesterone in the 6R animals was not evident on the day of weaning and was even in both groups, but vaginal opening in the irradiated rats was significantly delayed. The elevated level of progesterone might be responsible, among other endocrine changes, for the lower fertility of neonatally irradiated mature female rats.

  20. Characterizations and comparisons of eupnoea and gasping in neonatal rats.

    PubMed Central

    Wang, W; Fung, M L; Darnall, R A; St John, W M

    1996-01-01

    1. Our purpose was to characterize the ventilatory patterns of eupnoea and gasping in the neonatal rat. This study was precipitated by reports, using in vitro brainstem spinal cord preparations, that only a single pattern is present in neonatal rats. 2. In anaesthetized or decerebrate rat pups aged less than 13 days, eupnoea was characterized by a sudden onset of inspiratory activity and then a more gradual rise to peak levels. Following vagotomy, frequency fell and peak phrenic activity and tidal volume increased. The rate of rise of inspiratory activity also rose, but peak levels were still achieved during the latter half of inspiration. Vagal efferent activity exhibited bursts during both inspiration and the early expiration. This basic eupnoeic rhythm was not altered after sectioning of the carotid sinus nerves. 3. Upon exposure to hypoxia or anoxia, phrenic activity, tidal volume and frequency initially increased and then declined. In many animals, ventilatory activity then ceased, but later returned with a gasping pattern. 4. Gasping was characterized by a sudden onset of phrenic activity, which reached a peak intensity during the early portion of inspiration. The expiratory burst of vagal activity was eliminated. 5. Reductions of body temperature from 37 to 27 degrees C resulted in prolongations of inspiration and expiration and decreases of phrenic amplitude; phasic phrenic activity completely disappeared in some animals. Upon exposure to anoxia, gasping was observed, even in animals in which phrenic activity had disappeared in hyperoxia. 6. We conclude that, from the day of birth, rats can exhibit eupnoea and gasping patterns which are very similar to those of adult animals. 7. The rhythmic neural activities of the in vitro brainstem-spinal cord preparation, reported by others, differ markedly from eupnoea but are identical with gasping. We therefore conclude that this preparation is not suitable for investigation of the mechanisms that generate eupnoeic

  1. Effects of intracellular calcium on sodium current density in cultured neonatal rat cardiac myocytes.

    PubMed Central

    Chiamvimonvat, N; Kargacin, M E; Clark, R B; Duff, H J

    1995-01-01

    1. Na+ channel mRNA levels in the heart can be modulated by changes in intracellular Ca2+ ([Ca2+]i). We have investigated whether this regulation of Na+ channel biosynthesis by cytosolic Ca2+ translates into functional Na+ channels that can be detected electrophysiologically. 2. Whole-cell Na+ currents (INa) were recorded using patch-clamp techniques from single ventricular myocytes isolated from neonatal rats and maintained in tissue culture for 24 h. Na+ current density, measured at a membrane potential of -10 mV, was significantly decreased in the cells which were exposed for 24 h to culture medium containing 10 mM of both external Ca2+ and K+ in order to raise [Ca2+]i compared with control cells which were maintained in culture medium containing 2 and 5 mM of Ca2+ and K+, respectively. In contrast, Na+ current density (at -10 mV) was significantly increased in cells exposed for 24 h to 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid tetraacetoxymethyl ester (BAPTA AM; a cell membrane-permeable Ca2+ chelator) which lowered the average [Ca2+]i compared with control. 3. Changes in current density were not associated with changes in the voltage dependence of activation and inactivation of INa. There were no changes in single-channel conductances. 4. It is concluded that Na+ current density in neonatal rat cardiac myocytes is modulated by [Ca2+]i. The findings suggest that the differences in current density are attributable to a change in Na+ channel numbers rather than to changes in single-channel conductance or gating. These changes are consistent with the previously documented modulation of Na+ channel biosynthesis by cytosolic Ca2+. PMID:7650605

  2. Role of cyclooxygenase-2 in intestinal injury in neonatal rats.

    PubMed

    Lu, Hui; Zhu, Bing

    2014-11-01

    Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in premature neonates. The pathogenesis of NEC remains poorly understood. The present study aimed to investigate the dynamic change and role of cyclooxygenase-2 (COX-2) in neonatal rats with intestinal injury. Wistar rats, <24 h in age, received an intraperitoneal injection with 5 mg/kg lipopolysaccharide (LPS). Ileal tissues were collected at 1, 3, 6, 12 and 24 h following the LPS challenge for histological evaluation of NEC and for measurements of COX-2 mRNA. The correlation between the degree of intestinal injury and expression of COX-2 mRNA was determined. The LPS-injected pups showed a significant increase in injury scores compared to the control, and the most deteriorating change was at 12 h. COX-2 mRNA expression was upregulated following LPS injection. There was a significantly positive correlation between COX-2 mRNA and the grade of intestinal injury within 12 h, whereas COX-2 mRNA expression had a significantly negative correlation with the severity of intestinal injury at 24 h. COX-2 plays an important role in LPS-induced intestinal injury and the repair processes. Caution should be exerted concerning the potential therapeutic uses of COX-2 inhibitors or promoters in NEC.

  3. l-Arginine currents in rat cardiac ventricular myocytes

    PubMed Central

    Peluffo, R Daniel

    2007-01-01

    l-Arginine (l-Arg) is a basic amino acid that plays a central role in the biosynthesis of nitric oxide, creatine, agmantine, polyamines, proline and glutamate. Most tissues, including myocardium, must import l-Arg from the circulation to ensure adequate intracellular levels of this amino acid. This study reports novel l-Arg-activated inward currents in whole-cell voltage-clamped rat ventricular cardiomyocytes. Ion-substitution experiments identified extracellular l-Arg as the charge-carrying cationic species responsible for these currents, which, thus, represent l-Arg import into cardiac myocytes. This result was independently confirmed by an increase in myocyte nitric oxide production upon extracellular application of l-Arg. The inward movement of Arg molecules was found to be passive and independent of Na2+, K2+, Ca2+ and Mg2+. The process displayed saturation and membrane potential (Vm)-dependent kinetics, with a K0.5 for l-Arg that increased from 5 mm at hyperpolarizing Vm to 20 mm at +40 mV. l-Lysine and l-ornithine but not d-Arg produced currents with characteristics similar to that activated by l-Arg indicating that the transport process is stereospecific for cationic l-amino acids. l-Arg current was fully blocked after brief incubation with 0.2 mmN-ethylmaleimide. These features suggest that the activity of the low-affinity, high-capacity CAT-2A member of the y2+ family of transporters is responsible for l-Arg currents in acutely isolated cardiomyocytes. Regardless of the mechanism, we hypothesize that a low-affinity arginine transport process in heart, by ensuring substrate availability for sustained NO production, might play a cardio-protective role during catabolic states known to increase Arg plasma levels severalfold. PMID:17303641

  4. Deficiency or inhibition of lysophosphatidic acid receptor 1 protects against hyperoxia-induced lung injury in neonatal rats.

    PubMed

    Chen, X; Walther, F J; van Boxtel, R; Laghmani, E H; Sengers, R M A; Folkerts, G; DeRuiter, M C; Cuppen, E; Wagenaar, G T M

    2016-03-01

    Blocking of lysophosphatidic acid (LPA) receptor (LPAR) 1 may be a novel therapeutic option for bronchopulmonary dysplasia (BPD) by preventing the LPAR1-mediated adverse effects of its ligand (LPA), consisting of lung inflammation, pulmonary arterial hypertension (PAH) and fibrosis. In Wistar rats with experimental BPD, induced by continuous exposure to 100% oxygen for 10 days, we determined the beneficial effects of LPAR1 deficiency in neonatal rats with a missense mutation in cytoplasmic helix 8 of LPAR1 and of LPAR1 and -3 blocking with Ki16425. Parameters investigated included survival, lung and heart histopathology, fibrin and collagen deposition, vascular leakage and differential mRNA expression in the lungs of key genes involved in LPA signalling and BPD pathogenesis. LPAR1-mutant rats were protected against experimental BPD and mortality with reduced alveolar septal thickness, lung inflammation (reduced influx of macrophages and neutrophils, and CINC1 expression) and collagen III deposition. However, LPAR1-mutant rats were not protected against alveolar enlargement, increased medial wall thickness of small arterioles, fibrin deposition and vascular alveolar leakage. Treatment of experimental BPD with Ki16425 confirmed the data observed in LPAR1-mutant rats, but did not reduce the pulmonary influx of neutrophils, CINC1 expression and mortality in rats with experimental BPD. In addition, Ki16425 treatment protected against PAH and right ventricular hypertrophy. LPAR1 deficiency attenuates pulmonary injury by reducing pulmonary inflammation and fibrosis, thereby reducing mortality, but does not affect alveolar and vascular development and, unlike Ki16425 treatment, does not prevent PAH in neonatal rats with experimental BPD. © 2015 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

  5. Deficiency or inhibition of lysophosphatidic acid receptor 1 protects against hyperoxia-induced lung injury in neonatal rats

    PubMed Central

    Chen, Xueyu; Walther, Frans J; van Boxtel, Ruben; Laghmani, El Houari; Sengers, Rozemarijn M A; Folkerts, Gert; DeRuiter, Marco C.; Cuppen, Edwin; Wagenaar, Gerry T M

    2015-01-01

    Aim Blocking of lysophosphatidic acid (LPA) receptor (LPAR) 1 may be a novel therapeutic option for bronchopulmonary dysplasia (BPD) by preventing the LPAR1-mediated adverse effects of its ligand (LPA), consisting of lung inflammation, pulmonary arterial hypertension (PAH) and fibrosis. Methods In Wistar rats with experimental BPD, induced by continuous exposure to 100% oxygen for 10 days, we determined the beneficial effects of LPAR1 deficiency in neonatal rats with a missense mutation in cytoplasmic helix 8 of LPAR1 and of LPAR1 and -3 blocking with Ki16425. Parameters investigated included survival, lung and heart histopathology, fibrin and collagen deposition, vascular leakage, and differential mRNA expression in the lungs of key genes involved in LPA signalling and BPD pathogenesis. Results LPAR1 mutant rats were protected against experimental BPD and mortality with reduced alveolar septal thickness, lung inflammation (reduced influx of macrophages and neutrophils, and CINC1 expression), and collagen III deposition. However, LPAR1 mutant rats were not protected against alveolar enlargement, increased medial wall thickness of small arterioles, fibrin deposition, and vascular alveolar leakage. Treatment of experimental BPD with Ki16425 confirmed the data observed in LPAR1 mutant rats, but did not reduce the pulmonary influx of neutrophils, CINC1 expression, and mortality in rats with experimental BPD. In addition, Ki16425 treatment protected against PAH and right ventricular hypertrophy. Conclusion LPAR1 deficiency attenuates pulmonary injury by reducing pulmonary inflammation and fibrosis, thereby reducing mortality, but does not affect alveolar and vascular development and, unlike Ki16425 treatment, does not prevent PAH in neonatal rats with experimental BPD. PMID:26495902

  6. [Effect of berberine on left ventricular remodeling in renovascular hypertensive rats].

    PubMed

    Zhao, Hai-Ping; Hong, Ying; Xie, Jun-Da; Xie, Xin-Ran; Wang, Jing; Fan, Jiang-Bo

    2007-03-01

    The purpose of this study is to evaluate the effects and the underline mechanisms of berberine on the cardiac function and left ventricular remodeling in rats with renovascular hypertension. The renovascular hypertensive model was established by the two-kidney, two-clip (2K2C) method in Sprague-Dawley (SD) rats. Two weeks after surgery, all the operated SD rats were randomly assigned into four groups: (1) renovascular hypertensive model group; (2) berberine 5 mg x kg(-1) group; (3) berberine 10 mg x kg(-1) group; (4) captopril 45 mg x kg(-1) group; and the sham operated rats were used as control. Four weeks after the drugs were administered, the cardiac function was assessed. The ratios of heart weight to body weight (HW/BW), left ventricular weight to body weight (LVW/BW) and right ventricular weight to body weight (RVW/BW) were compared between groups. Coronal sections of the left ventricular tissue (LV) were prepared for paraffin sections, picrosirius red and HE staining was performed. The left ventricular wall thickness (LVWT), interventricular septal thickness (IVST), the parameters of myocardial fibrosis indicated by interstitial collagen volume fraction (ICVF) and perivascular collagen area (PVCA) were assessed. Nitric oxide (NO), adenosine cyclophosphate (cAMP) and guanosine cyclophosphate (cGMP) concentrations of left ventricular tissue were measured. Berberine 5 mg x kg(-1) and 10 mg x kg(-1) increased the left ventricular +/- dp/dt(max) and HR. Berberine 10 mg x kg(-1) decreased HW/BW and LVW/BW. The image analysis showed that both 5 and 10 mg x kg(-1) of berberine decreased LVWT, ICVF and PVCA, while increased the NO and cAMP contents in left ventricular tissue. Berberine could improve cardiac contractility of 2K2C model rats, and inhibit left ventricular remodeling especially myocardial fibrosis in renovascular hypertension rats. And such effects may partially associate with the increased NO and cAMP content in left ventricular tissue.

  7. Effects of hindlimb unloading on neuromuscular development of neonatal rats

    NASA Technical Reports Server (NTRS)

    Huckstorf, B. L.; Slocum, G. R.; Bain, J. L.; Reiser, P. M.; Sedlak, F. R.; Wong-Riley, M. T.; Riley, D. A.

    2000-01-01

    We hypothesized that hindlimb suspension unloading of 8-day-old neonatal rats would disrupt the normal development of muscle fiber types and the motor innervation of the antigravity (weightbearing) soleus muscles but not extensor digitorum longus (EDL) muscles. Five rats were suspended 4.5 h and returned 1.5 h to the dam for nursing on a 24 h cycle for 9 days. To control for isolation from the dam, the remaining five littermates were removed on the same schedule but not suspended. Another litter of 10 rats housed in the same room provided a vivarium control. Fibers were typed by myofibrillar ATPase histochemistry and immunostaining for embryonic, slow, fast IIA and fast IIB isomyosins. The percentage of multiple innervation and the complexity of singly-innervated motor terminal endings were assessed in silver/cholinesterase stained sections. Unique to the soleus, unloading accelerated production of fast IIA myosin, delayed expression of slow myosin and retarded increases in standardized muscle weight and fiber size. Loss of multiple innervation was not delayed. However, fewer than normal motor nerve endings achieved complexity. Suspended rats continued unloaded hindlimb movements. These findings suggest that motor neurons resolve multiple innervation through nerve impulse activity, whereas the postsynaptic element (muscle fiber) controls endplate size, which regulates motor terminal arborization. Unexpectedly, in the EDL of unloaded rats, transition from embryonic to fast myosin expression was retarded. Suspension-related foot drop, which stretches and chronically loads EDL, may have prevented fast fiber differentiation. These results demonstrate that neuromuscular development of both weightbearing and non-weightbearing muscles in rats is dependent upon and modulated by hindlimb loading.

  8. Frequency-dependent effects of 4-aminopyridine and almokalant on action-potential duration of adult and neonatal rabbit ventricular muscle.

    PubMed

    Elizalde, A; Barajas, H; Navarro-Polanco, R; Sánchez-Chapula, J

    1999-03-01

    The effects of 4-aminopyridine (1 mM) and almokalant (1 microM) on action-potential duration of neonatal and adult rabbit ventricular multicellular preparations and plateau membrane currents of single ventricular myocytes were studied. In adult ventricular preparations, 4-aminopyridine increased action-potential duration in a frequency-dependent manner, with a greater effect at low stimulation frequencies ("reverse" use dependence). In neonatal preparations, the increase in action-potential duration by 4-aminopyridine was significantly smaller than in adults, and the effect was frequency independent. Almokalant increased the action-potential duration more in neonatal than in adult myocytes. The effect of almokalant was frequency independent between 0.5 and 2 Hz. The block of transient outward current and delayed rectifier current in single myocytes was quantitatively similar. We propose that differences in the kinetic behavior of the transient outward current between adult and neonatal ventricular preparations, slower inactivation, and recovery from inactivation in adults determine differences in the frequency-dependent changes induced by 4-aminopyridine and almokalant on action-potential duration.

  9. Antidromic discharges of dorsal root afferents in the neonatal rat.

    PubMed

    Vinay, L; Brocard, F; Fellippa-Marques, S; Clarac, F

    1999-01-01

    Presynaptic inhibition of primary afferents can be evoked from at least three sources in the adult animal: 1) by stimulation of several supraspinal structures; 2) by spinal reflex action from sensory inputs; or 3) by the activity of spinal locomotor networks. The depolarisation in the intraspinal afferent terminals which is due, at least partly, to the activation of GABA(A) receptors may be large enough to reach firing threshold and evoke action potentials that are antidromically conducted into peripheral nerves. Little is known about the development of presynaptic inhibition and its supraspinal control during ontogeny. This article, reviewing recent experiments performed on the in vitro brainstem/spinal cord preparation of the neonatal rat, demonstrates that a similar organisation is present, to some extent, in the new-born rat. A spontaneous activity consisting of antidromic discharges can be recorded from lumbar dorsal roots. The discharges are generated by the underlying afferent terminal depolarizations reaching firing threshold. The number of antidromic action potentials increases significantly in saline solution with chloride concentration reduced to 50% of control. Bath application of the GABA(A) receptor antagonist, bicuculline (5-10 microM) blocks the antidromic discharges almost completely. Dorsal root discharges are therefore triggered by chloride-dependent GABA(A) receptor-mediated mechanisms; 1) activation of descending pathways by stimulation delivered to the ventral funiculus (VF) of the spinal cord at the C1 level; 2) activation of sensory inputs by stimulation of a neighbouring dorsal root; or 3) pharmacological activation of the central pattern generators for locomotion evokes antidromic discharges in dorsal roots. VF stimulation also inhibited the response to dorsal root stimulation. The time course of this inhibition overlapped with that of the dorsal root discharge suggesting that part of the inhibition of the monosynaptic reflex may be

  10. Neonatal glucocorticosteroid treatment causes systolic dysfunction and compensatory dilation in early life: studies in 4-week-old prepubertal rats.

    PubMed

    Bal, Miriam P; de Vries, Willem B; van der Leij, Feike R; van Oosterhout, Matthijs F M; Berger, Rolf M F; Baan, Jan; van der Wall, Ernst E; van Bel, Frank; Steendijk, Paul

    2005-07-01

    Glucocorticosteroid treatment is widely used to prevent chronic lung disease in premature infants. Recent studies in adult rats, treated with dexamethasone in the neonatal period, report negative long-term effects on the heart and severely reduced life expectancy. We treated neonatal rats with dexamethasone and studied cardiac function after 4 wk (prepubertal age) to investigate whether the late effects as previously described are preceded by detectable alterations in cardiac function at a younger age. Male rat pups (n = 12) were injected intraperitoneally with dexamethasone on d 1, 2, and 3 (0.5, 0.3, and 0.1 mug/g) of life. Control pups (n = 10) received saline. At 4 wk the animals were anesthetized, and a pressure-conductance catheter was introduced into the left ventricle to measure pressure-volume loops. Cardiac function was measured and pressure-volume relations were determined to quantify intrinsic systolic and diastolic function. Subsequently, hearts were excised for histologic examination. Compared with saline-treated animals, dexamethasone-treated rats had a reduced ventricular weight (270 +/- 40 versus 371 +/- 23 mg, p < 0.001) and reduced systolic function (end-systolic elastance: 1.24 +/- 0.43 versus 2.50 +/- 1.39 mm Hg/muL, p = 0.028). Cardiac output was maintained and end-diastolic volume was increased (84 +/- 23 versus 59 +/- 19 microL, p = 0.012) indicating a state of compensatory dilatation. Heart rate, diastolic function, and systemic vascular resistance were unchanged. Neonatal dexamethasone treatment causes cardiac alterations that can be detected in the prepubertal period and that may precede severe cardiac dysfunction later in life. If our findings are confirmed in humans, this may have consequences for a large patient population and cardiac screening at young age may be indicated to enable secondary prevention.

  11. Islands of spatially discordant APD alternans underlie arrhythmogenesis by promoting electrotonic dyssynchrony in models of fibrotic rat ventricular myocardium

    PubMed Central

    Majumder, Rupamanjari; Engels, Marc C.; de Vries, Antoine A. F.; Panfilov, Alexander V.; Pijnappels, Daniël A.

    2016-01-01

    Fibrosis and altered gap junctional coupling are key features of ventricular remodelling and are associated with abnormal electrical impulse generation and propagation. Such abnormalities predispose to reentrant electrical activity in the heart. In the absence of tissue heterogeneity, high-frequency impulse generation can also induce dynamic electrical instabilities leading to reentrant arrhythmias. However, because of the complexity and stochastic nature of such arrhythmias, the combined effects of tissue heterogeneity and dynamical instabilities in these arrhythmias have not been explored in detail. Here, arrhythmogenesis was studied using in vitro and in silico monolayer models of neonatal rat ventricular tissue with 30% randomly distributed cardiac myofibroblasts and systematically lowered intercellular coupling achieved in vitro through graded knockdown of connexin43 expression. Arrhythmia incidence and complexity increased with decreasing intercellular coupling efficiency. This coincided with the onset of a specialized type of spatially discordant action potential duration alternans characterized by island-like areas of opposite alternans phase, which positively correlated with the degree of connexinx43 knockdown and arrhythmia complexity. At higher myofibroblast densities, more of these islands were formed and reentrant arrhythmias were more easily induced. This is the first study exploring the combinatorial effects of myocardial fibrosis and dynamic electrical instabilities on reentrant arrhythmia initiation and complexity. PMID:27072041

  12. Islands of spatially discordant APD alternans underlie arrhythmogenesis by promoting electrotonic dyssynchrony in models of fibrotic rat ventricular myocardium

    NASA Astrophysics Data System (ADS)

    Majumder, Rupamanjari; Engels, Marc C.; de Vries, Antoine A. F.; Panfilov, Alexander V.; Pijnappels, Daniël A.

    2016-04-01

    Fibrosis and altered gap junctional coupling are key features of ventricular remodelling and are associated with abnormal electrical impulse generation and propagation. Such abnormalities predispose to reentrant electrical activity in the heart. In the absence of tissue heterogeneity, high-frequency impulse generation can also induce dynamic electrical instabilities leading to reentrant arrhythmias. However, because of the complexity and stochastic nature of such arrhythmias, the combined effects of tissue heterogeneity and dynamical instabilities in these arrhythmias have not been explored in detail. Here, arrhythmogenesis was studied using in vitro and in silico monolayer models of neonatal rat ventricular tissue with 30% randomly distributed cardiac myofibroblasts and systematically lowered intercellular coupling achieved in vitro through graded knockdown of connexin43 expression. Arrhythmia incidence and complexity increased with decreasing intercellular coupling efficiency. This coincided with the onset of a specialized type of spatially discordant action potential duration alternans characterized by island-like areas of opposite alternans phase, which positively correlated with the degree of connexinx43 knockdown and arrhythmia complexity. At higher myofibroblast densities, more of these islands were formed and reentrant arrhythmias were more easily induced. This is the first study exploring the combinatorial effects of myocardial fibrosis and dynamic electrical instabilities on reentrant arrhythmia initiation and complexity.

  13. Cardiac Body Surface Potentials in Rats with Experimental Pulmonary Hypertension during Ventricular Depolarization.

    PubMed

    Suslonova, O V; Smirnova, S L; Roshchevskaya, I M

    2016-11-01

    The spatial and the amplitude-temporal parameters of cardiac body surface potentials were examined in female Wistar rats with experimental pulmonary hypertension during ventricular depolarization. The cardiac body surface potentials have been led from 64 subcutaneous electrodes evenly distributed across the chest surface prior to and 4 weeks after subcutaneous injection of a single dose of monocrotaline (60 mg/kg). Right ventricular hypertrophy and electrophysiological remodeling of the heart developed in rats with experimental pulmonary hypertension in 4 weeks after monocrotaline injection; these changes led to a significant increase in amplitude and temporal characteristics of the cardioelectric field on the body surface in comparison with the initial state.

  14. Precocious development of cytochrome P-450 in neonatal rat liver after glucocorticoid treatment.

    PubMed Central

    Leakey, J E; Fouts, J R

    1979-01-01

    Intraperitoneal injection of neonatal rats with glucocorticoid hormones causes precocious development of hepatic cytochrome P-450. Glucagon injection fails to stimulate this cytochrome P-450 development. Adult liver cytochrome P-450 is less responsive to glucocorticoid stimulation than is that of neonatal rat liver. Adrenalectomy of prematurely delivered neonatal animals prevents the early postnatal development of cytochrome P-450. Glucocorticoids failed to increase cytochrome P-450 concentrations in foetal rat liver. These findings imply that, although glucocorticoids are mandatory regulatory factors controlling cytochrome P-450 development, they are not themselves the 'trigger' initiating onset of that development. PMID:40549

  15. ATP counteracts the rundown of gap junctional channels of rat ventricular myocytes by promoting protein phosphorylation.

    PubMed

    Verrecchia, F; Duthe, F; Duval, S; Duchatelle, I; Sarrouilhe, D; Herve, J C

    1999-04-15

    1. The degree of cell-to-cell coupling between ventricular myocytes of neonatal rats appeared well preserved when studied in the perforated version of the patch clamp technique or, in double whole-cell conditions, when ATP was present in the patch pipette solution. In contrast, when ATP was omitted, the amplitude of junctional current rapidly declined (rundown). 2. To examine the mechanism(s) of ATP action, an 'internal perfusion technique' was adapted to dual patch clamp conditions, and reintroduction of ATP partially reversed the rundown of junctional channels. 3. Cell-to-cell communication was not preserved by a non-hydrolysable ATP analogue (5'-adenylimidodiphosphate, AMP-PNP), indicating that the effect most probably did not involve direct interaction of ATP with the channel-forming proteins. 4. An ATP analogue supporting protein phosphorylation but not active transport processes (adenosine 5'-O-(3-thiotriphosphate), ATPgammaS) maintained normal intercellular communication, suggesting that the effect was due to kinase activity rather than to altered intracellular Ca2+. 5. A broad spectrum inhibitor of endogenous serine/threonine protein kinases (H7) reversibly reduced the intercellular coupling. A non-specific exogenous protein phosphatase (alkaline phosphatase) mimicked the effects of ATP deprivation. The non-specific inhibition of endogenous protein phosphatases resulted in the preservation of substantial cell-to-cell communication in ATP-free conditions. 6. The activity of gap junctional channels appears to require both the presence of ATP and protein kinase activity to counteract the tonic activity of endogenous phosphatase(s).

  16. Modeling CICR in rat ventricular myocytes: voltage clamp studies

    PubMed Central

    2010-01-01

    Background The past thirty-five years have seen an intense search for the molecular mechanisms underlying calcium-induced calcium-release (CICR) in cardiac myocytes, with voltage clamp (VC) studies being the leading tool employed. Several VC protocols including lowering of extracellular calcium to affect Ca2+ loading of the sarcoplasmic reticulum (SR), and administration of blockers caffeine and thapsigargin have been utilized to probe the phenomena surrounding SR Ca2+ release. Here, we develop a deterministic mathematical model of a rat ventricular myocyte under VC conditions, to better understand mechanisms underlying the response of an isolated cell to calcium perturbation. Motivation for the study was to pinpoint key control variables influencing CICR and examine the role of CICR in the context of a physiological control system regulating cytosolic Ca2+ concentration ([Ca2+]myo). Methods The cell model consists of an electrical-equivalent model for the cell membrane and a fluid-compartment model describing the flux of ionic species between the extracellular and several intracellular compartments (cell cytosol, SR and the dyadic coupling unit (DCU), in which resides the mechanistic basis of CICR). The DCU is described as a controller-actuator mechanism, internally stabilized by negative feedback control of the unit's two diametrically-opposed Ca2+ channels (trigger-channel and release-channel). It releases Ca2+ flux into the cyto-plasm and is in turn enclosed within a negative feedback loop involving the SERCA pump, regulating[Ca2+]myo. Results Our model reproduces measured VC data published by several laboratories, and generates graded Ca2+ release at high Ca2+ gain in a homeostatically-controlled environment where [Ca2+]myo is precisely regulated. We elucidate the importance of the DCU elements in this process, particularly the role of the ryanodine receptor in controlling SR Ca2+ release, its activation by trigger Ca2+, and its refractory characteristics

  17. Lactoferrin protects neonatal rats from gut-related systemic infection.

    PubMed

    Edde, L; Hipolito, R B; Hwang, F F; Headon, D R; Shalwitz, R A; Sherman, M P

    2001-11-01

    Lactoferrin is a milk protein that reportedly protects infants from gut-related, systemic infection. Proof for this concept is limited and was addressed during in vivo and in vitro studies. Neonatal rats pretreated orally with recombinant human lactoferrin (rh-LF) had less bacteremia and lower disease severity scores (P < 0.001) after intestinal infection with Escherichia coli. Control animals had 1,000-fold more colony-forming units of E. coli per milliliter of blood than treated animals (P < 0.001). Liver cultures from control animals had a twofold increase in bacterial counts compared with cultures from rh-LF-treated pups (P < 0.02). Oral therapy with rh-LF + FeSO(4) did not alter the protective effect. In vitro studies confirmed that rh-LF interacted with the infecting bacterium and rat macrophages. An in vitro assay showed that rh-LF did not kill E. coli, but a combination of rh-LF + lysozyme was microbicidal. In vitro studies showed that rat macrophages released escalating amounts of nitric oxide and tumor necrosis factor-alpha when stimulated with increasing concentrations of rh-LF. The in vitro studies suggest that rh-LF may act with other "natural peptide antibiotics" or may prime macrophages to kill E. coli in vivo.

  18. Hormonal regulation of glycogen metabolism in neonatal rat liver

    PubMed Central

    Schwartz, Alan L.; Rall, Theodore W.

    1973-01-01

    1. The development of active and inactive phosphorylase was determined in rat liver during the perinatal period. No inactive form could be found in tissues from animals less than 19 days gestation or older than the fifth postnatal day. 2. The regulation of phosphorylase in organ cultures of foetal rat liver was examined. None of the agents examined [glucagon, insulin or dibutyryl cyclic AMP (6-N,2′-O-dibutyryladenosine 3′:5′-cyclic monophosphate)] changed the amount of phosphorylase activity. 3. Glycogen concentration in these explants were nevertheless decreased more than twofold by 4h of incubation with glucagon or dibutyryl cyclic AMP. Incubation with insulin for 4h increased the glycogen content twofold. 4. Glycogen synthetase activity was examined in these explants. I-form activity (without glucose 6-phosphate) was found to decrease by a factor of two after 4h of incubation with dibutyryl cyclic AMP, whereas I+D activity (with glucose 6-phosphate) remained nearly constant. Incubation for 4h with insulin increased I-form activity threefold, with only a slight increase in I+D activity. 5. When explants were incubated with insulin followed by addition of dibutyryl cyclic AMP, the effects of insulin on glycogen concentration and glycogen synthetase activity were reversed. 6. These results indicate that the regulation of glycogen synthesis may be the major factor in the hormonal control of glycogen metabolism in neonatal rat liver. PMID:4357717

  19. Cardiac pathology in the hypertensive diabetic rat. Biventricular damage with right ventricular predominance.

    PubMed Central

    Fein, F. S.; Cho, S.; Zola, B. E.; Miller, B.; Factor, S. M.

    1989-01-01

    The hypertensive-diabetic rat is a new small animal model of cardiomyopathy characterized by ventricular damage. To determine the extent of pathology in this model, quantitation of light microscopic changes in hearts from 15 hypertensive-diabetic rats and 15 age-matched controls was performed. The fraction of myocardium involved by interstitial fibrosis, myocyte necrosis, replacement fibrosis, vascular sclerosis and perivascular fibrosis was computed separately for right and left ventricles. Spontaneously dying as well as deliberately killed hypertensive-diabetic rats were studied. Spontaneously dying animals had higher systolic blood pressures compared with rats killed deliberately. Body weights were lower and lung weights higher in the former group. Left and right ventricular necrosis and fibrosis were increased in spontaneously dying compared with deliberately killed rats. The degree of right ventricular necrosis and fibrosis paralleled that in the left ventricle, but was, unexpectedly, several times greater in magnitude. Thus, quantitative histology in the hypertensive-diabetic rat reveals more cardiac necrosis and fibrosis, in either ventricle, from spontaneously dying animals compared with deliberately killed rats. This damage, coupled with major functional alterations in the viable myocardium, may lead to congestive heart failure or arrhythmia. Images Figure 1 Figure 2 PMID:2719080

  20. Increased susceptibility of spontaneously hypertensive rats to ventricular tachyarrhythmias in early hypertension

    PubMed Central

    Sovari, Ali A.; Pezhouman, Arash; Iyer, Shankar; Cao, Hong; Ko, Christopher Y.; Bapat, Aneesh; Vahdani, Nooshin; Ghanim, Mostafa; Fishbein, Michael C.

    2016-01-01

    Key points Hypertension is a risk factor for sudden cardiac death caused by ventricular tachycardia and fibrillation.Whether hypertension in its early stage is associated with an increased risk of ventricular tachyarrhythmias is not known.Based on experiments performed at the cellular and whole heart levels, we show that, even early in chronic hypertension, the hypertrophied and fibrotic ventricles of spontaneously hypertensive rats aged 5 to 6 months have already developed increased stress‐induced arrhythmogenicity, and this increased susceptibility to ventricular arrhythmias is primarily a result of tissue remodelling rather than cellular electrophysiological changes.Our findings highlight the need for early hypertension treatment to minimize myocardial fibrosis, ventricular hypertrophy, and arrhythmias. Abstract Hypertension is a risk factor for sudden cardiac death caused by ventricular tachycardia and fibrillation (VT/VF). We hypothesized that, in early hypertension, the susceptibility to stress‐induced VT/VF increases. We compared the susceptibility of 5‐ to 6‐month‐old male spontaneously hypertensive rats (SHR) and age/sex‐matched normotensive rats (NR) to VT/VF during challenge with oxidative stress (H2O2; 0.15 mmol l−1). We found that only SHR hearts exhibited left ventricular fibrosis and hypertrophy. H2O2 promoted VT in all 30 SHR but none of the NR hearts. In 33% of SHR cases, focal VT degenerated to VF within 3 s. Simultaneous voltage‐calcium optical mapping of Langendorff‐perfused SHR hearts revealed that H2O2‐induced VT/VF arose spontaneously from focal activations at the base and mid left ventricular epicardium. Microelectrode recording of SHR hearts showed that VT was initiated by early afterdepolarization (EAD)‐mediated triggered activity. However, despite the increased susceptibility of SHR hearts to VT/VF, patch clamped isolated SHR ventricular myocytes developed EADs and triggered activity to the same extent as NR

  1. Kyotorphin transport and metabolism in rat and mouse neonatal astrocytes.

    PubMed

    Xiang, Jianming; Jiang, Huidi; Hu, Yongjun; Smith, David E; Keep, Richard F

    2010-08-06

    Neuropeptide inactivation is generally thought to occur via peptidase-mediated degradation. However, a recent study found increased analgesia after L-kyotorphin (L-Tyr-L-Arg; L-KTP) administration in mice lacking an oligopeptide transporter, PEPT2. The current study examines the role of PEPT2 in L-KTP uptake by astrocytes and compares it to astrocytic L-KTP degradation. L-[(3)H]KTP uptake was measured in primary cultures of neonatal astrocytes from rats and from Pept2(+/+) and Pept2(-/-) mice. Uptake was further characterized using potential inhibitors. L-[(3)H]KTP degradation was examined in primary astrocyte cultures from Pept2(-/-) mice by following the formation of L-[(3)H]tyrosine. The uptake of L-[(3)H]KTP in both rat and Pept2(+/+) mouse neonatal astrocytes was inhibited by known PEPT2 inhibitors. L-[(3)H]KTP uptake was also reduced in Pept2(-/-) astrocytes as compared to those from Pept2(+/+) mice. Kinetic analysis indicated the presence of a high affinity (K(m) approximately 50 microM) transporter for L-[(3)H]KTP, identified as Pept2, and a low affinity transporter (K(m) approximately 3-4 mM), inhibited by amastatin, bestatin and tyrosine. Astrocytes also degraded L-KTP through a low affinity peptidase (K(m) approximately 2 mM). Astrocytic clearance of L-KTP occurs via both peptidase activity and transport. These processes occur at similar rates and may be linked. This supports the contention that oligopeptide transport may have an impact on the extracellular clearance (and potentially activity) of certain neuropeptides. Copyright 2010 Elsevier B.V. All rights reserved.

  2. T-type Ca2+ channels are involved in high glucose-induced rat neonatal cardiomyocyte proliferation.

    PubMed

    Li, Ming; Zhang, Min; Huang, Luping; Zhou, Jianxin; Zhuang, Hean; Taylor, James T; Keyser, Brian M; Whitehurst, Richard M

    2005-04-01

    Infants develop hypertrophic cardiomyopathy in approximately 30% of diabetic pregnancies. We have characterized the effects of glucose on voltage-gated T-type Ca2+ channels and intracellular free calcium concentration, [Ca2+]i in neonatal rat cardiomyocytes. We found that T-type Ca2+ channel current density increased significantly in primary culture neonatal cardiac myocytes that were treated with 25 mM glucose for 48 h when compared with those that were treated with 5 mM glucose. High-glucose treatment also caused a higher Ca2+ influx elicited by 50 mM KCl in the myocytes. KCl-induced Ca2+ influx was attenuated when nickel was present. Real-time PCR studies demonstrated that mRNA levels of both alpha1G (Ca(v)3.1) and alpha1H (Ca(v)3.2) T-type Ca2+ channels were elevated after high-glucose treatment. High-glucose also significantly increased ventricular cell proliferation as well as the proportion of cells in the S-phase of the cell cycle; both effects were reversed by nickel or mibefradil. These results indicate that high glucose causes a rise in [Ca2+]i in neonatal cardiac myocytes by a mechanism that is associated with the regulation of the T-type Ca2+ channel activity.

  3. GESTATIONAL MERCURY VAPOR EXPOSURE AND DIET CONTRIBUTE TO MERCURY ACCUMULATION IN NEONATAL RATS.

    EPA Science Inventory

    Exposure of pregnant Long-Evans rats to elemental mercury (Hg0) vapor resulted in a significant

    accumulation of Hg in tissues of neonates. Because elevated Hg in neonatal tissues may adversely

    affect growth and development, we were interested in how rapidly Hg was...

  4. Development of Chemosensitivity in Neurons from the Nucleus Tractus Solitarii (NTS) of Neonatal Rats

    PubMed Central

    Conrad, Susan C.; Nichols, Nicole L.; Ritucci, Nick A.; Dean, Jay B.; Putnam, Robert W.

    2009-01-01

    We studied the development of chemosensitivity during the neonatal period in rat Nucleus tractus solitarii (NTS) neurons. We determined the percentage of neurons activated by hypercapnia (15% CO2) and assessed the magnitude of the response by calculating the chemosensitivity index (CI). There were no differences in the percentage of neurons that were inhibited (9%) or activated (44.8%) by hypercapnia or in the magnitude of the activated response (CI 164±4.9%) in NTS neurons from neonatal rats of all ages. To assess the degree of intrinsic chemosensitivity in these neurons we used chemical synaptic block medium and the gap junction blocker carbenoxolone. Chemical synaptic block medium slightly decreased basal firing rate but did not affect the percentage of NTS neurons that responded to hypercapnia at any neonatal age. However, in neonates aged neonates, chemical synaptic block medium increased CI. Carbenoxolone did not significantly alter the number of NTS neurons activated by hypercapnia in neonatal rats of any age. In summary, the response of NTS neurons from neonatal rats appears to be intrinsic and largely unchanged throughout early development. In young neonates (

  5. Electrophysiological properties of neonatal rat motoneurones studied in vitro.

    PubMed Central

    Fulton, B P; Walton, K

    1986-01-01

    The electroresponsive properties of neonatal lumbar spinal motoneurones were studied using isolated, hemisected spinal cords from neonatal rats aged 3-12 days. The extracellular and intracellular responses to electrical stimulation of the ventral and dorsal root were studied as well as the intracellular response to current injection. Field potentials recorded in the lateral motor area following electrical stimulation of lumbar ventral roots had a triphasic positive-negative-positive wave form. The negative component did not return to the base line smoothly but exhibited a 'shoulder' where the negativity increased in duration. Following electrical stimulation of the dorsal root, presynaptic field potentials were recorded upon activation of the afferent axons as well as following synaptic activation of interneurones and motoneurones. The input resistances of neonatal motoneurones determined from the slope of current-voltage plots were high compared with the adult. The resistance decreased with age with a mean of 18.1 M omega for animals 3-5 days old, 8.8 M omega for animals 6-8 days old and 5.4 M omega for animals 9-11 days old. Values for the membrane time constant were similar to those in the adult with a mean of 4.5 ms. Action potentials elicited by ventral or dorsal root stimulation or by intracellular current injection were marked by a pronounced after-depolarization (a.d.p.) and an after-hyperpolarization (a.h.p.). The amplitude of the a.h.p. varied with that of the a.d.p. The amplitude of excitatory post-synaptic potentials (e.p.s.p.s) elicited by electrical stimulation of the dorsal root was affected by intracellular current injection. Two types of e.p.s.p.s were distinguished: those with a biphasic reversal (early phase first) and those in which the early phase was unaffected by inward current injection while the later phase was reversed. Unlike in the adult, the reversals could be achieved with low current levels and the amplitude of both types of e

  6. Neonatal handling alters learning in adult male and female rats in a task-specific manner.

    PubMed

    Kosten, Therese A; Lee, Hongjoo J; Kim, Jeansok J

    2007-06-18

    We demonstrated that early life manipulations (neonatal isolation, neonatal handling, maternal separation) impaired fear conditioning in adult rats [Kosten, T.A., Miserendino, M.J.D., Bombace, J.C., Lee, H.J., Kim, J.J., 2005. Sex-selective effects of neonatal isolation on fear conditioning and foot shock sensitivity. Behav. Brain Res. 157, 235-244.; Kosten, T.A., Lee, H.J. and Kim, J.J., 2006. Early life stress impairs fear conditioning in adult male and female rats. Brain Res. 1087, 142-150.]. Although we found few effects on somatic responses to footshock, deficits in conditioned fear may reflect altered emotional reactivity to aversive stimuli not learning deficits. Here we test neonatal handling effects on learning and memory tasks that vary by aversive stimuli. Neonatal handling was chosen because it alters emotional reactivity in adult rats. Litters of Sprague-Dawley rats were assigned to neonatal handling (15-min separation from dam and nest on postnatal days 1-21) or control (nonseparated) conditions. Adult male and female rats with or without neonatal handling experience were compared on: (1) inhibitory avoidance that involves footshock; (2) a circular maze task that involves escape from bright light; and (3) object recognition that presumably does not involve aversive stimuli. Neonatal handling impaired inhibitory avoidance but enhanced object recognition. There were no differences in circular maze performance. In addition, sex differences emerged in both the inhibitory avoidance and object recognition tasks; female rats perform better in inhibitory avoidance and worse in object recognition compared to male rats. These data suggest that neonatal handling alters learning and memory in a task-specific manner that may reflect alterations in emotional reactivity or differential effects of the manipulation on unknown neurohormonal mechanisms.

  7. Differential expression of parvalbumin in neonatal phencyclidine-treated rats and socially isolated rats.

    PubMed

    Kaalund, Sanne S; Riise, Jesper; Broberg, Brian V; Fabricius, Katrine; Karlsen, Anna S; Secher, Thomas; Plath, Niels; Pakkenberg, Bente

    2013-02-01

    Decreased parvalbumin expression is a hallmark of the pathophysiology of schizophrenia and has been associated with abnormal cognitive processing and decreased network specificity. It is not known whether this decrease is due to reduced expression of the parvalbumin protein or degeneration of parvalbumin-positive interneurons (PV(+) interneurons). In this study, we examined PV(+) expression in two rat models of cognitive dysfunction in schizophrenia: the environmental social isolation (SI) and pharmacological neonatal phencyclidine (neoPCP) models. Using a stereological method, the optical fractionator, we counted neurons, PV(+) interneurons, and glial cells in the medial prefrontal cortex (mPFC) and hippocampus (HPC). In addition, we quantified the mRNA level of parvalbumin in the mPFC. There was a statistically significant reduction in the number of PV(+) interneurons (p = 0.021) and glial cells (p = 0.024) in the mPFC of neonatal phencyclidine rats, but not in SI rats. We observed no alterations in the total number of neurons, hippocampal PV(+) interneurons, parvalbumin mRNA expression or volume of the mPFC or HPC in the two models. Thus, as the total number of neurons remains unchanged following phencyclidine (PCP) treatment, we suggest that the decreased number of counted PV(+) interneurons represents a reduced parvalbumin protein expression below immunohistochemical detection limit rather than a true cell loss. Furthermore, these results indicate that the effect of neonatal PCP treatment is not limited to neuronal populations.

  8. Cardiac spinal deafferentation reduces the susceptibility to sustained ventricular tachycardia in conscious rats

    PubMed Central

    Lujan, Heidi L.; Krishnan, Sandhya

    2011-01-01

    The response to myocardial ischemia is complex and involves the cardio-cardiac sympathetic reflex. Specifically, cardiac spinal (sympathetic) afferents are excited by ischemic metabolites and elicit an excitatory sympathetic reflex, which plays a major role in the genesis of ventricular arrhythmias. For example, brief myocardial ischemia leads to ATP release, which activates cardiac spinal afferents through stimulation of P2 receptors. Clinical work with patients and preclinical work with animals document that disruption of this reflex protects against ischemia-induced ventricular arrhythmias. However, the role of afferent signals in the initiation of sustained ventricular tachycardia has not been investigated. Therefore, we tested the hypothesis that cardiac spinal deafferentation reduces the susceptibility to sustained ventricular tachycardia in adult (12–15 wk of age), conscious, male Sprague-Dawley rats. To test this hypothesis, the susceptibility to ventricular tachyarrhythmias produced by occlusion of the left main coronary artery was determined in two groups of conscious rats: 1) deafferentation (bilateral excision of the T1-T5 dorsal root ganglia) and 2) control (sham deafferentation). The ventricular arrhythmia threshold (VAT) was defined as the time from coronary occlusion to sustained ventricular tachycardia resulting in a reduction in arterial pressure. Results document a significantly higher VAT in the deafferentation group (7.0 ± 0.7 min) relative to control (4.3 ± 0.3 min) rats. The decreased susceptibility to tachyarrhythmias with deafferentation was associated with a reduced cardiac metabolic demand (lower rate-pressure product and ST segment elevation) during ischemia. PMID:21677267

  9. Neonatal hypothyroidism affects the adenine nucleotides metabolism in astrocyte cultures from rat brain.

    PubMed

    Braganhol, Elizandra; Bruno, Alessandra Nejar; Bavaresco, Luci; Barreto-Chaves, Maria Luiza M; Sarkis, João José Freitas; Battastini, Ana Maria Oliveira

    2006-04-01

    Neonatal hypothyroidism is associated with multiple and severe brain alterations. We recently demonstrated a significant increase in hydrolysis of AMP to adenosine in brain of hypothyroid rats at different ages. However, the origin of this effect was unclear. Considering the effects of adenine nucleotides to brain functions and the harmful effects of neonatal hypothyroidism to normal development of the central nervous system, in this study we investigated the metabolism of adenine nucleotides in hippocampal, cortical and cerebellar astrocyte cultures from rats submitted to neonatal hypothyroidism. ATP and AMP hydrolysis were enhanced by 52 and 210%, respectively, in cerebellar astrocytes from hypothyroid rats. In hippocampus of hypothyroid rats, the 47% increase in AMP hydrolysis was significantly reverted when the astrocytes were treated with T3. Therefore, the imbalance in the ATP and adenosine levels in astrocytes, during brain development, may contribute to some of the effects described in neonatal hypothyroidism.

  10. Neuregulin-1 attenuates doxorubicin-induced autophagy in neonatal rat cardiomyocytes.

    PubMed

    An, Tao; Huang, Yan; Zhou, Qiong; Wei, Bing Qi; Zhang, Rong Cheng; Yin, Shi Jie; Zou, Chang Hong; Zhang, Yu Hui; Zhang, Jian

    2013-08-01

    Recombinant human neuregulin-1 (rhNRG-1) improves cardiac function in animal models of doxorubicin (DOX)-induced cardiomyopathy, but the underlying mechanism remains largely unknown. Here, we confirm a role for rhNRG-1 in attenuating DOX-induced autophagy and define the signaling pathways through which it mediates some of its effects. Neonatal rat ventricular myocytes were subjected to different treatments both to induce autophagy and to determine the effects of rhNRG-1 on the process. The rhNRG-1 inhibited DOX-induced autophagy, reduced reactive oxygen species production and increased protein expression of Bcl-2, effects that were recapitulated when the cells were treated with the antioxidant N-acetylcysteine. These effects were blocked by the phosphatidylinositol 3-kinase inhibitor LY294002, pointing to the involvement of the Akt pathway in mediating the process. Inhibition of Bcl-2 expression with small interfering RNA silencing also inhibited rhNRG-1's ability to attenuate DOX-induced autophagy. The rhNRG-1 is a potent inhibitor of DOX-induced autophagy and multiple signaling pathways, including Akt and activation of reactive oxygen species, play important roles in the anti-autophagy effect. The rhNRG-1 is a novel drug that may be effectively therapeutically in protecting further damage in DOX-induced damaged myocardium.

  11. Ligand activation of cannabinoid receptors attenuates hypertrophy of neonatal rat cardiomyocytes.

    PubMed

    Lu, Yan; Akinwumi, Bolanle C; Shao, Zongjun; Anderson, Hope D

    2014-11-01

    : Endocannabinoids are bioactive amides, esters, and ethers of long-chain polyunsaturated fatty acids. Evidence suggests that activation of the endocannabinoid pathway offers cardioprotection against myocardial ischemia, arrhythmias, and endothelial dysfunction of coronary arteries. As cardiac hypertrophy is a convergence point of risk factors for heart failure, we determined a role for endocannabinoids in attenuating endothelin-1-induced hypertrophy and probed the signaling pathways involved. The cannabinoid receptor ligand anandamide and its metabolically stable analog, R-methanandamide, suppressed hypertrophic indicators including cardiomyocyte enlargement and fetal gene activation (ie, the brain natriuretic peptide gene) elicited by endothelin-1 in isolated neonatal rat ventricular myocytes. The ability of R-methanandamide to suppress myocyte enlargement and fetal gene activation was mediated by CB2 and CB1 receptors, respectively. Accordingly, a CB2-selective agonist, JWH-133, prevented only myocyte enlargement but not brain natriuretic peptide gene activation. A CB1/CB2 dual agonist with limited brain penetration, CB-13, inhibited both hypertrophic indicators. CB-13 activated AMP-activated protein kinase (AMPK) and, in an AMPK-dependent manner, endothelial nitric oxide synthase (eNOS). Disruption of AMPK signaling, using compound C or short hairpinRNA knockdown, and eNOS inhibition using L-NIO abolished the antihypertrophic actions of CB-13. In conclusion, CB-13 inhibits cardiomyocyte hypertrophy through AMPK-eNOS signaling and may represent a novel therapeutic approach to cardioprotection.

  12. Remote ischemic preconditioning impairs ventricular function and increases infarct size after prolonged ischemia in the isolated neonatal rabbit heart.

    PubMed

    Schmidt, Michael R; Støttrup, Nicolaj B; Michelsen, Marie M; Contractor, Hussain; Sørensen, Keld E; Kharbanda, Rajesh K; Redington, Andrew N; Bøtker, Hans E

    2014-03-01

    Remote ischemic preconditioning (rIPC) reduces myocardial injury in adults and children undergoing cardiac surgery. We compared the effect of rIPC in adult and neonatal rabbits to investigate whether protection against ischemia-reperfusion injury can be achieved in the newborn heart by (1) in vivo rIPC and (2) dialysate from adult rabbits undergoing rIPC. Isolated hearts from newborn and adult rabbits were randomized into 3 subgroups (control, in vivo rIPC, and dialysate obtained from adult, remotely preconditioned rabbits). Remote preconditioning was induced by four 5-minute cycles of lower limb ischemia. Left ventricular (LV) function was assessed using a balloon-tipped catheter, glycolytic flux by tracer kinetics, and infarct size by tetrazolium staining. Isolated hearts underwent stabilization while perfused with standard Krebs-Henseleit buffer (control and in vivo rIPC) or Krebs-Henseleit buffer with added dialysate, followed by global no-flow ischemia and reperfusion. Within the age groups, the baseline LV function was similar in all subgroups. In the adult rabbit hearts, rIPC and rIPC dialysate attenuated glycolytic flux and protected against ischemia-reperfusion injury, with better-preserved LV function compared with that of the controls. In contrast, in the neonatal hearts, the glycolytic flux was lower and LV function was better preserved in the controls than in the rIPC and dialysate groups. In the adult hearts, the infarct size was reduced in the rIPC and dialysate groups compared with that in the controls. In the neonatal hearts, the infarct size was smaller in the controls than in the rIPC and dialysate groups. Remote ischemic preconditioning does not protect against ischemia-reperfusion injury in isolated newborn rabbit hearts and might even cause deleterious effects. Similar adverse effects were induced by dialysate from remotely preconditioned adult rabbits. Copyright © 2014 The American Association for Thoracic Surgery. All rights reserved.

  13. Olfactory learning in the rat neonate soon after birth

    PubMed Central

    Miller, Stacie S.; Spear, Norman E.

    2008-01-01

    The first hours of a newborn rat’s life entail locating and attaching to the mother’s nipple not only for nutrition but also for protection and warmth. The present study sought to characterize olfactory learning in the rat neonate immediately after birth. Newborn rats were exposed to an odor at various time periods soon after birth and tested for behavioral activation and attachment to a surrogate nipple in the presence of this odor at 4–5 hours postpartum. Regardless of when pups were presented the odor (0, 1, or 2 hours after birth) motor activity was greater among pups previously exposed to the odor than pups with no odor experience. Similarly, latency to attach to the nipple in the presence of the odor was lower among odor-preexposed pups, especially when odor exposure began within an hour of cesarean delivery. Odor exposure immediately after birth for just 15 minutes was sufficient to increase motor activity and to decrease latency to attach to a similarly scented surrogate nipple. These results suggest that olfactory experience very soon after birth can shape subsequent olfactory responses. The relative importance of the dearth of postnatal experience or of elevated neurochemicals immediately after birth and possible associative mechanisms underlying this learning is discussed. PMID:18683189

  14. Maternal caffeine intake affects acetylcholinesterase in hippocampus of neonate rats.

    PubMed

    da Silva, Rosane Souza; Richetti, Stefânia Konrad; da Silveira, Vanessa Gass; Battastini, Ana Maria Oliveira; Bogo, Mauricio Reis; Lara, Diogo R; Bonan, Carla Denise

    2008-01-01

    Transcriptional factors and signalling molecules from intracellular metabolism modulate a complex set of events during brain development. Neurotransmitter and neuromodulator synthesis and their receptor expressions vary according to different stages of brain development. The dynamics of signalling systems is often accompanied by alterations in enzyme expression and activity. Adenosine is a neuromodulator that controls the release of several neurotransmitters, including acetylcholine, which is an important neurotransmitter during brain development. Caffeine is a non-specific antagonist of adenosine receptors and can reach the immature brain. We evaluated the effects of rat maternal caffeine intake (1g/L) on acetylcholine degradation and acetylcholinesterase expression from hippocampus of 7-, 14- and 21-day-old neonates in caffeine-treated and control groups. Caffeine was not able to change the age-dependent increase of acetylcholinesterase activity or the age-dependent decrease of acetylcholinesterase expression. However, caffeine promoted an increase of acetylcholinesterase activity (42%) without modifications on the level of acetylcholinesterase mRNA transcripts in 21-day-old rats. Considering the high score of phosphorylatable residues on acetylcholinesterase, this profile can be associated with a possible regulation by specific phosphorylation sites. These results highlight the ability of maternal caffeine intake to interfere on cholinergic neurotransmission during brain development.

  15. Aldosterone increases T-type calcium channel expression and in vitro beating frequency in neonatal rat cardiomyocytes.

    PubMed

    Lalevée, Nathalie; Rebsamen, Michela C; Barrère-Lemaire, Stéphanie; Perrier, Emeline; Nargeot, Joël; Bénitah, Jean-Pierre; Rossier, Michel F

    2005-08-01

    Although aldosterone has been implicated in the pathogenesis of cardiac hypertrophy and heart failure, its cellular mechanism of action on cardiomyocyte function is not yet completely elucidated. This study was designed to investigate the effect of aldosterone on calcium channel expression and cardiomyocyte contraction frequency. Cultured neonatal rat ventricular cardiomyocytes were stimulated in vitro with 1 micromol/L aldosterone for 24 h. Calcium currents were then measured with the patch clamp technique, while calcium channel expression was assessed by real-time RT-PCR. In the present study, we show that aldosterone increases Ca2+ currents by inducing channel expression. Indeed, aldosterone led to a substantial increase of L- and T-type Ca2+ current amplitudes, and we found a concomitant 55% increase of the mRNA coding for alpha1C and beta2 subunits of cardiac L channels. Although T-type currents were relatively small under control conditions, they increased 4-fold and T channel alpha1H isoform expression rose in the same proportion after aldosterone treatment. Because T channels have been implicated in the modulation of membrane electrical activity, we investigated whether aldosterone affects the beating frequency of isolated cardiomyocytes. In fact, aldosterone dose-dependently increased the spontaneous beating frequency more than 4-fold. This effect of aldosterone was prevented by actinomycin D and spironolactone and reduced by RU486, suggesting a mixed mineralocorticoid/glucocorticoid receptor-dependent transcriptional mechanism. Moreover, inhibition of T currents with Ni2+ or mibefradil significantly reduced beating frequency towards control values, while conditions affecting L-type currents completely blocked contractions. Aldosterone modulates the expression of cardiac voltage-operated Ca2+ channels and accelerates beating in cultured neonatal rat ventricular myocytes. This chronotropic action of aldosterone appears to be linked to increased T channel

  16. Cardioprotective effect of polydatin on ventricular remodeling after myocardial infarction in coronary artery ligation rats.

    PubMed

    Gao, Yan; Gao, Jianping; Chen, Changxun; Wang, Huilin; Guo, Juan; Wu, Rong

    2015-05-01

    The purpose of this study was to explore the effect of polydatin on ventricular remodeling after myocardial infarction in coronary artery ligation rats and to elucidate the underlying mechanisms. A rat model of ventricular remodeling after myocardial infarction was established by left coronary artery ligation. Rats with coronary artery ligation were randomly divided into five groups: control, plus 40 mg/kg captopril, plus 25 mg/kg polydatin, plus 50 mg/kg polydatin, and plus 100 mg/kg polydatin. The sham-operated group was used as a negative control. Rats were administered intragastrically with the corresponding drugs or drinking water for seven weeks. At the end of the treatment, the left ventricular weight index and heart weight index were assessed. The cross-sectional size of cardiomyocytes was measured by staining myocardium tissue with hematoxylin and eosin. Collagen content was counted by Sirius red in aqueous saturated picric acid. The concentrations of angiotensin I, angiotensin II, aldosterone, and endothelin 1 in myocardium or serum were determined by radioimmunoassay. Hydroxyproline and nitric oxide concentrations and glutathione peroxidase and catalase activities in serum were measured by ultraviolet spectrophotometry. Our results showed that seven weeks of polydatin treatment resulted in a significantly reduced left ventricular weight index, heart weight index, serum concentrations of hydroxyproline and aldosterone, an increased concentration of nitric oxide as well as enhanced activities of glutathione peroxidase and catalase. Myocardial angiotensin I, angiotensin II, and endothelin 1 levels were also reduced. The cardiomyocyte cross-sectional area and collagen deposition diminished. This study suggests that polydatin may attenuate ventricular remodeling after myocardial infarction in coronary artery ligation rats through restricting the excessive activation of the renin-angiotensin-aldosterone system and inhibiting peroxidation. Georg Thieme

  17. Correction of long-lasting negative effects of neonatal isolation in white rats using semax.

    PubMed

    Volodina, M A; Sebentsova, E A; Glazova, N Yu; Manchenko, D M; Inozemtseva, L S; Dolotov, O V; Andreeva, L A; Levitskaya, N G; Kamensky, A A; Myasoedov, N F

    2012-01-01

    Adverse experience during the early postnatal period induces negative alterations in physiological and neurobiological functions, resulting in long-term disorder in animal behavior. The aim of the present work was to study the long-lasting effects of chronic neonatal stress in white rats and to estimate the possibility of their correction using Semax, an analogue of ACTH fragment (4-10). Early neonatal isolation was used as a model of early-life stress. Rat pups were separated from their mothers and littermates for 5 h daily during postnatal days 1-14. The pups of the control group were left undisturbed with the dams. Half of the rats subjected to neonatal isolation received an intranasal injection of Semax at a dose of 50 µg/kg daily, from postnatal day 15 until day 28. The other animals received intranasal vehicle injections daily at the same time points. It was shown that neonatal isolation leads to a delay in physical development, metabolic disturbances, and a decrease in the corticosterone stress response in white rats. These changes were observed during the first two months of life. Semax administration weakened the influence of neonatal isolation on the animals, body weight , reduced metabolic dysfunction, and led to an increase in stress-induced corticosterone release to the control values. So the chronic intranasal administration of Semax after termination of the neonatal isolation procedure diminishes the negative effects of neonatal stress.

  18. Correction of Long-Lasting Negative Effects of Neonatal Isolation in White Rats Using Semax

    PubMed Central

    Volodina, M.A.; Sebentsova, E.A.; Glazova, N.Yu.; Manchenko, D.M.; Inozemtseva, L.S.; Dolotov, O.V.; Andreeva, L.A.; Levitskaya, N.G.; Kamensky, A.A.; Myasoedov, N.F.

    2012-01-01

    Adverse experience during the early postnatal period induces negative alterations in physiological and neurobiological functions, resulting in long-term disorder in animal behavior. The aim of the present work was to study the long-lasting effects of chronic neonatal stress in white rats and to estimate the possibility of their correction using Semax, an analogue of ACTH fragment (4–10). Early neonatal isolation was used as a model of early-life stress. Rat pups were separated from their mothers and littermates for 5 h daily during postnatal days 1–14. The pups of the control group were left undisturbed with the dams. Half of the rats subjected to neonatal isolation received an intranasal injection of Semax at a dose of 50 µg/kg daily, from postnatal day 15 until day 28. The other animals received intranasal vehicle injections daily at the same time points. It was shown that neonatal isolation leads to a delay in physical development, metabolic disturbances, and a decrease in the corticosterone stress response in white rats. These changes were observed during the first two months of life. Semax administration weakened the influence of neonatal isolation on the animals, body weight , reduced metabolic dysfunction, and led to an increase in stress-induced corticosterone release to the control values. So the chronic intranasal administration of Semax after termination of the neonatal isolation procedure diminishes the negative effects of neonatal stress. PMID:22708068

  19. Hyaluronate degradation affects ventricular function of the early postlooped embryonic rat heart in situ.

    PubMed

    Baldwin, H S; Lloyd, T R; Solursh, M

    1994-02-01

    Hyaluronic acid is the major glycosaminoglycan of the early cardiac extracellular matrix or "cardiac jelly," yet little is known about its role in the ontogeny of early ventricular performance. To investigate the in situ effect of hyaluronate degradation on ventricular function, whole rat embryos were cultured in rat serum alone (control embryos) or rat serum plus 20 TRU/mL of Streptomyces hyaluronidase (treatment embryos) from gestational day 9.5 (before formation of the heart tube) through initial looping of the heart. Cardiac function was measured before looping (24 hours in culture) and immediately after looping (36 hours in culture) by video motion analysis of the external wall motion of the bulbus cordis and primitive ventricle. Degradation of hyaluronic acid in the treated embryos was confirmed by Alcian blue staining at pH 2.5. Significant increases in heart rate, circumferential shortening fraction, maximum velocity of circumferential contraction, and maximum velocity of circumferential relaxation were observed with looping in both control and treatment embryos. Although there was minimal difference in ventricular performance between control and treatment embryos before looping, there was a significant increase in all parameters of ventricular performance in the hyaluronidase-treated embryos immediately after looping of the heart. Endocardial cushions were absent in hyaluronidase-treated embryos, and an additional group of embryos cultured in the presence of Streptomyces hyaluronidase for 48 to 72 hours failed to develop endocardial cushions. These experiments are the first to (1) document a quantifiable increase in ventricular performance during early cardiac looping and (2) demonstrate that hyaluronate degradation results in abnormal endocardial cushion formation and altered ventricular performance of the postlooped heart.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. [The influence of interfered circadian rhythm on pregnancy and neonatal rats].

    PubMed

    Chen, Wen-Jun; Sheng, Wen-Jie; Guo, Yin-Hua; Tan, Yong

    2015-10-25

    The aim of this study was to observe the influence of interfered circadian rhythm on pregnancy of rats and growth of neonatal rats, and to explore the relationship between the interfered circadian rhythm and the changes of melatonin and progesterone. Continuous light was used to inhibit melatonin secretion and therefore the interfered circadian rhythm animal model was obtained. The influence of interfered circadian rhythm on delivery of pregnant rats was observed. Serum was collected from rats during different stages of pregnancy to measure the concentrations of melatonin and progesterone. In order to observe the embryo resorption rate, half of pregnant rats were randomly selected to undergo a laparotomy, and the remainder was used to observe delivery and assess the growth of neonatal rats after delivery. The results showed that the interfered circadian rhythm induced adverse effects on pregnancy outcomes, including an increase of embryo resorption rate and a decrease in the number of live births; inhibited the secretion of melatonin along with decreased serum progesterone level; prolonged the stage of labor, but not the duration of pregnancy; and disturbed the fetal intrauterine growth and the growth of neonatal rats. The results suggest that interfered circadian rhythm condition made by continuous light could make adverse effects on both pregnant rats and neonatal rats. The results of our study may provide a way to modulate pregnant women's circadian rhythm and a possibility of application of melatonin on pregnant women.

  1. Persistent Pulmonary Hypertension in a Neonate With Transposition of Great Arteries and Intact Ventricular Septum: A Case Report and Review of the Literature.

    PubMed

    Karimi, Mohsen; Kirshbom, Paul M; Kopf, Gary S; Steele, Margaret M; Sullivan, Jill M

    2015-07-01

    Transposition of the great arteries (TGA) with intact ventricular septum (IVS) has very favorable short- and long-term surgical outcome. Although rare, when associated with persistent pulmonary hypertension (PPH), it exhibits significant mortality risk and management challenges. We report the case of a neonate with TGA with IVS and PPH who underwent successful early surgical repair with emphasis on clinical management and review of the literature.

  2. [Anxiety-like behavior in rats neonatally and adultly treated with 5,7-dihydroxytryptamine].

    PubMed

    Yamada, Ikuko; Iwasaki, Tsuneo

    2002-10-01

    A large body of evidence has shown the involvement of serotonin (5-HT) in anxiety. The administration of serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into adult rats has been shown to produce a prolonged reduction in the content of brain 5-HT along with anxiolytic effects. In this experiment, 5,7-DHT was administrated intraventricularly to neonatal and adult rats. All rats were tested in an elevated plus maze at 30, 50, 70, and 90 days old to evaluate the anxiety level. Adult treatment increased the time spent in open-arm, and decreased the brain 5-HT content in all the regions measured. In contrast, neonatal treatment decreased the time spent in open-arm, and 5-HT contents in these animals did not decrease in the hypothalamus and medulla oblongata. A 5-HT syndrome test was conducted once when the rats were 91 to 97 days old to evaluate the sensitivity of 5-HT recepotors. It was found that 5-HTP (25 mg/kg) produces a severe serotonin syndrome in the adult 5,7-DHT-treated rats, but only a moderate syndrome in the neonatal-treated animals. Significant negative correlation coefficients were obtained between the score of serotonin syndrome and 5-HT content in the hypothalamus, midbrain, medulla oblongata, and cerebellum of the neonatal 5,7-DHT-treated rats. The results suggest that neonatal 5,7-DHT treatment produces an anxiogenic effect in contrast with the anxiolytic effect with adult treatment.

  3. Neonatal exposure to lipopolysaccharide enhances methamphetamine-induced reinstated behavioral sensitization in adult rats

    PubMed Central

    Tien, Lu-Tai; Cai, Zhengwei; Rhodes, Philip G.; Fan, Lir-Wan

    2011-01-01

    Our previous studies have shown that neonatal exposure to lipopolysaccharide (LPS) resulted in long-lasting dopaminergic injury and enhanced methamphetamine (METH)-induced increase of locomotion in the adult male rat. To further investigate the effect of neonatal LPS exposure-induced dopaminergic injury, we used our neonatal rat model of LPS exposure (1 mg/kg, intracerebral injection in postnatal day 5, P5, rats) to examine the METH sensitization as an indicator of drug addiction in the adult rats. On P70, animals began a treatment schedule of 5 daily subcutaneous (s.c.) administration of METH (0.5 mg/kg) or saline (P70-P74) to induce behavioral sensitization. Ninety-six hours after the 5th treatment with METH or saline (P78), animals received a single dose of 0.5 mg/kg METH (s.c.) or saline. Neonatal LPS exposure enhanced the level of development of behavioral sensitization including distance traveled, rearing events and stereotypy to METH administration in both male and female rats. Neonatal LPS exposure also enhanced the reinstated behavioral sensitization in both male and female rats after the administration had ceased for ninety-six hours. However, neonatal LPS exposure induced alteration in the reinstated behaviors sensitization of distance traveled and rearing events to METH administration appears to be greater in male than in female rats. These results indicate that neonatal brain LPS exposure produces a persistent lesion in the dopaminergic system, as indicated by enhanced METH-induced locomotor and stereotyped behavioral sensitization in later life. These findings show that early-life brain inflammation may enhance susceptibility to the development of drug addiction in later life. PMID:21669234

  4. Neonatal exposure to lipopolysaccharide enhances methamphetamine-induced reinstated behavioral sensitization in adult rats.

    PubMed

    Tien, Lu-Tai; Cai, Zhengwei; Rhodes, Philip G; Fan, Lir-Wan

    2011-10-10

    Our previous studies have shown that neonatal exposure to lipopolysaccharide (LPS) resulted in long-lasting dopaminergic injury and enhanced methamphetamine (METH)-induced increase of locomotion in the adult male rat. To further investigate the effect of neonatal LPS exposure-induced dopaminergic injury, we used our neonatal rat model of LPS exposure (1mg/kg, intracerebral injection in postnatal day 5, P5, rats) to examine the METH sensitization as an indicator of drug addiction in the adult rats. On P70, animals began a treatment schedule of 5 daily subcutaneous (s.c.) administration of METH (0.5mg/kg) or saline (P70-P74) to induce behavioral sensitization. Ninety-six hours after the 5th treatment with METH or saline (P78), animals received a single dose of 0.5mg/kg METH (s.c.) or saline. Neonatal LPS exposure enhanced the level of development of behavioral sensitization including distance traveled, rearing events and stereotypy to METH administration in both male and female rats. Neonatal LPS exposure also enhanced the reinstated behavioral sensitization in both male and female rats after the administration had ceased for 96h. However, neonatal LPS exposure induced alteration in the reinstated behaviors sensitization of distance traveled and rearing events to METH administration appears to be greater in male than in female rats. These results indicate that neonatal brain LPS exposure produces a persistent lesion in the dopaminergic system, as indicated by enhanced METH-induced locomotor and stereotyped behavioral sensitization in later life. These findings show that early-life brain inflammation may enhance susceptibility to the development of drug addiction in later life. Copyright © 2011 Elsevier B.V. All rights reserved.

  5. Strychnine-sensitive glycine responses of neonatal rat hippocampal neurones.

    PubMed Central

    Ito, S; Cherubini, E

    1991-01-01

    1. Intracellular recordings employing current and voltage clamp techniques were used to study the effects of glycine on rat CA3 hippocampal neurones during the first 3 weeks of postnatal (P) life. 2. Glycine (0.3-1 mM) depolarized neurones from rats less than 4 days old (P4). Neurones from older neonates (P5-P7) were hyperpolarized by glycine, whereas adult neurones were unaffected. 3. Both depolarizing and hyperpolarizing responses were associated with large conductance increases; they reversed polarity at a potential which changed with the extracellular chloride concentration. The responses persisted in tetrodotoxin (1 microM) or in a solution with a much reduced calcium concentration. 4. Strychnine (1 microM) but not bicuculline (10-50 microM) antagonized the effects of glycine. The action of strychnine was apparently competitive with a dissociation constant of 350 nM. 5. In voltage clamp experiments, glycine elicited a non-desensitizing outward current at -60 mV. When a maximal concentration of glycine was applied at the same time as gamma-aminobutyric acid (GABA), the conductance increase induced by the two agonists was additive, suggesting the activation of different populations of channels. 6. Concentrations of glycine lower than 100 microM did not affect membrane potential. However, at 30-50 microM glycine increased the frequency of spontaneous GABA-mediated synaptic responses; this action was not blocked by strychnine. 7. It is concluded that during the first 2 weeks of life glycine acts at strychnine-sensitive receptors to open chloride channels. PMID:1804982

  6. Contribution of ventricular remodeling to pathogenesis of heart failure in rats.

    PubMed

    Brower, G L; Janicki, J S

    2001-02-01

    We previously reported an approximately 50% incidence of rats with symptoms of congestive heart failure (CHF) at 8 wk postinfrarenal aorto-caval fistula. However, it was not clear whether compensatory ventricular remodeling could continue beyond 8 wk or whether the remaining animals would have developed CHF or died. Therefore, the intent of this study was to complete the characterization of this model of sustained volume overload by determining the morbidity and mortality and the temporal response of left ventricular (LV) remodeling and function beyond 8 wk. The findings demonstrate an upper limit to LV hypertrophy and substantial increases in LV volume and compliance, matrix metalloproteinase activity, and collagen volume fraction associated with the development of CHF. There was an 80% incidence of morbidity and mortality following 21 wk of chronic volume overload. These findings indicate that the development of CHF is triggered by marked ventricular dilatation and increased compliance occurring once the myocardial hypertrophic response is exhausted.

  7. Neonatal Administration of Memantine Enhances Social Cognition in Adult Rats Subjected to Early Maternal Deprivation

    PubMed Central

    Sánchez-Mendoza, Eduardo; Nieves, Nayadoleni; Merchor, Gustavo

    2016-01-01

    Schizophrenia is considered a neurodevelopmental disorder; however, all the available treatment options are used when the disease becomes clinically significant in adolescence or early adulthood. Using a developmental rat model of schizophrenia, we examined whether neonatal treatment with memantine, an NMDA receptor modulator, can improve schizophrenic-like symptoms in adulthood. Early maternal deprivation in rats produces deficits in social interaction behaviors in adulthood. In contrast, memantine administrated in neonatal rats subjected to early maternal deprivation significantly reduces deficits in social interaction behaviors in adulthood. These results raise the possibility that pharmacological treatment with memantine at the early developmental stage helps people with a risk to develop schizophrenic-like symptoms. PMID:28035183

  8. Xenon preconditioning reduces brain damage from neonatal asphyxia in rats.

    PubMed

    Ma, Daqing; Hossain, Mahmuda; Pettet, Garry K J; Luo, Yan; Lim, Ta; Akimov, Stanislav; Sanders, Robert D; Franks, Nicholas P; Maze, Mervyn

    2006-02-01

    Xenon attenuates on-going neuronal injury in both in vitro and in vivo models of hypoxic-ischaemic injury when administered during and after the insult. In the present study, we sought to investigate whether the neuroprotective efficacy of xenon can be observed when administered before an insult, referred to as 'preconditioning'. In a neuronal-glial cell coculture, preexposure to xenon for 2 h caused a concentration-dependent reduction of lactate dehydrogenase release from cells deprived of oxygen and glucose 24 h later; xenon's preconditioning effect was abolished by cycloheximide, a protein synthesis inhibitor. Preconditioning with xenon decreased propidium iodide staining in a hippocampal slice culture model subjected to oxygen and glucose deprivation. In an in vivo model of neonatal asphyxia involving hypoxic-ischaemic injury to 7-day-old rats, preconditioning with xenon reduced infarction size when assessed 7 days after injury. Furthermore, a sustained improvement in neurologic function was also evident 30 days after injury. Phosphorylated cAMP (cyclic adenosine 3',5'-monophosphate)-response element binding protein (pCREB) was increased by xenon exposure. Also, the prosurvival proteins Bcl-2 and brain-derived neurotrophic factor were upregulated by xenon treatment. These studies provide evidence for xenon's preconditioning effect, which might be caused by a pCREB-regulated synthesis of proteins that promote survival against neuronal injury.

  9. Accessory Mitral Valve Leaflet Causing Severe Left Ventricular Outflow Tract Obstruction in a Preterm Neonate with a Partial Atrioventricular Septal Defect

    PubMed Central

    Fraser, Charles D.; Seery, Thomas J.

    2016-01-01

    Atrioventricular septal defects represent a class of congenital cardiac malformations that vary in presentation and management strategy depending upon the severity of the particular lesions present. We present the case of a premature neonate who had a partial atrioventricular septal defect and an accessory mitral (or left atrioventricular) valve leaflet. The latter caused severe left ventricular outflow tract obstruction and severely depressed left ventricular function. We found only one other report of this atrioventricular valve abnormality in association with atrioventricular septal defect. To our knowledge, our patient (at a body weight of 1,800 g) is the smallest to survive corrective surgery of an accessory mitral valve leaflet with severe left ventricular outflow tract obstruction. In addition to our patient's case, we discuss the relevant medical literature. PMID:28100980

  10. Swimming exercise training prior to acute myocardial infarction attenuates left ventricular remodeling and improves left ventricular function in rats.

    PubMed

    Dayan, Anat; Feinberg, Micha S; Holbova, Radka; Deshet, Naamit; Scheinowitz, Mickey

    2005-01-01

    The effect of exercise training prior to acute myocardial infarction (AMI) on left ventricular (LV) remodeling is poorly understood. This study investigated the protective effect of 3 weeks of swimming exercise training prior to AMI on cardiac morphology and function. Male Sprague-Dawley rats (n = 35) were randomly assigned to 3 groups: swimming training (n = 14, 90 min, 5 days/wk, 3 wk), sedentary (n =14), and controls (n = 7, no exercise, no MI). At the end of the training/sedentary period, rats were subjected to AMI (ExMI and SedMI) induced by surgical ligation of the left coronary artery. Thereafter, the rats remained sedentary for a 4-wk recovery period. Trans-thoracic echocardiography was performed in each group at the end of the exercise/sedentary period (pre-AMI), 24 hr after AMI, and following recovery (4 wk after AMI). No differences were observed in LV dimensions and function pre-AMI among the 3 groups; however, LV-end systolic diameter (LVESD) and LV-end systolic area (LVES-area) were significantly lower in the prior trained rats, 24 hr post-AMI with no additional change 4 wk post-AMI, during remodeling. Both LV-shortening fraction (SF%) and fractional area change (FAC%) were higher in the trained animals 4 wk post-AMI (39+/-12% vs 23+/-8%; p 0.002, and 48+/-14% vs. 38+/-9%; p 0.07, respectively). In conclusion, 3 wk of swimming exercise training prior to AMI significantly attenuated LV remodeling and improved LV function, despite no changes in LV dimensions or systolic function at the end of the exercise session. The data suggest that even a short-term training period is sufficient to induce cardiac protection.

  11. Structural characterization of rat ventricular tissue exposed to the smoke of two types of waterpipe

    PubMed Central

    Al-Awaida, Wajdy; Najjar, Hossam; Shraideh, Ziad

    2015-01-01

    Objective(s): this study focused on the effect of waterpipe smoke exposure toxicity on the structure of albino rat’s ventricular tissue and their recovery. Materials and Methods: Albino rats were divided into three groups: control, flavored, and unflavored. The control group was exposed to normal air while the flavored and unflavored groups were exposed to waterpipe smoke for a period of 90 days. Each group was followed by a period of 90 days of fresh air exposure. Following each period, the ventricular tissue was removed for biochemical and histopathological studies. Results: The ventricular tissues of waterpipe exposed rats showed some degree of separation between cardiac muscle fibers, infiltration of lymphocytes, and congestion of blood vessel. Also, thin cross sections of ventricular cells revealed pleomorphic mitochondria with partially disrupted cristae, partial disruption of the myofibrils, and deposited toxic materials. The unflavored waterpipe has more deleterious effects on heart ventricular tissues than the flavored one. Waterpipe smoke didn’t induce apoptosis in the ventricular tissue. We also found very high levels of plasma thiocyanate after exposure to smoke in the flavored and unflavored groups, while the control group showed no increase. After the recovery period, those tissues showed partial recovery. Conclusion: Waterpipe smoke induces structural changes in the heart ventricle tissues, causing a negative impact on the capacity of the cardiac muscle for pumping blood and may lead to heart attack due to accumulation of free radicals and tissue inflammation. Cessation of smoking is important in returning most of these changes to their normal structure. PMID:26730327

  12. Assessment of left ventricular myocardial systolic acceleration in diabetic rats using velocity vector imaging.

    PubMed

    Zhang, Haibin; Wei, Zhangrui; Zhu, Xiaoxing; Li, Hongling; Yu, Ming; Duan, Yunyan; Zhu, Ting; Zhang, Jun; Zhou, Xiaodong; Zhu, Miaozhang

    2014-05-01

    The purpose of this study was to investigate how the myocardial acceleration during isovolumic contraction changed in rats with diabetic cardiomyopathy and a normal left ventricular ejection fraction (LVEF) by using velocity vector imaging. Velocity vector imaging was performed in 12 control rats and 15 rats with streptozotocin-induced diabetic cardiomyopathy 12 weeks after streptozotocin injection. The segmental radial displacement, velocity, acceleration, and percent wall thickening were measured at the mid-left ventricular (LV) level. Compared to control rats, rats with cardiomyopathy had a significant decrease in the peak radial acceleration during isovolumic contraction in most segments of the LV wall (including the anterior, anterolateral, inferolateral, and inferior segments; P < .05) but a similar LVEF, fractional shortening, and segmental displacement. Rats with cardiomyopathy also had a significant increase in LV end-diastolic and end-systolic diameters when corrected for body mass (P < .001; P = .003, respectively) and a significant decrease in the radial peak systolic velocities of the inferolateral and inferior wall segments (P < .05). In addition, rats with cardiomyopathy had a significant decrease in the peak radial diastolic acceleration in most segments of the LV wall (except for the anterolateral one; P< .05) but similar peak radial diastolic velocities in all LV wall segments compared to controls. Pathologic examination in rats with cardiomyopathy revealed ultrastructural impairment of the capillary and cardiocyte without any atherosclerotic lesion in the coronary artery compared to control rats. Myocardial acceleration during isovolumic contraction decreases in rats with diabetic cardiomyopathy and a preserved LVEF, suggesting the presence of regional LV systolic dysfunction.

  13. Reduced mechanical efficiency in left‐ventricular trabeculae of the spontaneously hypertensive rat

    PubMed Central

    Han, June‐Chiew; Tran, Kenneth; Johnston, Callum M.; Nielsen, Poul M. F.; Barrett, Carolyn J.; Taberner, Andrew J.; Loiselle, Denis S.

    2014-01-01

    Abstract Long‐term systemic arterial hypertension, and its associated compensatory response of left‐ventricular hypertrophy, is fatal. This disease leads to cardiac failure and culminates in death. The spontaneously hypertensive rat (SHR) is an excellent animal model for studying this pathology, suffering from ventricular failure beginning at about 18 months of age. In this study, we isolated left‐ventricular trabeculae from SHR‐F hearts and contrasted their mechanoenergetic performance with those from nonfailing SHR (SHR‐NF) and normotensive Wistar rats. Our results show that, whereas the performance of the SHR‐F differed little from that of the SHR‐NF, both SHR groups performed less stress‐length work than that of Wistar trabeculae. Their lower work output arose from reduced ability to produce sufficient force and shortening. Neither their heat production nor their enthalpy output (the sum of work and heat), particularly the energy cost of Ca2+ cycling, differed from that of the Wistar controls. Consequently, mechanical efficiency (the ratio of work to change of enthalpy) of both SHR groups was lower than that of the Wistar trabeculae. Our data suggest that in hypertension‐induced left‐ventricular hypertrophy, the mechanical performance of the tissue is compromised such that myocardial efficiency is reduced. PMID:25413328

  14. Effects of Tribuli saponins on ventricular remodeling after myocardial infarction in hyperlipidemic rats.

    PubMed

    Guo, Yan; Shi, Da-Zhuo; Yin, Hui-Jun; Chen, Ke-Ji

    2007-01-01

    This experiment was designed to determine whether Tribuli saponins (TS) relieve left ventricular remodeling (VR) after myocardial infarction (MI) in a murine hyperlipemia (HL) model. MI and HL models were induced and high and low doses of TS and simvastatin were administrated to the rats. Four weeks later, echocardiographic observation was performed and the left and right ventricular weight index (LVWI, RVWI) was calculated. Echocardiographic results showed that both high dose of TS and simvastatin had a beneficial effect on increasing fractional shortening (FS) and ejection fraction (EF), reducing left ventricular end diastolic volume (LVEDV), systolic volume (LVESV), left ventricular dimension end diastole (LVDd) and systole (LVDs), and decreasing LVWI, as compared to those in the HL-MI model group (p < 0.05, 0.01). Both medicines had little impact on thickness of the anterior and posterior wall. No significant difference was observed between each treatment group (p > 0.05). In conclusion, TS not only lowered serum lipidemia, but also relieved left ventricular remodeling, and improved cardiac function in the early stage after MI.

  15. Effect of neonatal body temperature on postanoxic, potentially neurotoxic iron accumulation in the rat brain.

    PubMed

    Rogalska, Justyna; Danielisova, Viera; Caputa, Michał

    2006-01-30

    In asphyxiated newborns iron, released from heme and ferritin and deposited in the brain, contributes to neurodegeneration. Because hypothermia provides neuroprotection, newborn mammals, showing spontaneously reduced body temperature, might avoid the iron-mediated neurotoxicity. Therefore, we decided to study the effects of body temperature and chelation of iron with deferoxamine on iron accumulation in the brain of three weeks old rats exposed neonatally to a critical anoxia. At the age of two days, newborn rats were exposed to anoxia in 100% nitrogen atmosphere. Rectal temperature was kept at 33 degrees C (typical of the rat neonates), or elevated to a level typical of febrile (39 degrees C) adults. Control rats were exposed to atmospheric air in the respective thermal conditions. Half of the rats exposed to anoxia under hyperthermic conditions were injected with deferoxamine (DF), immediately after anoxia and 24 h later. Regional changes in cerebral iron deposition were examined in the frontal cortex, the hippocampus and the striatum, using iron histochemistry, when the rats reached the age of three weeks. Increased iron staining was found in neurons of each of the three cerebral regions in rats exposed to neonatal anoxia under hyperthermic conditions and the iron accumulation was prevented by postanoxic DF injection. In conclusion, febrile body temperature amplifies cerebral hyperferremia, which might induce neurodegenerative disturbances in the brain. On the other hand, a protection against the brain hyperferremia can be achieved by both the reduced physiological neonatal body temperature and by postasphyxic DF administration.

  16. Rat umbilical cord blood cells attenuate hypoxic–ischemic brain injury in neonatal rats

    PubMed Central

    Nakanishi, Keiko; Sato, Yoshiaki; Mizutani, Yuka; Ito, Miharu; Hirakawa, Akihiro; Higashi, Yujiro

    2017-01-01

    Increasing evidence has suggested that human umbilical cord blood cells (hUCBC) have a favorable effect on hypoxic–ischemic (HI) brain injury. However, the efficacy of using hUCBCs to treat this injury has been variable and the underlying mechanism remains elusive. Here, we investigated its effectiveness using stereological analysis in an allogeneic system to examine whether intraperitoneal injection of cells derived from UCBCs of green fluorescent protein (GFP)-transgenic rats could ameliorate brain injury in neonatal rats. Three weeks after the HI event, the estimated residual brain volume was larger and motor function improved more in the cell-injected rats than in the control (PBS-treated) rats. The GFP-positive cells were hardly detectable in the brain (0.0057% of injected cells) 9 days after injection. Although 60% of GFP-positive cells in the brain were Iba1-positive, none of these were positive for NeuroD or DCX. While the number of proliferating cells increased in the hippocampus, that of activated microglia/macrophages decreased and a proportion of M2 microglia/macrophages increased in the ipsilateral hemisphere of cell-injected rats. These results suggest that intraperitoneal injection of cells derived from UCBCs could ameliorate HI injury, possibly through an endogenous response and not by supplying differentiated neurons derived from the injected stem cells. PMID:28281676

  17. Cell-to-cell coupling in engineered pairs of rat ventricular cardiomyocytes: relation between Cx43 immunofluorescence and intercellular electrical conductance

    PubMed Central

    McCain, Megan L.; Desplantez, Thomas; Geisse, Nicholas A.; Rothen-Rutishauser, Barbara; Oberer, Helene; Parker, Kevin Kit

    2012-01-01

    Gap junctions are composed of connexin (Cx) proteins, which mediate intercellular communication. Cx43 is the dominant Cx in ventricular myocardium, and Cx45 is present in trace amounts. Cx43 immunosignal has been associated with cell-to-cell coupling and electrical propagation, but no studies have directly correlated Cx43 immunosignal to electrical cell-to-cell conductance, gj, in ventricular cardiomyocyte pairs. To assess the correlation between Cx43 immunosignal and gj, we developed a method to determine both parameters from the same cell pair. Neonatal rat ventricular cardiomyocytes were seeded on micropatterned islands of fibronectin. This allowed formation of cell pairs with reproducible shapes and facilitated tracking of cell pair locations. Moreover, cell spreading was limited by the fibronectin pattern, which allowed us to increase cell height by reducing the surface area of the pattern. Whole cell dual voltage clamp was used to record gj of cell pairs after 3–5 days in culture. Fixation of cell pairs before removal of patch electrodes enabled preservation of cell morphology and offline identification of patched pairs. Subsequently, pairs were immunostained, and the volume of junctional Cx43 was quantified using confocal microscopy, image deconvolution, and three-dimensional reconstruction. Our results show a linear correlation between gj and Cx43 immunosignal within a range of 8–50 nS. PMID:22081700

  18. High rate of right ventricular infarction after ligation of mid left anterior descending artery in rats.

    PubMed

    Samsamshariat, Seyed Ahmad; Movahed, Mohammad-Reza

    2005-01-01

    The left anterior descending artery (LAD) supplies the left ventricle in humans. LAD ligation has been commonly used in rats to induce left ventricular (LV) infarction for research purposes. However, the myocardial supply territories of LAD are not well established in rats. We measured the infarction zone in rats after ligation of the mid-LAD. Twenty-four male Sprague-Dawley rats weighing 300-350 g were selected for LAD ligation for the induction of ischemic cardiomyopathy. The surgery was performed under full anesthesia. Left-sided thoracotomy was performed through cuts in the fifth and sixth ribs. Ligation of the LAD was performed 1 to 2 mm distal to a line between the left border of the pulmonary conus and the right border of the left atrial appendage. LAD was ligated after the first diagonal and septal branches. After 24 h, the hearts were removed and stained with Tetrazolium Tetrachloride (TTC) for the detection of infracted areas. Ligation of LAD induces 85% infarction of the right anterior free wall and anterior right ventricular septum and induces 100% infarction of the anterior free wall of the left ventricle and anterior septum. Infarction after LAD ligation extends all the way to the distal of the ligation site down to the apex of the heart. Mid-LAD ligation after the first septal and diagonal branches causes substantial right ventricular infarction in addition to LV infarct in rats. Therefore, the hemodynamic effect of right ventricle infarct should be considered in research involving LAD ligation in rats.

  19. Gestational Mercury Vapor Exposure and Diet Contribute to Mercury Accumulation in Neonatal Rats

    PubMed Central

    Morgan, Daniel L.; Price, Herman C.; Fernando, Reshan; Chanda, Sushmita M.; O’Connor, Robert W.; Barone, Stanley S.; Herr, David W.; Beliles, Robert P.

    2006-01-01

    Exposure of pregnant Long-Evans rats to elemental mercury (Hg0) vapor resulted in a significant accumulation of Hg in tissues of neonates. Because elevated Hg in neonatal tissues may adversely affect growth and development, we were interested in how rapidly Hg was eliminated from neonatal tissues. Pregnant rats were exposed to 1, 2, or 4 mg Hg0 vapor/m3 or air (controls) for 2 hr/day from gestation day 6 (GD6) through GD15. Neonatal brain, liver, and kidney were analyzed for total Hg at various times between birth and postnatal day 90 (PND90). Milk was analyzed for Hg between birth and weaning (PND21). Before weaning, the Hg levels in neonatal tissues were proportional to maternal exposure concentrations and were highest in kidney followed by liver and then brain. There was no elimination of Hg between birth and weaning, indicating that neonates were exposed continuously to elevated levels of Hg during postpartum growth and development. Consumption of milk from exposed dams resulted in a slight increase in kidney Hg concentration during this period. Unexpectedly, neonatal Hg accumulation increased rapidly after weaning. Increased Hg was measured in both control and exposed neonates and was attributed to consumption of NIH-07 diet containing trace levels of Hg. By PND90, tissue Hg levels equilibrated at concentrations similar to those in unexposed adult Long-Evans rats fed the same diet. These data indicate that dietary exposure to trace amounts of Hg can result in a significantly greater accumulation of Hg in neonates than gestational exposure to high concentrations of Hg0 vapor. PMID:16675429

  20. Effect of Wenxin Granule on Ventricular Remodeling and Myocardial Apoptosis in Rats with Myocardial Infarction

    PubMed Central

    Wu, Aiming; Zhai, Jianying; Zhang, Dongmei; Lou, Lixia; Zhu, Haiyan; Gao, Yonghong; Chai, Limin; Xing, Yanwei; Lv, Xiying; Zhu, Lingqun; Zhao, Mingjing; Wang, Shuoren

    2013-01-01

    Aim. To determine the effect of a Chinese herbal compound named Wenxin Granule on ventricular remodeling and myocardial apoptosis in rats with myocardial infarction (MI). Methods. Male Sprague-Dawley (SD) rats were randomly divided into four groups: the control group, the model group, the metoprolol group, and the Wenxin Granule group (WXKL group) with sample size (n) of 7 rats in each group. An MI model was established in all rats by occlusion of the left anterior descending coronary artery (the control group was without occlusion). Wenxin Granule (1.35 g/kg/day), metoprolol (12 mg/kg/day), and distilled water (5 mL/kg/day for the control and model groups) were administered orally for 4 weeks. Ultrasonic echocardiography was used to examine cardiac structural and functional parameters. Myocardial histopathological changes were observed using haematoxylin and eosin (H&E) dyeing. Myocardial apoptosis was detected by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) staining. Serum angiotensin II (Ang II) concentration was measured using the enzyme-linked immunosorbent assay (ELISA). Results. It was found that Wenxin Granule could partially reverse ventricular remodeling, improve heart function, alleviate the histopathological damage, inhibit myocardial apoptosis, and reduce Ang II concentration in rats with MI. Conclusions. The results of the current study suggest that Wenxin Granule may be a potential alternative and complementary medicine for the treatment of MI. PMID:23997803

  1. Differential cholinoceptor subtype-dependent activation of signal transduction pathways in neonatal versus adult rat atria.

    PubMed

    Borda, E S; Perez Leiros, C; Camusso, J J; Bacman, S; Sterin-Borda, L

    1997-04-04

    In this study, we investigated the expression and distribution of muscarinic cholinergic receptors (mAChRs) and the different signaling pathways associated with mAChR activation in atria isolated from adult and neonatal rats. Carbachol stimulation of mAChRs in both neonatal and adult rat atria led to a negative inotropic response with activation of phosphoinositide hydrolysis, an increase in cyclic GMP levels, and a decrease in cyclic AMP production. However, compared with adult atria, neonatal atria showed hypersensitivity in the contractile effect induced by carbachol. Pharmacological analysis with mAChR antagonists indicated that M1 and M2 mAChR subtypes are important mediators of the response to carbachol in neonatal atria. In contrast, in adult atria the effect of the agonist was coupled only to the M2 mAChR subtype. Moreover, an increased number of total mAChRs was labeled in neonatal atrial membranes compared with those of adults. Although a predominant M2 mAChR population is expressed in atria at both stages of development studied, competition binding parameters calculated for carbachol indicated the presence of high-affinity binding sites, with higher affinity in neonates than in adults. These results suggest that the differences observed between neonatal and adult atria in their response to a cholinergic agonist may be related to differential expression of mAChR subtypes and/or changes in functional coupling of mAChR subtypes during development.

  2. Vanadate induces necrotic death in neonatal rat cardiomyocytes through mitochondrial membrane depolarization.

    PubMed

    Soares, Sandra Sofia; Henao, Fernando; Aureliano, Manuel; Gutiérrez-Merino, Carlos

    2008-03-01

    Besides the well-known inotropic effects of vanadium in cardiac muscle, previous studies have shown that vanadate can stimulate cell growth or induce cell death. In this work, we studied the toxicity to neonatal rat ventricular myocytes (cardiomyocytes) of two vanadate solutions containing different oligovanadates distribution, decavanadate (containing decameric vanadate, V 10) and metavanadate (containing monomeric vanadate and also di-, tetra-, and pentavanadate). Incubation for 24 h with decavanadate or metavanadate induced necrotic cell death of cardiomyocytes, without significant caspase-3 activation. Only 10 microM total vanadium of either decavanadate (1 microM V 10) or metavanadate (10 microM total vanadium) was needed to produce 50% loss of cell viability after 24 h (assessed with MTT and propidium iodide assays). Atomic absorption spectroscopy showed that vanadium accumulation in cardiomyocytes after 24 h was the same when incubation was done with decavanadate or metavanadate. A decrease of 75% of the rate of mitochondrial superoxide anion generation, monitored with dihydroethidium, and a sustained rise of cytosolic calcium (monitored with Fura-2-loaded cardiomyocytes) was observed after 24 h of incubation of cardiomyocytes with decavanadate or metavanadate concentrations close to those inducing 50% loss of cell viability produced. In addition, mitochondrial membrane depolarization within cardiomyocytes, monitored with tetramethylrhodamine ethyl esther or with 3,3',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine iodide, were observed after only 6 h of incubation with decavanadate or metavanadate. The concentration needed for 50% mitochondrial depolarization was 6.5 +/- 1 microM total vanadium for both decavanadate (0.65 microM V 10) and metavanadate. In conclusion, mitochondrial membrane depolarization was an early event in decavanadate- and monovanadate-induced necrotic cell death of cardiomyocytes.

  3. Neonatal immune challenge affects the regulation of estrus cyclicity and feeding behavior in female rats.

    PubMed

    Iwasa, Takeshi; Matsuzaki, Toshiya; Murakami, Masahiro; Kinouchi, Riyo; Shimizu, Fumi; Kuwahara, Akira; Yasui, Toshiyuki; Irahara, Minoru

    2009-02-01

    A single immune challenge with lipopolysaccharide (LPS) in the neonatal period has a long-lasting influence on immune response. Using female Sprague-Dawley rats, we examined whether neonatal LPS challenge influences the life-long neuroendocrine sensitivity of reproductive function and feeding behavior to LPS, and whether stress-related neuropeptides and their receptors are involved in neonatal LPS-induced physiological change. On day 10 after birth, all pups were injected with LPS (100 microg/kg, i.p.) or saline. Then, in Experiment 1, LPS (100 microg/kg, i.p.) or saline was injected at diestrous in adulthood, and the length of the estrous cycle, 24h food intake and body weight change were recorded. In Experiment 2, the mRNA expression levels of corticotropin-releasing hormone (CRH), urocortin (UCN), urocortin 2 (UCN2), CRH receptor type 1 (CRH-R1) and CRH receptor type 2 (CRH-R2) in the hypothalamus were measured using real-time PCR. LPS injection in adulthood prolonged the estrous cycle in neonatal LPS-injected rats. LPS injection in adulthood decreased food intake and body weight in both neonatal LPS- and saline-injected rats, more so in the latter. Basal expressions of UCN2 and CRH-R2 mRNA were higher in neonatal LPS-injected rats than in saline-injected rats. These findings indicate that neonatal immune challenge influences the anti-stress regulation of the estrous cycle and feeding behavior in adulthood. Increased expression of UCN2 and CRH-R2 might enhance the sensitivity of the estrous cycle in suppressing the effects of LPS.

  4. Neonatal exposure to phenobarbital potentiates schizophrenia-like behavioral outcomes in the rat

    PubMed Central

    Bhardwaj, S.K.; Forcelli, P.A; Palchik, G.; Gale, K.; Srivastava, L.K.; Kondratyev, A.

    2012-01-01

    Previous work has indicated an association between seizures early in life and increased risk of psychiatric disorders, including schizophrenia. However, because early life seizures are commonly treated with antiepileptic drugs (AEDs) such as phenobarbital, the possibility that drug treatment may affect later-life psychiatric outcomes needs to be evaluated. We therefore tested the hypothesis that phenobarbital exposure in the neonatal rat increases the risk of schizophrenia-like behavioral abnormalities in adulthood. Thus, in this study, we examined the effects of a single acute neonatal exposure to phenobarbital on adult behavioral outcomes in the rat neonatal ventral hippocampal (nVH) lesion model of schizophrenia. We compared these outcomes to those in rats a) without nVH lesions and b) with nVH lesions, without phenobarbital. The tasks used for behavioral evaluation were: amphetamine-induced locomotion, prepulse inhibition, elevated plus-maze, and novel object recognition task. We found that neonatal phenobarbital treatment (in the absence of nVH lesions) was sufficient to disrupt sensorimotor gating (as tested by prepulse inhibition) in adulthood to an extent equivalent to nVH lesions. Additionally, neonatal phenobarbital exposure enhanced the locomotor response to amphetamine in adult animals with and without nVH lesions. Our findings suggest that neonatal exposure to phenobarbital can predispose to schizophrenia-like behavioral abnormalities. Our findings underscore the importance of examining AED exposure early in life as a potential risk factor for later-life neuropsychiatric abnormalities in clinical populations. PMID:22366076

  5. Neonatal rat heart cells cultured in simulated microgravity

    NASA Technical Reports Server (NTRS)

    Akins, R. E.; Schroedl, N. A.; Gonda, S. R.; Hartzell, C. R.

    1997-01-01

    In vitro characteristics of cardiac cells cultured in simulated microgravity are reported. Tissue culture methods performed at unit gravity constrain cells to propagate, differentiate, and interact in a two-dimensional (2D) plane. Neonatal rat cardiac cells in 2D culture organize predominantly as bundles of cardiomyocytes with the intervening areas filled by nonmyocyte cell types. Such cardiac cell cultures respond predictably to the addition of exogenous compounds, and in many ways they represent an excellent in vitro model system. The gravity-induced 2D organization of the cells, however, does not accurately reflect the distribution of cells in the intact tissue. We have begun characterizations of a three-dimensional (3D) culturing system designed to mimic microgravity. The NASA-designed High-Aspect Ratio Vessel (HARV) bioreactors provide a low shear environment that allows cells to be cultured in static suspension. HARV-3D cultures were prepared on microcarrier beads and compared to control-2D cultures using a combination of microscopic and biochemical techniques. Both systems were uniformly inoculated and medium exchanged at standard intervals. Cells in control cultures adhered to the polystyrene surface of the tissue culture dishes and exhibited typical 2D organization. Cells cultured in HARVs adhered to microcarrier beads, the beads aggregated into defined clusters containing 8 to 15 beads per cluster, and the clusters exhibited distinct 3D layers: myocytes and fibroblasts appeared attached to the surfaces of beads and were overlaid by an outer cell type. In addition, cultures prepared in HARVs using alternative support matrices also displayed morphological formations not seen in control cultures. Generally, the cells prepared in HARV and control cultures were similar; however, the dramatic alterations in 3D organization recommend the HARV as an ideal vessel for the generation of tissuelike organization of cardiac cells in vitro.

  6. Neonatal rat heart cells cultured in simulated microgravity

    NASA Technical Reports Server (NTRS)

    Akins, R. E.; Schroedl, N. A.; Gonda, S. R.; Hartzell, C. R.

    1997-01-01

    In vitro characteristics of cardiac cells cultured in simulated microgravity are reported. Tissue culture methods performed at unit gravity constrain cells to propagate, differentiate, and interact in a two-dimensional (2D) plane. Neonatal rat cardiac cells in 2D culture organize predominantly as bundles of cardiomyocytes with the intervening areas filled by nonmyocyte cell types. Such cardiac cell cultures respond predictably to the addition of exogenous compounds, and in many ways they represent an excellent in vitro model system. The gravity-induced 2D organization of the cells, however, does not accurately reflect the distribution of cells in the intact tissue. We have begun characterizations of a three-dimensional (3D) culturing system designed to mimic microgravity. The NASA-designed High-Aspect Ratio Vessel (HARV) bioreactors provide a low shear environment that allows cells to be cultured in static suspension. HARV-3D cultures were prepared on microcarrier beads and compared to control-2D cultures using a combination of microscopic and biochemical techniques. Both systems were uniformly inoculated and medium exchanged at standard intervals. Cells in control cultures adhered to the polystyrene surface of the tissue culture dishes and exhibited typical 2D organization. Cells cultured in HARVs adhered to microcarrier beads, the beads aggregated into defined clusters containing 8 to 15 beads per cluster, and the clusters exhibited distinct 3D layers: myocytes and fibroblasts appeared attached to the surfaces of beads and were overlaid by an outer cell type. In addition, cultures prepared in HARVs using alternative support matrices also displayed morphological formations not seen in control cultures. Generally, the cells prepared in HARV and control cultures were similar; however, the dramatic alterations in 3D organization recommend the HARV as an ideal vessel for the generation of tissuelike organization of cardiac cells in vitro.

  7. Neonatal rat heart cells cultured in simulated microgravity

    NASA Technical Reports Server (NTRS)

    Akins, Robert E.; Schroedl, Nancy A.; Gonda, Steve R.; Hartzell, Charles R.

    1994-01-01

    In vitro characteristics of cardiac cells cultured in simulated microgravity are reported. Tissue culture methods performed at unit gravity constrain cells to propagate, differentiate, and interact in a two dimensional (2D) plane. Neonatal rat cardiac cells in 2D culture organize predominantly as bundles of cardiomyocytes with the intervening areas filled by non-myocyte cell types. Such cardiac cell cultures respond predictably to the addition of exogenous compounds, and in many ways they represent an excellent in vitro model system. The gravity-induced 2D organization of the cells, however, does not accurately reflect the distribution of cells in the intact tissue. We have begun characterizations of a three-dimensional (3D) culturing system designed to mimic microgravity. The NASA designed High-Aspect-Ratio-Vessel (HARV) bioreactors provide a low shear environment which allows cells to be cultured in static suspension. HARV-3D cultures were prepared on microcarrier beads and compared to control-2D cultures using a combination of microscopic and biochemical techniques. Both systems were uniformly inoculated and medium exchanged at standard intervals. Cells in control cultures adhered to the polystyrene surface of the tissue culture dishes and exhibited typical 2D organization. Cells in cultured in HARV's adhered to microcarrier beads, the beads aggregated into defined clusters containing 8 to 15 beads per cluster, and the clusters exhibited distinct 3D layers: myocytes and fibroblasts appeared attached to the surfaces of beads and were overlaid by an outer cell type. In addition, cultures prepared in HARV's using alternative support matrices also displayed morphological formations not seen in control cultures. Generally, the cells prepared in HARV and control cultures were similar, however, the dramatic alterations in 3D organization recommend the HARV as an ideal vessel for the generation of tissue-like organizations of cardiac cells in simulated microgravity.

  8. Early life triclocarban exposure during lactation affects neonate rat survival.

    PubMed

    Kennedy, Rebekah C M; Menn, Fu-Min; Healy, Laura; Fecteau, Kellie A; Hu, Pan; Bae, Jiyoung; Gee, Nancy A; Lasley, Bill L; Zhao, Ling; Chen, Jiangang

    2015-01-01

    Triclocarban (3,4,4'-trichlorocarbanilide; TCC), an antimicrobial used in bar soaps, affects endocrine function in vitro and in vivo. This study investigates whether TCC exposure during early life affects the trajectory of fetal and/or neonatal development. Sprague Dawley rats were provided control, 0.2% weight/weight (w/w), or 0.5% w/w TCC-supplemented chow through a series of 3 experiments that limited exposure to critical growth periods: gestation, gestation and lactation, or lactation only (cross-fostering) to determine the susceptible windows of exposure for developmental consequences. Reduced offspring survival occurred when offspring were exposed to TCC at concentrations of 0.2% w/w and 0.5% w/w during lactation, in which only 13% of offspring raised by 0.2% w/w TCC dams survived beyond weaning and no offspring raised by 0.5% w/w TCC dams survived to this period. In utero exposure status had no effect on survival, as all pups nursed by control dams survived regardless of their in utero exposure status. Microscopic evaluation of dam mammary tissue revealed involution to be a secondary outcome of TCC exposure rather than a primary effect of compound administration. The average concentration of TCC in the milk was almost 4 times that of the corresponding maternal serum levels. The results demonstrate that gestational TCC exposure does not affect the ability of dams to carry offspring to term but TCC exposure during lactation has adverse consequences on the survival of offspring although the mechanism of reduced survival is currently unknown. This information highlights the importance of evaluating the safety of TCC application in personal care products and the impacts during early life exposure.

  9. Early Life Triclocarban Exposure During Lactation Affects Neonate Rat Survival

    PubMed Central

    Kennedy, Rebekah C. M.; Menn, Fu-Min; Healy, Laura; Fecteau, Kellie A.; Hu, Pan; Bae, Jiyoung; Gee, Nancy A.; Lasley, Bill L.; Zhao, Ling

    2015-01-01

    Triclocarban (3,4,4′-trichlorocarbanilide; TCC), an antimicrobial used in bar soaps, affects endocrine function in vitro and in vivo. This study investigates whether TCC exposure during early life affects the trajectory of fetal and/or neonatal development. Sprague Dawley rats were provided control, 0.2% weight/weight (w/w), or 0.5% w/w TCC-supplemented chow through a series of 3 experiments that limited exposure to critical growth periods: gestation, gestation and lactation, or lactation only (cross-fostering) to determine the susceptible windows of exposure for developmental consequences. Reduced offspring survival occurred when offspring were exposed to TCC at concentrations of 0.2% w/w and 0.5% w/w during lactation, in which only 13% of offspring raised by 0.2% w/w TCC dams survived beyond weaning and no offspring raised by 0.5% w/w TCC dams survived to this period. In utero exposure status had no effect on survival, as all pups nursed by control dams survived regardless of their in utero exposure status. Microscopic evaluation of dam mammary tissue revealed involution to be a secondary outcome of TCC exposure rather than a primary effect of compound administration. The average concentration of TCC in the milk was almost 4 times that of the corresponding maternal serum levels. The results demonstrate that gestational TCC exposure does not affect the ability of dams to carry offspring to term but TCC exposure during lactation has adverse consequences on the survival of offspring although the mechanism of reduced survival is currently unknown. This information highlights the importance of evaluating the safety of TCC application in personal care products and the impacts during early life exposure. PMID:24803507

  10. Neonatal, lethal noncompaction of the left ventricular myocardium is allelic with Barth syndrome.

    PubMed Central

    Bleyl, S B; Mumford, B R; Thompson, V; Carey, J C; Pysher, T J; Chin, T K; Ward, K

    1997-01-01

    Loss-of-function mutations in the G4.5 gene have been shown to cause Barth syndrome (BTHS), an X-linked disorder characterized by cardiac and skeletal myopathy, short stature, and neutropenia. We recently reported a family with a severe X-linked cardiomyopathy described as isolated noncompaction of the left ventricular myocardium (INVM). Other findings associated with BTHS (skeletal myopathy, neutropenia, growth retardation, elevated urinary organic acids, and mitochondrial abnormalities) were either absent or inconsistent. A linkage study of the X chromosome localized INVM to the Xq28 region near the BTHS locus, suggesting that these disorders are allelic. We screened the G4.5 gene for mutations in this family with SSCP and direct sequencing and found a novel glycine-to-arginine substitution at position 197. This position is conserved in a homologous Caenorhabditis elegans protein. We conclude that INVM is a severe allelic variant of BTHS with a specific effect on the heart. This finding provides further structure-function information about the G4.5 gene product and has implications for unexplained cases of severe infantile hypertrophic cardiomyopathy in males. Images Figure 2 PMID:9382097

  11. Pharmacologically induced hypothermia attenuates traumatic brain injury in neonatal rats.

    PubMed

    Gu, Xiaohuan; Wei, Zheng Zachory; Espinera, Alyssa; Lee, Jin Hwan; Ji, Xiaoya; Wei, Ling; Dix, Thomas A; Yu, Shan Ping

    2015-05-01

    Neonatal brain trauma is linked to higher risks of mortality and neurological disability. The use of mild to moderate hypothermia has shown promising potential against brain injuries induced by stroke and traumatic brain injury (TBI) in various experimental models and in clinical trials. Conventional methods of physical cooling, however, are difficult to use in acute treatments and in induction of regulated hypothermia. In addition, general anesthesia is usually required to mitigate the negative effects of shivering during physical cooling. Our recent investigations demonstrate the potential therapeutic benefits of pharmacologically induced hypothermia (PIH) using the neurotensin receptor (NTR) agonist HPI201 (formerly known as ABS201) in stroke and TBI models of adult rodents. The present investigation explored the brain protective effects of HPI201 in a P14 rat pediatric model of TBI induced by controlled cortical impact. When administered via intraperitoneal (i.p.) injection, HPI201 induced dose-dependent reduction of body and brain temperature. A 6-h hypothermic treatment, providing an overall 2-3°C reduction of brain and body temperature, showed significant effect of attenuating the contusion volume versus TBI controls. Attenuation occurs whether hypothermia is initiated 15min or 2h after TBI. No shivering response was seen in HPI201-treated animals. HPI201 treatment also reduced TUNEL-positive and TUNEL/NeuN-colabeled cells in the contusion area and peri-injury regions. TBI-induced blood-brain barrier damage was attenuated by HPI201 treatment, evaluated using the Evans Blue assay. HPI201 significantly decreased MMP-9 levels and caspase-3 activation, both of which are pro-apototic, while it increased anti-apoptotic Bcl-2 gene expression in the peri-contusion region. In addition, HPI201 prevented the up-regulation of pro-inflammatory tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6. In sensorimotor activity assessments, rats in the HPI201

  12. Hypercholesterolemic diet applied to rat dams protects their offspring against cognitive deficits. Simulated neonatal anoxia model.

    PubMed

    Bohr, Iwo

    2004-09-30

    There is accumulating data suggesting a neuroprotective activity of cholesterol, especially in stroke and Alzheimer's disease (AD). In the present study, a protective activity of this lipid in simulated neonatal anoxia was investigated. Rats were subjected to high cholesterol by feeding their dams with a diet enriched with cholesterol. Half of these rats were subjected to anoxia. One and a half months later, the rats were tested for their ability to acquire a spatial memory, one group on the linear maze and the other on the Morris water maze. After these assessments, the level of total plasma cholesterol was measured. Rats from dams subjected to neonatal anoxia on standard diet performed worse than control rats in both types of behavioral experiments, whereas anoxic rats from dams were housed on hypercholesterolemic diet performed as control animals. It suggests that dietetic cholesterol applied by their dams protected rats against cognitive deficits elicited by neonatal anoxia. Furthermore, offspring of anoxic rats housed on standard diet had elevated levels of blood cholesterol in relation to control animals. Generally, anoxia affected the concentration of this lipid much stronger than hypercholesterolemic diet of their dams. It might mean that the anoxia-related rise of cholesterol could be involved in physiological phenomenon being an adaptive response to neurotoxic processes. This concept is discussed in relation to pathological mechanisms in AD. Copyright 2004 Elsevier Inc.

  13. The superoxide dismutase mimetic, tempol, blunts right ventricular hypertrophy in chronic hypoxic rats

    PubMed Central

    Elmedal, Britt; de Dam, Mette Y; Mulvany, Michael John; Simonsen, Ulf

    2003-01-01

    The purpose of this study was to investigate whether a membrane-permeable superoxide dismutase mimetic, tempol, added either alone or in combination with the nitric oxide (NO) donor molsidomine, prevents the development of pulmonary hypertension (PH) in chronic hypoxic rats.Chronic hypobaric hypoxia (10% oxygen) for 2 weeks increased the right ventricular systolic pressure (RVSP), right ventricle and lung wet weight. Relaxations evoked by acetylcholine (ACh) and the molsidomine metabolite SIN-1 were impaired in isolated proximal, but not distal pulmonary arteries, from chronic hypoxic rats.Treatment with tempol (86 mg kg−1 day−1 in drinking water) normalized RVSP and reduced right ventricular hypertrophy, while systemic blood pressure, lung and liver weights, and blunted ACh relaxation of pulmonary arteries were unchanged.Treatment with molsidomine (15 mg kg−1 day−1 in drinking water) had the same effects as tempol, except that liver weight was reduced, and potassium and U46619-evoked vasoconstrictions in pulmonary arteries were increased. Combining tempol and molsidomine did not have additional effects compared to tempol alone. ACh relaxation in pulmonary arteries was not normalized by these treatments.The media to lumen diameter ratio of the pulmonary arteries was greater for the hypoxic rats compared to the normoxic rats, and was not reversed by treatment with tempol, molsidomine, or the combination of tempol and molsidomine.We conclude that tempol, like molsidomine, is able to correct RVSP and reduce right ventricular weight in the rat hypoxic model. Functional and structural properties of pulmonary small arteries were little affected. The results support the possibility that superoxide dismutase mimetics may be a useful means for the treatment of PH. PMID:14656807

  14. Albumin resuscitation improves ventricular contractility and myocardial tissue oxygenation in rat endotoxemia.

    PubMed

    Tokunaga, Chiho; Bateman, Ryon M; Boyd, John; Wang, Yingjin; Russell, James A; Walley, Keith R

    2007-05-01

    Fluid resuscitation to improve delivery of oxygen to vital organs is a principal clinical intervention for septic patients. We previously reported that albumin resuscitation in rat endotoxemia improved contractility in isolated cardiomyocytes, but whether this effect occurs in vivo is unknown. We hypothesized that albumin resuscitation would improve decreased ventricular contractility and myocardial tissue oxygenation in vivo. Randomized, controlled, prospective animal study. University animal laboratory. Male Sprague-Dawley rats (250-350 g). Rats were randomized into three groups: control with no lipopolysaccharide (n = 8), lipopolysaccharide (10 mg/kg) without albumin resuscitation (n = 8), and lipopolysaccharide with albumin resuscitation (n = 6). Five hours after lipopolysaccharide injection, animals were resuscitated with 10 mL/kg 5% rat albumin in 0.9% saline. Six hours after 10 mL/kg lipopolysaccharide, a pressure-volume conductance catheter (MIKRO-Tip 2.0-Fr, Millar Instruments, Houston, TX) was inserted into the left ventricle to quantify maximum elastance as an index of contractility. Myocardial tissue Po2 was measured using a fiberoptic oxygen probe. Maximum elastance decreased after lipopolysaccharide relative to control (47%, from 5.9 +/- 0.8 to 3.1 +/- 0.4 mm Hg/microL, p < .05). Albumin resuscitation prevented the lipopolysaccharide-induced decrease in maximum elastance (7.0 +/- 1.2 mm Hg/microL, p < .05 vs. lipopolysaccharide). Myocardial tissue Po2 was reduced in endotoxemia compared with control (53%, from 10.1 +/- 0.9 to 4.7 +/- 0.6 mm Hg, p < .05), and albumin resuscitation improved the lipopolysaccharide-induced tissue hypoxia toward the control value (9.0 +/- 1.4 mm Hg, p < .05). Albumin resuscitation improved decreased ventricular contractility and myocardial oxygenation in endotoxemic rats. This result suggests that albumin resuscitation may improve ventricular dysfunction by improving myocardial hypoxia.

  15. Endothelin-B Receptors and Left Ventricular Dysfunction after Regional versus Global Ischaemia-Reperfusion in Rat Hearts.

    PubMed

    Bibli, Sofia-Iris; Toli, Eleni V; Vilaeti, Agapi D; Varnavas, Varnavas C; Baltogiannis, Giannis G; Papalois, Apostolos; Kyriakides, Zenon S; Kolettis, Theofilos M

    2012-01-01

    Background. Endothelin-1 (ET-1) is implicated in left ventricular dysfunction after ischaemia-reperfusion. ETA and ETB receptors mediate diverse actions, but it is unknown whether these actions depend on ischaemia type and duration. We investigated the role of ETB receptors after four ischaemia-reperfusion protocols in isolated rat hearts. Methods. Left ventricular haemodynamic variables were measured in the Langendorff-perfused model after 40- and 20-minute regional or global ischaemia, followed by 30-minute reperfusion. Wild-type (n = 39) and ETB-deficient (n = 41) rats were compared. Infarct size was measured using fluorescent microspheres after regional ischaemia-reperfusion. Results. Left ventricular dysfunction was more prominent in ETB-deficient rats, particularly after regional ischaemia. Infarct size was smaller (P = 0.006) in wild-type (31.5 ± 4.4%) than ETB-deficient (45.0 ± 7.3%) rats after 40 minutes of regional ischaemia-reperfusion. Although the recovery of left ventricular function was poorer after 40-minute ischaemia-reperfusion, end-diastolic pressure in ETB-deficient rats was higher after 20 than after 40 minutes of regional ischaemia-reperfusion. Conclusion. ETB receptors exert cytoprotective effects in the rat heart, mainly after regional ischaemia-reperfusion. Longer periods of ischaemia suppress the recovery of left ventricular function after reperfusion, but the role of ETB receptors may be more important during the early phases.

  16. Endothelin-B Receptors and Left Ventricular Dysfunction after Regional versus Global Ischaemia-Reperfusion in Rat Hearts

    PubMed Central

    Bibli, Sofia-Iris; Toli, Eleni V.; Vilaeti, Agapi D.; Varnavas, Varnavas C.; Baltogiannis, Giannis G.; Papalois, Apostolos; Kyriakides, Zenon S.; Kolettis, Theofilos M.

    2012-01-01

    Background. Endothelin-1 (ET-1) is implicated in left ventricular dysfunction after ischaemia-reperfusion. ETA and ETB receptors mediate diverse actions, but it is unknown whether these actions depend on ischaemia type and duration. We investigated the role of ETB receptors after four ischaemia-reperfusion protocols in isolated rat hearts. Methods. Left ventricular haemodynamic variables were measured in the Langendorff-perfused model after 40- and 20-minute regional or global ischaemia, followed by 30-minute reperfusion. Wild-type (n = 39) and ETB-deficient (n = 41) rats were compared. Infarct size was measured using fluorescent microspheres after regional ischaemia-reperfusion. Results. Left ventricular dysfunction was more prominent in ETB-deficient rats, particularly after regional ischaemia. Infarct size was smaller (P = 0.006) in wild-type (31.5 ± 4.4%) than ETB-deficient (45.0 ± 7.3%) rats after 40 minutes of regional ischaemia-reperfusion. Although the recovery of left ventricular function was poorer after 40-minute ischaemia-reperfusion, end-diastolic pressure in ETB-deficient rats was higher after 20 than after 40 minutes of regional ischaemia-reperfusion. Conclusion. ETB receptors exert cytoprotective effects in the rat heart, mainly after regional ischaemia-reperfusion. Longer periods of ischaemia suppress the recovery of left ventricular function after reperfusion, but the role of ETB receptors may be more important during the early phases. PMID:22844633

  17. Metabolites of MDMA induce oxidative stress and contractile dysfunction in adult rat left ventricular myocytes.

    PubMed

    Shenouda, Sylvia K; Varner, Kurt J; Carvalho, Felix; Lucchesi, Pamela A

    2009-03-01

    Repeated administration of 3,4-methylenedioxymethamphetamine (MDMA) (ecstasy) produces eccentric left ventricular (LV) dilation and diastolic dysfunction. While the mechanism(s) underlying this toxicity are unknown, oxidative stress plays an important role. MDMA is metabolized into redox cycling metabolites that produce superoxide. In this study, we demonstrated that metabolites of MDMA induce oxidative stress and contractile dysfunction in adult rat left ventricular myocytes. Metabolites of MDMA used in this study included alpha-methyl dopamine, N-methyl alpha-methyl dopamine and 2,5-bis(glutathion-S-yl)-alpha-MeDA. Dihydroethidium was used to detect drug-induced increases in reactive oxygen species (ROS) production in ventricular myocytes. Contractile function and changes in intracellular calcium transients were measured in paced (1 Hz), Fura-2 AM loaded, myocytes using the IonOptix system. Production of ROS in ventricular myocytes treated with MDMA was not different from control. In contrast, all three metabolites of MDMA exhibited time- and concentration-dependent increases in ROS that were prevented by N-acetyl-cysteine (NAC). The metabolites of MDMA, but not MDMA alone, significantly decreased contractility and impaired relaxation in myocytes stimulated at 1 Hz. These effects were prevented by NAC. Together, these data suggest that MDMA-induced oxidative stress in the left ventricle can be due, at least in part, to the metabolism of MDMA to redox active metabolites.

  18. Ventricular fibrillation-induced cardiac arrest in the rat as a model of global cerebral ischemia

    PubMed Central

    Dave, Kunjan R.; Della-Morte, David; Saul, Isabel; Prado, Ricardo; Perez-Pinzon, Miguel A.

    2013-01-01

    Cardiopulmonary arrest remains one of the leading causes of death and disability in Western countries. Although ventricular fibrillation (VF) models in rodents mimic the “square wave” type of insult (rapid loss of pulse and pressure) commonly observed in adult humans at the onset of cardiac arrest (CA), they are not popular because of the complicated animal procedure, poor animal survival and thermal injury. Here we present a modified, simple, reliable, ventricular fibrillation-induced rat model of CA that will be useful in studying mechanisms of CA-induced delayed neuronal death as well as the efficacy of neuroprotective drugs. CA was induced in male Sprague Dawley rats using a modified method of von Planta et al. In brief, VF was induced in anesthetized, paralyzed, mechanically ventilated rats by an alternating current delivered to the entrance of the superior vena cava into the heart. Resuscitation was initiated by administering a bolus injection of epinephrine and sodium bicarbonate followed by mechanical ventilation and manual chest compressions and countershock with a 10-J DC current. Neurologic deficit score was higher in the CA group compared to the sham group during early reperfusion periods, suggesting brain damage. Significant damage in CA1 hippocampus (21% normal neurons compared to control animals) was observed following histopathological assessment at seven days of reperfusion. We propose that this method of VF-induced CA in rat provides a tool to study the mechanism of CA-induced neuronal death without compromising heart functions. PMID:24187598

  19. The relationship between ventricular dilatation, neuropathological and neurobehavioural changes in hydrocephalic rats

    PubMed Central

    2012-01-01

    Background The motor and cognitive deficits observed in hydrocephalus are thought to be due to axonal damage within the periventricular white matter. This study was carried out to investigate the relationship between ventricular size, cellular changes in brain, and neurobehavioural deficits in rats with experimental hydrocephalus. Methods Hydrocephalus was induced in three-week old rats by intracisternal injection of kaolin. Behavioural and motor function were tested four weeks after hydrocephalus induction and correlated to ventricular enlargement which was classified into mild, moderate or severe. Gross brain morphology, routine histology and immunohistochemistry for oligodendrocytes (CNPase), microglia (Iba-1) and astrocytes (GFAP) were performed to assess the cellular changes. Results Decreases in open field activity and forelimb grip strength in hydrocephalus correlated with the degree of ventriculomegaly. Learning in Morris water maze was significantly impaired in hydrocephalic rats. Gradual stretching of the ependymal layer, thinning of the corpus callosum, extracellular oedema and reduced cortical thickness were observed as the degree of ventriculomegaly increased. A gradual loss of oligodendrocytes in the corpus callosum and cerebral cortex was most marked in the severely-hydrocephalic brains, whereas the widespread astrogliosis especially in the subependymal layer was most marked in the brains with mild hydrocephalus. Retraction of microglial processes and increase in Iba-1 immunoreactivity in the white matter was associated ventriculomegaly. Conclusions In hydrocephalic rats, oligodendrocyte loss, microglia activation, astrogliosis in cortical areas and thinning of the corpus callosum were associated with ventriculomegaly. The degree of ventriculomegaly correlated with motor and cognitive deficits. PMID:22938200

  20. A novel anionic conductance affects action potential duration in isolated rat ventricular myocytes.

    PubMed

    Spencer, C I; Uchida, W; Kozlowski, R Z

    2000-01-01

    Effects of extracellular anions were studied in electrophysiological experiments on freshly isolated rat ventricular myocytes. Under current-clamp, action potential duration (APD) was prolonged by reducing the extracellular Cl(-) concentration and shortened by replacement of extracellular Cl(-) with I(-). Under voltage-clamp, membrane potential steps or ramps evoked an anionic background current (I(AB)) carried by either Cl(-), Br(-), I(-) or NO(3)(-). Activation of I(AB) was Ca(2+)- and cyclic AMP-independent, and was unaffected by cell shrinkage. I(AB) was insensitive to stilbene and fenamate anion transport blockers at concentrations that inhibit Ca(2+)-, cyclic AMP- and swelling-activated Cl(-) currents in ventricular cells of other mammals. These results suggest that I(AB) may be carried by a novel class of Cl(-) channel. Correlation of anion substitution experiments on membrane current and action potentials revealed that I(AB) could play a major role in controlling rat ventricular APD. These findings have important implications for those studying cardiac Cl(-) channels as potential targets for novel antiarrythmic agents.

  1. Neonatal exposure to estradiol valerate increases dopamine content in nigrostriatal pathway during adulthood in the rat.

    PubMed

    Cruz, G; Riquelme, R; Espinosa, P; Jara, P; Dagnino-Subiabre, A; Renard, G M; Sotomayor-Zárate, R

    2014-05-01

    Research in programming has focused in the study of stimuli that affect sensitive periods of development such as prenatal and neonatal stage. We previously showed that exposure to estradiol valerate to female rats during the first 12 h of life increased catecholamine content in ventromedial-arcuatus hypothalamus of the adult rat. However, changes in others dopaminergic circuits have not been studied. The purpose of this work was to determine the neurotransmitters changes induced by neonatal estradiol valerate (0.1 mg/50 μl s. c. per rat) administration on nigrostriatal pathway of adult female rats. Sesame oil (50 μl s. c. per rat) was administered in a control parallel group. EV-1 adult rats presented effective markers of long-term estrogenization as decreased serum levels of progesterone and a reduction in the size of estrogen-sensitive organs. In the brain, neonatal estradiol valerate administration led to a significant increase in dopamine content in striatum, substantia nigra and ventral tegmental area. With respect to the contents of dopamine metabolites, only 3-methoxytyramine content increased in substantia nigra and ventral tegmental area. In addition, the content of noradrenaline increased only in striatum. Interestingly, estrogenized rats lacked locomotor activity induced by acute dose of amphetamine (1 mg/kg i. p.). Altogether, these results show that neonatal exposure to estradiol valerate permanently modified the content of monoamine neurotransmitters in nigrostriatal pathway and amphetamine-induced locomotor activity of adult female rats. This might imply that estrogenized rats could have changes in the expression of key proteins in dopaminergic regulation, as tyrosine hydroxylase and dopamine transporter. © Georg Thieme Verlag KG Stuttgart · New York.

  2. Ventricular-subcutaneous shunt for the treatment of experimental hydrocephalus in young rats: technical note.

    PubMed

    Santos, Marcelo Volpon; Garcia, Camila Araujo Bernardino; Jardini, Evelise Oliveira; Romeiro, Thais Helena; da Silva Lopes, Luiza; Machado, Hélio Rubens; de Oliveira, Ricardo Santos

    2016-08-01

    Hydrocephalus is a complex disease that affects cerebrospinal fluid (CSF) dynamics and is very common in children. To this date, CSF shunting is still the standard treatment for childhood hydrocephalus, but, nevertheless, the effects of such an operation on the developing brain are widely unknown. To help overcome this, experimental models of CSF shunts are surely very useful tools. The objective of this study was to describe a feasible and reliable technique of an adapted ventricular-subcutaneous shunt for the treatment of kaolin-induced hydrocephalus in young rats. We developed a ventricular-subcutaneous shunt (VSCS) technique which was used in 31 Wistar young rats with kaolin-induced hydrocephalus. Hydrocephalus was induced at 7 days of age, and shunt implantation was performed 7 days later. Our technique used a 0.7-mm gauge polypropylene catheter tunneled to a subcutaneous pocket created over the animal's back and inserted into the right lateral ventricle. All animals were sacrificed 14 days after shunt insertion. Twenty-four rats survived and remained well until the study was ended. No major complications were seen. Their weight gain went back to normal. They all underwent ambulatory behavioral testing prior and after VSCS, which showed improvement in their motor skills. We have also obtained magnetic resonance (MR) scans of 16 pups confirming reduction of ventricular size after shunting and indicating effective treatment. Histopathological analysis of brain samples before and after shunting showed reversion of ependymal and corpus callosum disruption, as well as fewer reactive astrocytes in shunted animals. An experimental CSF shunt technique was devised. Excessive CSF of hydrocephalic rats is diverted into the subcutaneous space where it can be resorbed. This technique has a low complication rate and is effective. It might be applied to various types of experimental studies involving induction and treatment of hydrocephalus.

  3. Induction of transient hyperprolactinaemia in neonatal rats by direct or maternal treatment with the dopamine receptor blocker, sulpiride.

    PubMed

    Lewis, M; Howie, P W

    1987-07-01

    Prolactin was measured in the plasma of neonatal rats after iv and ip injection of the dopamine receptor blocking drug sulpiride, and after its ip injection to neonatal rats' nursing mothers. The sulpiride dose PRL response relationship in 10-25 day old neonatal rats was similar to that found in lactating rats, with a threshold sensitivity around 29 nmol sulpiride/kg body weight and a maximal response at about 2.9 mumol/kg. Absolute levels of PRL in the neonate (both peak and increment-over-basal) were, however, 90% lower than in adults. Treatment of lactating mothers with a maximally stimulatory dose of sulpiride (2.9 mumol/kg) twice daily for 4 days resulted in small but highly significant increases in neonatal PRL on days 1 and 2 but complete loss of response by day 4. These data demonstrate that there is a close similarity between the responses of maternal and neonatal rats to sulpiride and that transfer of the drug to the neonate via milk can induce neonatal hyperprolactinaemia. The subsequent loss of the neonatal PRL response on chronic exposure to sulpiride may indicate a degree of disturbance of hypothalamic dopaminergic mechanisms. In the clinical situation this would suggest that doses of dopamine receptor-blocking drugs used to enhance maternal milk production should be carefully chosen.

  4. Sex differences in pain responses at maturity following neonatal repeated minor pain exposure in rats.

    PubMed

    Page, Gayle G; Hayat, Matthew J; Kozachik, Sharon L

    2013-01-01

    There is mounting evidence of long-lasting changes in pain sensitivity in school-age children who were cared for in a neonatal intensive care unit. Such care involves multiple pain exposures, 70% of which are accounted for by heel lance to monitor physiological well-being. The authors sought to model the repeated brief pain resulting from heel lance by administering repeated paw needle stick to neonatal rat pups. Repeated needle stick during the first 8 days of life was sex-specific in altering responses to mechanical and inflammatory stimuli, but not to a thermal stimulus, at maturity. Specifically, neonatal paw needle stick males exhibited significantly greater mechanical sensitivity in response to von Frey hair testing, whereas neonatal paw needle stick females exhibited significantly greater pain behavior scores following hindpaw formalin injection. This is the first study to show such sex-dependent changes in pain responsiveness at maturity in animals having experienced repeated neonatal needle stick pain. These findings support existing evidence that there are long-term sensory sequelae following neonatal pain experiences in rats and further suggest that there are sex-linked differences in the nature of the consequences. If these relationships hold in humans, these findings suggest that even mild painful insults early in life are not without sensory consequences.

  5. Role of the T-type calcium channel CaV3.2 in the chronotropic action of corticosteroids in isolated rat ventricular myocytes.

    PubMed

    Maturana, Andrés; Lenglet, Sébastien; Python, Magaly; Kuroda, Shun'ichi; Rossier, Michel F

    2009-08-01

    The mineralocorticoid receptor is involved in the development of several cardiac dysfunctions, including lethal ventricular arrhythmias associated with heart failure or hyperaldosteronism, but the molecular mechanisms responsible for these effects remain to be clarified. Reexpression of low voltage-activated T-type calcium channels in ventricular myocytes together with other fetal genes during cardiac pathologies could confer automaticity to these cells and would represent a pro-arrhythmogenic condition if occurring in vivo. In the present study, we demonstrated that in isolated neonatal rat ventricular myocytes, corticosteroids selectively induced the expression of a particular isoform of T channel, Ca(V)3.2/alpha1H. This response was accompanied by an increase of the Ca(V)3.2 T-type current, identified with the patch clamp technique by its sensitivity to nickel, and a concomitant acceleration of the myocyte spontaneous contractions. Silencing Ca(V)3.2 expression markedly reduced the chronotropic response to steroids. Moreover, modulation of the frequency of cell contractions by different redox agents was independent of channel expression but involved a direct regulation of channel activity. Although oxidants increased both Ca(V)3.2 current amplitude and beating frequency, they decreased L-type channel activity. Reducing agents had the opposite effect on these parameters. In conclusion, the acceleration of ventricular myocyte spontaneous contractions induced by corticosteroids in vitro appears dependent on the expression of the Ca(V)3.2 T channel isoform and modulated by the redox potential of the cells. These results provide a molecular model that could explain the high incidence of arrhythmias observed in patients upon combination of inappropriate activation of the mineralocorticoid receptor and oxidative stress.

  6. Enhanced locomotor activity in adult rats with neonatal administration of N-omega-nitro-L-arginine.

    PubMed

    Mejorada, Alejandro; Aguilar-Alonso, Patricia; León-Chavez, Bertha Alicia; Flores, Gonzalo

    2006-09-01

    Nitric oxide (NO) is a neuronal messenger molecule that plays important roles in the development, maintenance, and functional modifications of brain circuits. We investigated whether the NO levels at different postnatal day (P) periods of the brain develop interference with the locomotion in a novel environment during the postpuberal age (P60). First, using the determination of the nitrite accumulation, we evaluated whether treatment with the NO-synthase inhibitor N-nitro-L-arginine (L-NNA) during different neonatal ages (P1 to P3, P4 to P6, and P7 to P9) affected the levels of NO activity in different regions in the neonatal brain of the rat. We then evaluated whether the locomotor activity in the adult rat (P60) is affected by the blocking of the neonatal NO-activity during a specific period of the development of the nervous system. Neonatal rats with L-NNA administration at P4 to P6 and P7 to P9 show a significant decrease in the levels of NO activity in all the brain regions. However, the blocking of NO synthesis during the neonatal period between P4 to P6 produced an increase in the locomotion after puberty. These data suggest that during a specific step in the development of the brain, the NO levels may play a critical role in the structures that control the spontaneous locomotion in a novel environment after puberty.

  7. Estrogen fails to facilitate resuscitation from ventricular fibrillation in male rats

    PubMed Central

    Miao, Yang; Edelheit, Ari; Velmurugan, Sathya; Borovnik-Lesjak, Vesna; Radhakrishnan, Jeejabai; Gazmuri, Raúl J

    2015-01-01

    Administration of 17β-estradiol has been shown to exert myocardial protective effects in hemorrhagic shock. We hypothesized that similar protective effects could help improve resuscitation from cardiac arrest. Three series of 18, 40, and 12 rats each, underwent ventricular fibrillation for 8 minutes followed by 8 minutes of chest compression and delivery of electrical shocks. In series-1, rats were randomized 1:1 to receive a bolus dose of 17β-estradiol (1 mg/kg) or 0.9% NaCl before chest compression; in series-2, rats were randomized 1:1:1:1 to receive a continuous infusion of 0.9% NaCl or a 17β-estradiol solution designed to attain a plasma level of 100, 102, or 104 nM during chest compression; and in series-3, rats were randomized 1:1 to receive a continuous infusion of 17β-estradiol to attain a plasma level of 102 nM or 0.9% NaCl during chest compression, providing inotropic support during the post-resuscitation interval using dobutamine infusion. 17β-estradiol failed to facilitate resuscitation in each of the 3 series. In series-1 and series-2, resuscitability and short-term survival was reduced in 17β-estradiol groups attaining statistical significance in series-2 when the three 17β-estradiol groups were combined (p = 0.035). In series-3, all rats were resuscitated and survived for 180 minutes aided by dobutamine which partially reversed post-resuscitation myocardial dysfunction but without additional benefits on myocardial function in the 17β-estradiol group. The present study failed to support a beneficial effect of 17β-estradiol for resuscitation from cardiac arrest and raised the possibility of detrimental cardiac effects compromising initial resuscitability and subsequent survival in a male rat model of ventricular fibrillation and closed chest resuscitation. PMID:26045892

  8. Expression and activity of epithelial sodium channel in hyperoxia-induced bronchopulmonary dysplasia in neonatal rats.

    PubMed

    Ji, Weihua; Fu, Jianhua; Nie, Hongguang; Xue, Xindong

    2012-12-01

    The aim of the present study was to investigate the expression and activity of epithelial sodium channel (ENaC) in hyperoxia-induced bronchopulmonary dysplasia (BPD) in neonatal rats. Neonatal rats were exposed to hyperoxia to establish BPD models (control group was exposed to air), lung water was measured and Western blot was applied to detect the expression of three homologous subunits: α-, β- and γ-ENaC in the lung tissues. Furthermore, ATII cells were isolated from neonatal rats, and primarily cultured under normoxic or hyperoxic conditions. The ENaC expression was also examined in these cells. In addition, the amiloride-sensitive Na(+) currents induced by hyperoxia were recorded using the whole-cell patch clamp technique. The α-ENaC expression was increased after 5 days of hyperoxia in rat lung tissues, whereas not after 1, 3 and 7 days. ATII cells showed α-ENaC expression was reduced after 1 and 2 days' hyperoxia, but no change after 3 days. In contrast, β- and γ-ENaC expression was increased after hyperoxia in both in vivo and in vitro experiments. The amiloride-sensitive Na(+) currents in hyperoxia-exposed ATII cells were also increased, which was consistent with the upregulated expression of β- and γ-ENaC. Hyperoxia upregulates the expression of ENaC, especially β- and γ-ENaC subunits, in both neonatal rat lung tissues and ATII cells. Hyperoxia also enhanced the activity of ENaC in neonatal rat ATII cells. Dysfunctional transport of Na(+) may not be a key factor involving pulmonary edema at the early stage of BPD. © 2012 The Authors. Pediatrics International © 2012 Japan Pediatric Society.

  9. Formation of binucleated myocardial cells in the neonatal rat. An index for growth hypertrophy.

    PubMed

    Clubb, F J; Bishop, S P

    1984-05-01

    The purposes of this study were to characterize myocardial cell growth in neonatal rats and investigate the mechanism of binucleation in myocardial cells. To test the hypothesis that binucleated myocardial cells result from karyokinesis without cytokinesis, experiments were designed to measure the rate of DNA synthesis and the percentage of binucleated myocardial cells in neonatal rats during growth. Estimates of myocardial cell nuclear divisions were obtained from rats pulsed with tritiated thymidine at 17 days of gestation. Autoradiograms were prepared from isolated myocardial cells of rats killed at various ages postpartum, and the number of developed silver halide grains over myocardial cell nuclei was calculated. This estimated the mitotic activity of nuclei. To determine myocardial cell DNA synthesis postpartum, another set of rats were injected at various time periods with 4 hourly doses of tritiated thymidine, and hearts were fixed by perfusion 1 hour later. Labeling index of myocardial cells was calculated (labeled/total myocardial cells) from autoradiograms prepared on 1 micron thick, methacrylate-embedded heart cross-sections. Results of this study indicated that the growth of myocardial cells in the neonatal period can be divided into three phases: (a) a hyperplastic phase, (b) a transitional phase, and (c) a hypertrophic phase. Binucleation of myocardial cells was not due to fusion of mononucleated cells, because there was continued DNA synthesis in the neonatal hearts, reflected by continued incorporation of tritiated thymidine; in addition, the grain counts per nucleus of the binucleated myocardial cells were half that of mononucleated cells; nor was binucleation due to amitotic splitting of single nuclei, since binucleated myocardial cells had similar grain counts over each nucleus. We conclude that the formation of binucleated myocardial cells is an early indicator of growth hypertrophy in the neonatal rat and a result of mitosis without

  10. Effects of Neonatal Dexamethasone Exposure on Adult Neuropsychiatric Traits in Rats

    PubMed Central

    Robertson, Donald; Rodger, Jennifer; Martin-Iverson, Mathew T.

    2016-01-01

    The effects of early life stress in utero or in neonates has long-term consequences on hypothalamic-pituitary-adrenal (HPA) stress axis function and neurodevelopment. These effects extend into adulthood and may underpin a variety of mental illnesses and be related to various developmental and cognitive changes. We examined the potential role of neonatal HPA axis activation on adult psychopathology and dopamine sensitivity in the mature rat using neonatal exposure to the synthetic glucocorticoid receptor agonist and stress hormone, dexamethasone. We utilized a comprehensive battery of assessments for behaviour, brain function and gene expression to determine if elevated early life HPA activation is associated with adult-onset neuropsychiatric traits. Dexamethasone exposure increased startle reactivity under all conditions tested, but decreased sensitivity of sensorimotor gating to dopaminergic disruption–contrasting with what is observed in several neuropsychiatric diseases. Under certain conditions there also appeared to be mild long-term changes in stress and anxiety-related behaviours with neonatal dexamethasone exposure. Electrophysiology revealed that there were no consistent neuropsychiatric abnormalities in auditory processing or resting state brain function with dexamethasone exposure. However, neonatal dexamethasone altered auditory cortex glucocorticoid activation, and auditory cortex synchronization. Our results indicate that neonatal HPA axis activation by dexamethasone alters several aspects of adult brain function and behaviour and may induce long-term changes in emotional stress-reactivity. However, neonatal dexamethasone exposure is not specifically related to any particular neuropsychiatric disease. PMID:27936175

  11. Aspects of the Development of Housing for the Spaceflight of Pregnant and Lactating Rats with Neonates

    NASA Technical Reports Server (NTRS)

    Hinds, William E.; Mayer, David J.; Evans, Juli; Spratt, Shahn; Lane, Philip K.; Rodriguez, Shari L.; Navidi, Meena; Armstrong, Rachel; Lemos, Bonnie; Dalton, Bonnie P. (Technical Monitor)

    1996-01-01

    Recent and upcoming spaceflights are investigating the effect of weightlessness on developing neural and organ systems. Pregnant rats and dams with neonates have to be accommodated in cages that support the special requirements of these animals. Extensive ground testing of cage concepts, the effect of launch and landing stresses on the maintenance of pregnancy and maternal behavior at different neonatal ages, and techniques for monitoring adaptability to change are discussed. A spaceflight opportunity for the NlH.R3 payload of rat families at three different postnatal ages demonstrated that the survival of very young animals was not good but that older newborns could be returned to Earth in reasonably good health. The development of cages for the Research Animal Holding Facility (RAHF) to support the flight of neonates on Neurolab was continued and incorporated modifications that were demonstrated by the NIH.R3 flight. Other modifications to the RAHF are discussed. Data from biocompatibility and experiment verification testing are presented.

  12. Aspects of the Development of Housing for the Spaceflight of Pregnant and Lactating Rats with Neonates

    NASA Technical Reports Server (NTRS)

    Hinds, William E.; Mayer, David J.; Evans, Juli; Spratt, Shahn; Lane, Philip K.; Rodriguez, Shari L.; Navidi, Meena; Armstrong, Rachel; Lemos, Bonnie; Dalton, Bonnie P. (Technical Monitor)

    1996-01-01

    Recent and upcoming spaceflights are investigating the effect of weightlessness on developing neural and organ systems. Pregnant rats and dams with neonates have to be accommodated in cages that support the special requirements of these animals. Extensive ground testing of cage concepts, the effect of launch and landing stresses on the maintenance of pregnancy and maternal behavior at different neonatal ages, and techniques for monitoring adaptability to change are discussed. A spaceflight opportunity for the NlH.R3 payload of rat families at three different postnatal ages demonstrated that the survival of very young animals was not good but that older newborns could be returned to Earth in reasonably good health. The development of cages for the Research Animal Holding Facility (RAHF) to support the flight of neonates on Neurolab was continued and incorporated modifications that were demonstrated by the NIH.R3 flight. Other modifications to the RAHF are discussed. Data from biocompatibility and experiment verification testing are presented.

  13. Nuclear ploidy of neonatal rat livers: effects of two hepatic carcinogens (mirex and dimethylnitrosamine)

    SciTech Connect

    Carlson, J.; Abraham, R.

    1985-01-01

    The effect of two hepatic carcinogens, dimethylnitrosamine (DMN) (genotoxic) and mirex (epigenetic), on polyploidization in 12-d-old neonatal rats was investigated by Coulter counteranalysis and (/sup 3/H) thymidine uptake in isolated hepatic nuclear classes. DMN disturbed the normal ploidy development in the neonatal liver and the proportion of nuclei in the ploidy classes by inducing the premature formation of a significant population of tetraploids with a concommitant reduction in diploids. A great proportion of the replicative activity was present in tetraploid nuclei as measured by the incorporation of (/sup 3/H) thymidine. The labeling index and number of mitoses were also increased. In contrast to DMN, mirex had no influence on polyploidization. The neonatal rats used in these studies thus offer an opportunity to investigate in vivo the mode of action of genotoxic versus epigenetic compounds with reference to their effect on DNA.

  14. Citrobacter koseri brain abscess in the neonatal rat: survival and replication within human and rat macrophages.

    PubMed

    Townsend, Stacy M; Pollack, Harvey A; Gonzalez-Gomez, Ignacio; Shimada, Hiroyuki; Badger, Julie L

    2003-10-01

    A unique feature of Citrobacter koseri is the extremely high propensity to initiate brain abscesses during neonatal meningitis. Previous clinical reports and studies on infant rats have documented many Citrobacter-filled macrophages within the ventricles and brain abscesses. It has been hypothesized that intracellular survival and replication within macrophages may be a mechanism by which C. koseri subverts the host response and elicits chronic infection, resulting in brain abscess formation. In this study, we showed that C. koseri causes meningitis and brain abscesses in the neonatal rat model, and we utilized histology and magnetic resonance imaging technology to visualize brain abscess formation. Histology and electron microscopy (EM) revealed that macrophages (and not fibroblasts, astrocytes, oligodendrocytes, or neurons) were the primary target for long-term C. koseri infection. To better understand C. koseri pathogenesis, we have characterized the interactions of C. koseri with human macrophages. We found that C. koseri survives and replicates within macrophages in vitro and that uptake of C. koseri increases in the presence of human pooled serum in a dose-dependent manner. EM studies lend support to the hypothesis that C. koseri uses morphologically different methods of uptake to enter macrophages. FcgammaRI blocking experiments show that this receptor primarily facilitates the entry of opsonized C. koseri into macrophages. Further, confocal fluorescence microscopy demonstrates that C. koseri survives phagolysosomal fusion and that more than 90% of intracellular C. koseri organisms are colocalized within phagolysosomes. The ability of C. koseri to survive phagolysosome fusion and replicate within macrophages may contribute to the establishment of chronic central nervous system infection including brain abscesses.

  15. Neonatal Treatment With Beta-Cell Stimulatory Agents Reduces the Incidence of Diabetes in BB Rats

    PubMed Central

    Bock, Troels; Pedersen, Charlotte R.; Hansen, Susanne V.; Aaen, Kim; JØrgensen, Merete; Hansen, Michael WØllike; Kjaer, Troels W.; Hageman, Ida; Josefsen, Knud

    2000-01-01

    The aim of the study was to investigate whether various beta-cell stimulatory drugs, given neonatally, influence the incidence of diabetes in BB rats. Newborn BB rats were treated twice daily for 6 days and diabetes development was observed during the following 200-day study period. Compared to a diabetes incidence of 63.8% in 163 control BB rats which received saline or were untreated, the percentage of experimental BB rats that developed diabetes was as follows in the different subgroups: arginineglucose: 47% (n= 73, p < 0.02); glucagon: 37% (n = 93, p < 0.0001); tolbutamide-glucose: 36% (n = 58, p < 0.0005); and theophylline-glucose: 39% (n = 41, p < 0.005). A long-term arginine-glucose treatment was not superior to the shorter neonatal treatment. Histological examination revealed a higher degree of insulitis in diabetic than in non-diabetic animals but no difference according to the kind of treatment was observed. Finally, we found that the diabetes incidence in BB rats was higher in the first litter compared to subsequent litters (p = 0.04). Thus, neonatal treatment with various beta-cell stimulatory agents reduces diabetes incidence in BB rats. The theory behind the study, that the treatment accelerates beta-cell maturation leading to increased immunological tolerance towards beta cells, is discussed. PMID:11469386

  16. Increased rat neonatal activity influences adult cytokine levels and relative muscle mass

    PubMed Central

    Buchowicz, Bryce; Yu, Tiffany; Nance, Dwight M.; Zaldivar, Frank P.; Cooper, Dan M.; Adams, Gregory R.

    2011-01-01

    Little is known about the effect of physical activity in early life on subsequent growth and regulation of inflammation. We previously reported that exposure of muscles in growing rats to IL-6 results in decreased muscle growth apparently due to a state of resistance to growth factors such IGF-I and that running exercise could ameliorate this growth defect. Herein we hypothesized that increased activity, for a brief period during neonatal life, would pattern the adult rat towards a less inflammatory phenotype. Neonatal rats were induced to move about their cage for brief periods from day 5 to day 15 postpartum. Additional groups were undisturbed controls (CON) and handled (HAND). Sub-groups of rats were sampled at 30 and 65 days of age. Relative to CON and HAND, neonatal exercise (EX) results in decreased circulating levels of TNFα, IL-6 and IL-1β in adulthood, primarily in male rats. In addition, adult male EX rats had lower body mass and increased skeletal muscle mass suggesting a leaner phenotype. The results of this study suggest that moderate increases in activity early in life can influence the adult toward a more healthy phenotype with regard to inflammatory mediators and relative muscle mass. PMID:20657345

  17. Bi-ventricular finite element model of right ventricle overload in the healthy rat heart.

    PubMed

    Masithulela, Fulufhelo

    2016-11-25

    The recognition of RV overpressure is critical to human life, as this may signify morbidity and mortality. Right ventricle (RV) dysfunction is understood to have an impact on the performance of the left ventricle (LV), but the mechanisms remain poorly understood. It is understood that ventricular compliance has the ability to affect cardiac performance. In this study, a bi-ventricular model of the rat heart was used in preference to other, single-ventricle models. Finite element analysis (FEA) of the bi-ventricular model provides important information on the function of the healthy heart. The passive myocardium was modelled as a nearly incompressible, hyperelastic, transversely isotropic material using finite element (FE) methods. Bi-ventricular geometries of healthy rat hearts reconstructed from magnetic resonance images were imported in Abaqus©. In simulating the normal passive filling of the rat heart, pressures of 4.8 kPa and 0.0098 kPa were applied to the inner walls of the LV and RV respectively. In addition, to simulate the overpressure of the RV, pressures of 2.4 kPa and 4.8 kPa were applied to the endocardial walls of the LV and RV respectively. As boundary conditions, the circumferential and longitudinal displacements at the base were set to zero. The radial displacements at the base were left free. The results show that the average circumferential stress at the mid-wall in the overloaded model increased from 2.8 kPa to 18.2 kPa. The average longitudinal stress increased from 1.5 kPa to 9.7 kPa. Additionally, in the radial direction, the average stress increased from 0.1 kPa to 0.6 kPa in the mid-wall. The average circumferential strain was found to be 0.138 and 0.100 on the endocardium of the over pressured and healthy model respectively. The average circumferential stress at the epicardium, mid-wall and endocardium in the case of a normal heart is 10 times lower than in the overloaded heart model. The finite analysis method is able to provide

  18. Mesothelin promotes cell proliferation in the remodeling of neonatal rat pancreas

    PubMed Central

    Yin, Dan-Dan; You, Liang-Hui; Yuan, Qing-Xin; Liang, Xiao-Di; Wang, Ning; Wang, Lin-Tao; Yuan, Li; Wang, Ke-Ming; De, Wei

    2014-01-01

    AIM: To investigate the effect of mesothelin in the remodeling of the endocrine pancreas in neonatal rats. METHODS: Overexpression or downregulation of mesothelin expression in INS-1 cells was carried out to investigate the effect of mesothelin during cell proliferation and cell apoptosis in vitro. Adenovirus-mediated RNA interference was performed to block mesothelin in vivo to directly assess the role of mesothelin in the remodeling of the endocrine pancreas in neonatal rats. RESULTS: Exogenous overexpression of mesothelin promoted cell proliferation, cell colony formation and enhanced cell resistance to apoptosis of INS-1 cells. Down-regulation of mesothelin made no difference in cell proliferation and apoptosis compared with that in the control group. After an injection of adenovirus-mesothelin, a significantly increased number of small islets appeared, and the expression of PCNA was decreased on day 7 and day 14 compared with the Ad-EGFP group. CONCLUSION: Mesothelin was able to promote β cell proliferation in the remodeling stage of neonatal rats. Mesothelin may have an important role in the remodeling of the endocrine pancreas in neonatal rats. PMID:24944479

  19. EFFECTS OF PERFLUOROOCTANE SULFONATE (PFOS) ON THYROID HORMONE STATUS IN ADULT AND NEONATAL RATS

    EPA Science Inventory

    EFFECTS OF PERFLUOROOCTANE SULFONATE (PFOS) ON THYROID HORMONE STATUS IN ADULT AND NEONATAL RATS. M.N. Logan1, J.R. Thibodeaux2, R.G. Hanson2, C. Lau2. 1North Carolina Central University, Durham, NC, 2Reprod. Tox. Div. NHEERL, US EPA, Research Triangle Park, NC.

    Perfluor...

  20. Effect of diazepam on sociability of rats submitted to neonatal seizures

    PubMed Central

    Leite, Ingrid Stanize; Castelhano, Adelissandra S.S.; Cysneiros, Roberta M.

    2016-01-01

    Status epilepticus (SE), an acute condition characterized by repetitive or ongoing seizures activity, may produce long-term deleterious consequences. Previous data demonstrated that Wistar rats subjected to neonatal SE displayed autistic behavior, characterized by social play impairment, low preference by novelty, deficit in social discrimination; anxiety related behavior and stereotyped behavior with no changes in locomotor activity (doi: http://dx.doi.org/10.1007/s00702-010-0460-1, doi: http://dx.doi.org/10.3389/fnbeh.2013.00036, doi: http://dx.doi.org/10.1007/s00702-014-1291-2[1], [2], [3]). Taking into account the bi-directional relationship between the state of anxiety and social interaction (doi: http://dx.doi.org/10.1007/s10567-009-0062-3[4]), we evaluated the impact of the state of anxiety on social interaction. Male Wistar rats at postnatal day 9 were subjected to pilocarpine-induced neonatal SE (380 mg/kg, ip) and the controls received 0.9% saline (0.1 ml/10 g). The groups received saline or diazepam (1.0 mg/kg) 45 min prior each behavioral testing that started from 60 days of postnatal life. In the open field, rats subjected to neonatal seizure exhibited less central zone activity as compared to animals treated with diazepam, with no changes in the total locomotor activity. In elevated plus maze, rats subjected to neonatal seizure and treated with diazepam exhibited higher locomotor activity and spent more time on the open arms as compared to untreated animals. In approach phase of sociability paradigm, animals subjected to neonatal seizures similarly to controls, regardless the treatment, spent more time with social stimulus as compared to non social stimulus. In social novelty phase of sociability paradigm, animals subjected to neonatal seizures differently of controls, regardless the treatment, spent similar time with familiar and novel stimulus. PMID:27054178

  1. Distribution Dynamics of Recombinant Lactobacillus in the Gastrointestinal Tract of Neonatal Rats

    PubMed Central

    Bao, Sujin; Zhu, Libin; Zhuang, Qiang; Wang, Lucia; Xu, Pin-Xian; Itoh, Keiji; Holzman, Ian R.; Lin, Jing

    2013-01-01

    One approach to deliver therapeutic agents, especially proteins, to the gastro-intestinal (GI) tract is to use commensal bacteria as a carrier. Genus Lactobacillus is an attractive candidate for use in this approach. However, a system for expressing exogenous proteins at a high level has been lacking in Lactobacillus. Moreover, it will be necessary to introduce the recombinant Lactobacillus into the GI tract, ideally by oral administration. Whether orally administered Lactobacillus can reach and reside in the GI tract has not been explored in neonates. In this study, we have examined these issues in neonatal rats. To achieve a high level of protein expression in Lactobacillus, we tested the impact of three promoters and two backbones on protein expression levels using mRFP1, a red fluorescent protein, as a reporter. We found that a combination of an L-lactate dehydrogenase (ldhL) promoter of Lactobacillus sakei with a backbone from pLEM415 yielded the highest level of reporter expression. When this construct was used to transform Lactobacillus casei, Lactobacillus delbrueckii and Lactobacillus acidophilus, high levels of mRFP1 were detected in all these species and colonies of transformed Lactobacillus appeared pink under visible light. To test whether orally administered Lactobacillus can be retained in the GI tract of neonates, we fed the recombinant Lactobacillus casei to neonatal rats. We found that about 3% of the bacteria were retained in the GI tract of the rats at 24 h after oral feeding with more recombinant Lactobacillus in the stomach and small intestine than in the cecum and colon. No mortality was observed throughout this study with Lactobacillus. In contrast, all neonatal rats died within 24 hours after fed with transformed E. coli. Taken together, our results indicate that Lactobacillus has the potential to be used as a vehicle for the delivery of therapeutic agents to neonates. PMID:23544119

  2. Neonatal endotoxin exposure changes neuroendocrine, cardiovascular function and mortality during polymicrobial sepsis in adult rats.

    PubMed

    Saia, Rafael Simone; Oliveira-Pelegrin, Gabriela Ravanelli; da Silva, Maria Emília Nadaletto Bonifácio; Aguila, Fábio Alves; Antunes-Rodrigues, José; Rocha, Maria José Alves; Cárnio, Evelin Capellari

    2011-08-08

    Our aim was to investigate whether neonatal LPS challenge may improve hormonal, cardiovascular response and mortality, this being a beneficial adaptation when adult rats are submitted to polymicrobial sepsis by cecal ligation and puncture (CLP). Fourteen days after birth, pups received an intraperitoneal injection of lipopolysaccharide (LPS; 100μg/kg) or saline. After 8-12 weeks, they were submitted to CLP, decapitated 4, 6 or 24h after surgery and blood was collected for vasopressin (AVP), corticosterone and nitrate measurement, while AVP contents were measured in neurohypophysis, supra-optic (SON) and paraventricular (PVN) nuclei. Moreover, rats had their mean arterial pressure (MAP) and heart rate (HR) evaluated, and mortality and bacteremia were determined at 24h. Septic animals with neonatal LPS exposure had higher plasma AVP and corticosterone levels, and higher c-Fos expression in SON and PVN at 24h after surgery when compared to saline treated rats. The LPS pretreated group showed increased AVP content in SON and PVN at 6h, while we did not observe any change in neurohypophyseal AVP content. The nitrate levels were significantly reduced in plasma at 6 and 24h after surgery, and in both hypothalamic nuclei only at 6h. Septic animals with neonatal LPS exposure showed increase in MAP during the initial phase of sepsis, but HR was not different from the neonatal saline group. Furthermore, neonatally LPS exposed rats showed a significant decrease in mortality rate as well as in bacteremia. These data suggest that neonatal LPS challenge is able to promote beneficial effects on neuroendocrine and cardiovascular responses to polymicrobial sepsis in adulthood. Copyright © 2011 Elsevier B.V. All rights reserved.

  3. A chloride current component induced by hypertrophy in rat ventricular myocytes.

    PubMed

    Bénitah, J P; Gómez, A M; Delgado, C; Lorente, P; Lederer, W J

    1997-05-01

    The effect of hypertrophy on membrane currents of rat left ventricular myocytes was studied with the whole cell voltage-clamp method. We found that the slope of the total time-independent current density-voltage relationship was increased in hypertrophied cells. No change in the zero-current potential was observed. Surprisingly, the dominant time-independent current, the inward rectifier K+ current (measured as the Ba(2+)-sensitive current density) was unchanged. We therefore investigated the identity of the outwardly rectifying Ba(2+)-resistant current seen in the hypertrophied rat ventricular myocytes but not present in control cells. We found that this current 1) was not carried by monovalent cations, 2) was partially blocked by anthracene-9-carboxylic acid (9-AC), and 3) was sensitive to variations in extracellular Cl concentration. These findings are consistent with the current being carried at least partially by Cl-. The presence of an additional Cl(-)-dependent component in hypertrophied cells is supported by the actions of 9-AC on the measured action potentials (APs). 9-AC had no effect on control cells APs but prolonged hypertrophied cell APs. We conclude that a Cl- current component develops in hypertrophied rat heart cells. This component appears to shorten the AP duration and might thus provide protection from cardiac arrhythmias.

  4. ET-receptor antagonism, myocardial gene expression, and ventricular remodeling during CHF in rats.

    PubMed

    Oie, E; Bjønerheim, R; Grogaard, H K; Kongshaug, H; Smiseth, O A; Attramadal, H

    1998-09-01

    Both myocardial and plasma endothelin-1 (ET-1) are elevated in congestive heart failure (CHF). However, the role played by endogenous ET-1 in the progression of CHF remains unknown. The aim of the present study was to investigate and correlate myocardial gene expression programs and left ventricular (LV) remodeling during chronic ET-receptor antagonism in CHF rats. After ligation of the left coronary artery, rats were randomized to oral treatment with a nonselective ET-receptor antagonist (bosentan, 100 mg . kg-1 . day-1, n = 11) or vehicle (saline, n = 13) for 15 days, starting 24 h after induction of myocardial infarction. Bosentan substantially attenuated LV dilatation during postinfarction failure as evaluated by echocardiography. Furthermore, bosentan decreased LV systolic and end-diastolic pressures and increased fractional shortening. Myocardial expression of preproET-1 mRNA and a fetal gene program characteristic of myocardial hypertrophy were increased in the CHF rats and were not affected by bosentan. Consistently, right ventricular-to-body weight ratios, diameters of cardiomyocytes, and echocardiographic analysis demonstrated a sustained hypertrophic response and a normalized relative wall thickness after intervention with bosentan. Thus the modest reduction of preload and afterload provided by bosentan substantially attenuates LV dilatation, causing improved pressure-volume relationships. However, the compensatory hypertrophic response was not altered by ET-receptor antagonism. Therefore, ET-1 does not appear to play a crucial role in the mechanisms of myocardial hypertrophy during the early phase of postinfarction failure.

  5. Effect of resveratrol on L-type calcium current in rat ventricular myocytes.

    PubMed

    Zhang, Li-ping; Yin, Jing-xiang; Liu, Zheng; Zhang, Yi; Wang, Qing-shan; Zhao, Juan

    2006-02-01

    To study the effect of resveratrol on L-type calcium current (I(Ca-L)) in isolated rat ventricular myocytes and the mechanisms underlying these effects. I(Ca-L) was examined in isolated single rat ventricular myocytes by using the whole cell patch-clamp recording technique. Resveratrol (10-40 micromol/L) reduced the peak amplitude of I(Ca-L) and shifted the current-voltage (I-V) curve upwards in a concentration-dependent manner. Resveratrol (10, 20, 40 micromol/L) decreased the peak amplitude of I(Ca-L) from -14.2+/-1.5 pA/pF to -10.5+/-1.5 pA/pF (P<0.05), -7.5+/-2.4 pA/pF (P<0.01), and -5.2+/-1.2 pA/pF (P<0.01), respectively. Resveratrol (40 micromol/L) shifted the steady-state activation curve of I(Ca-L) to the right and changed the half-activation potential (V0.5) from -19.4+/-0.4 mV to -15.4+/-1.9 mV (P<0.05). Resveratrol at a concentration of 40 micromol/L did not affect the steady-state inactivation curve of I(Ca-L), but did markedly shift the time-dependent recovery curve of I(Ca-L) to the right, and slow down the recovery of I(Ca-L) from inactivation. Sodium orthovanadate (Na(3)VO(4); 1 mmol/L), a potent inhibitor of tyrosine phosphatase, significantly inhibited the effects of resveratrol (P<0.01). Resveratrol inhibited I(Ca-L) mainly by inhibiting the activation of L-type calcium channels and slowing down the recovery of L-type calcium channels from inactivation. This inhibitory effect of resveratrol was mediated by the inhibition of protein tyrosine kinase in rat ventricular myocytes.

  6. Comparison of sarcolemmal calcium channel current in rabbit and rat ventricular myocytes.

    PubMed Central

    Yuan, W; Ginsburg, K S; Bers, D M

    1996-01-01

    1. Fundamental properties of Ca2+ channel currents in rat and rabbit ventricular myocytes were measured using whole cell voltage clamp. 2. In rat, as compared with rabbit myocytes, Ca2+ channel current (ICa) was half-activated at about 10 mV more negative potential, decayed slower, was half-inactivated (in steady state) at about 5 mV more positive potential, and recovered faster from inactivation. 3. These features result in a larger steady-state window current in rat, and also suggest that under comparable voltage clamp conditions, including action potential (AP) clamp, more Ca2+ influx would be expected in rat myocytes. 4. Ca2+ channel current carried by Na+ and Cs+ in the absence of divalent ions (Ins) also activated at more negative potential and decayed more slowly in rat. 5. The reversal potential for Ins was 6 mV more positive in rabbit, consistent with a larger permeability ratio (PNa/PCs) in rabbit than in rat. ICa also reversed at slightly more positive potentials in rabbit (such that PCa/PCs might also be higher). 6. Ca2+ influx was calculated by integration of ICa evoked by voltage clamp pulses (either square pulses or pulses based on recorded rabbit or rat APs). For a given clamp waveform, the Ca2+ influx was up to 25% greater in rat, as predicted from the fundamental properties of ICa and Ins. 7. However, the longer duration of the AP in rabbit myocytes compensated for the difference in influx, such that the integrated Ca2+ influx via ICa in response to the species-appropriate waveform was about twice as large as that seen in rat. PMID:8799895

  7. Pharmacokinetics of bisphenol A in neonatal and adult Sprague-Dawley rats

    SciTech Connect

    Doerge, Daniel R.; Twaddle, Nathan C.; Vanlandingham, Michelle; Fisher, Jeffrey W.

    2010-09-01

    Bisphenol A (BPA) is an important industrial chemical used in the manufacture of polycarbonate plastic products and epoxy resin-based food can liners. The presence of BPA in urine of > 90% of Americans aged 6-60 suggests ubiquitous and frequent exposure. The current study used LC/MS/MS to measure serum pharmacokinetics of aglycone (active) and conjugated (inactive) BPA in adult and neonatal Sprague-Dawley rats by oral and injection routes. Deuterated BPA was used to avoid issues of background contamination. Linear pharmacokinetics were observed in adult rats treated orally in the range of 0-200 {mu}g/kg bw. Evidence for enterohepatic recirculation of conjugated, but not aglycone, BPA was observed in adult rats. Significant inverse relationships were observed between postnatal age and measures of internal exposures to aglycone BPA and its elimination. In neonatal rats treated orally, internal exposures to aglycone BPA were substantially lower than from subcutaneous injection. The results reinforce the critical role for first-pass Phase II metabolism of BPA in gut and liver after oral exposure that attenuates internal exposure to the aglycone form in rats of all ages. The internal exposures to aglycone BPA observed in adult and neonatal rats following a single oral dose of 100 {mu}g/kg bw are inconsistent with effects mediated by classical estrogen receptors based on binding affinities. However, an impact on alternative estrogen signaling pathways that have higher receptor affinity cannot be excluded in neonatal rats. These findings emphasize the importance of matching aglycone BPA internal dosimetry with receptor affinities in experimental animal studies reporting toxicity.

  8. Learning and cognitive deficits in hypoxic neonatal rats intensified by BAX mediated apoptosis: protective role of glucose, oxygen, and epinephrine.

    PubMed

    Raveendran, Anju Thoppil; Skaria, Paulose Cheramadatikudiyil

    2013-02-01

    Hypoxic brain injury during neonatal development can lead to neuronal damage and produce learning and cognitive impairments. TOPRO-3 staining was used to visualize cell loss and real-time polymerase chain reaction (PCR) analysis of BAX mRNA was used to evaluate the level of apoptosis in the cerebral cortex, cerebellum, brain stem, and striatum of hypoxic neonatal rats and hypoxic rats resuscitated with glucose, oxygen, and epinephrine. The long-term effects of neonatal hypoxic insult on cognition and behavior were studied using Morris water maze experiment on 1-month-old rats exposed to neonatal hypoxia. In hypoxic neonatal rats, a significant cell loss (p < .001) within the brain regions was observed in TOPRO-3 staining and BAX mRNA expression was significantly upregulated (p < .001). Immediate resuscitation of hypoxic neonates with glucose, alone and along with oxygen, significantly downregulated (p < .001) BAX mRNA expression. The BAX expression in epinephrine resuscitated and 100% oxygen resuscitated groups were found to be upregulated in the brain regions. In water maze experiment, 1-month-old rats exposed to neonatal hypoxia spent lesser time in the platform quadrant (p < .001) and showed longer escape latency (p < .001) highlighting the learning and cognitive deficits. Our study revealed the effect of glucose resuscitation alone and along with oxygenation in ameliorating the spatial memory and learning deficits induced by neonatal hypoxic insult mediated brain cell loss.

  9. Paraplegia increased cardiac NGF content, sympathetic tonus, and the susceptibility to ischemia-induced ventricular tachycardia in conscious rats

    PubMed Central

    Lujan, Heidi L.; Chen, Ying; DiCarlo, Stephen E.

    2009-01-01

    Midthoracic spinal cord injury is associated with ventricular arrhythmias that are mediated, in part, by enhanced cardiac sympathetic activity. Furthermore, it is well known that sympathetic neurons have a lifelong requirement for nerve growth factor (NGF). NGF is a neurotrophin that supports the survival and differentiation of sympathetic neurons and enhances target innervation. Therefore, we tested the hypothesis that paraplegia is associated with an increased cardiac NGF content, sympathetic tonus, and susceptibility to ischemia-induced ventricular tachyarrhythmias. Intact and paraplegic (6–9 wk posttransection, T5 spinal cord transection) rats were instrumented with a radiotelemetry device for recording arterial pressure, temperature, and ECG, and a snare was placed around the left main coronary artery. Following recovery, the susceptibility to ventricular arrhythmias (coronary artery occlusion) was determined in intact and paraplegic rats. In additional groups of matched intact and paraplegic rats, cardiac nerve growth factor content (ELISA) and cardiac sympathetic tonus were determined. Paraplegia, compared with intact, increased cardiac nerve growth factor content (2,146 ± 286 vs. 180 ± 36 pg/ml, P < 0.05) and cardiac sympathetic tonus (154 ± 4 vs. 68 ± 4 beats/min, P < 0.05) and decreased the ventricular arrhythmia threshold (3.6 ± 0.2 vs. 4.9 ± 0.2 min, P < 0.05). Thus altered autonomic behavior increases the susceptibility to ventricular arrhythmias in paraplegic rats. PMID:19286942

  10. Pulmonary vascular responsiveness in rats following neonatal exposure to high altitude or carbon monoxide

    SciTech Connect

    Tucker, A.; Penney, D.G. Wayne State Univ., Detroit, MI )

    1993-01-01

    Exposure of adult and neonatal rats to high altitude increases pulmonary vascular responsiveness during the exposure. A study was undertaken to determine if a short exposure of neonatal rats to either high-altitude or carbon monoxide (CO) hypoxia would cause persistent alterations in pulmonary vascular responsiveness postexposure. One-day-old male Sprague-Dawley rats were obtained as 16 litters of 10-12 pups each. At 2 days of age, 4 litters were exposed to CO (500 ppm) for 32 days, and 4 litters were exposed to ambient air (AIR) in Detroit (200 m). Another 4 litters were exposed to 3500 m altitude (ALT) in a chamber for 32 days, and 3 litters were exposed to ambient conditions in Fort Collins (CON, 1524 m). After the exposures, all rats were maintained at 1524 m. At 2, 40, 76 and 112 days postexposure, lungs were isolated and perfused with Earle's salt solution (+Ficoll, 4 g%). Pulmonary vascular responsiveness was assessed by dose responses to angiotensin II (AII, 0.025-0.40 [mu]g) and acute hypoxia (3% O[sub 2] for 3 min). AII responses were higher in ALT vs CON rats at 2 and 40 days postexposure, but no differences were noted between CO and AIR rats. Baseline pulmonary vascular resistance and pulmonary arterial pressure (in isolated lungs) were higher in ALT rats at all four ages compared to the other three groups. Both the ALT and CO rats displayed hypertrophy of the right ventricle (RV) and the left ventricle (LV) at the termination of treatment and elevated hematocrit. LV hypertrophy and polycythemia regressed with time, but RV hypertrophy remained significant in the ALT rats through 112 days postexposure. The results indicate that neonatal exposure to ALT, but no CO, causes a persistent increase in pulmonary vascular responsiveness and RV hypertrophy for at least 112 days after termination of the exposure. 40 refs., 3 figs., 2 tabs.

  11. Problem solving following neonatal exposure to cocaine, ethanol, or cocaine/ethanol in combination in rats.

    PubMed

    Barron, S; Hansen-Trench, L; Kaiser, D H; Segar, T M

    1996-01-01

    This study examined the effects of neonatal drug exposure on performance in a digging maze. Subjects were Sprague-Dawley rats, artificially reared (AR) and fed through a gastrostomy tube from postnatal days (PND) 4-10. The AR groups included a cocaine group (20 mg/kg/day cocaine hydrochloride), an ethanol group (4 g/kg/day ethanol), a cocaine/ethanol group (20 mg/kg/day cocaine and 4 g/kg/day ethanol), and an AR control group. A suckled control raised by its dam was also included. At approximately PND 55, subjects were tested in a digging maze paradigm. The digging maze required subjects to use a species typical behavior (digging) to solve a novel problem (gaining access to water). While neonatal treatment had no effect on acquisition of a simple runway task for water reward, neonatal exposure to cocaine and ethanol in combination resulted in impaired performance on the digging maze task. None of the other neonatal treatment groups showed impairments on this task. These findings suggest that exposure to these doses of cocaine and ethanol during neonatal development may have more serious effects on problem solving tasks in rats than exposure to either drug alone.

  12. Neonatal isolation alters LTP in freely moving juvenile rats: sex differences.

    PubMed

    Bronzino, J D; Kehoe, P; Austin-LaFrance, R J; Rushmore, R J; Kurdian, J

    1996-01-01

    We have previously reported that neonatal isolation significantly enhanced the magnitude of hippocampal long-term potentiation (LTP) recorded from freely moving male rats tested at 30 days of age. The present study extends this work to examine the effects of neonatal isolation on hippocampal LTP in male and female juvenile rats. Changes in dentate granule cell population measures, i.e., EPSP slope and population spike amplitude (PSA), evoked by tetanization of the medial perforant pathway were used to assess the effects of neonatal isolation on LTP over a period of 96 hrs. Prior to tetanization, significant sex differences were obtained for input/output (I/O) response measures of EPSP slope and PSA, with males showing consistently higher values than females. No significant effect of treatment was obtained within either sex for baseline measures. Following tetanization significant sex differences were also obtained for both measures, with males showing significantly greater enhancement than females. Comparisons made at 1 hr post-tetanization (establishment of LTP) indicated that isolated males showed significantly greater enhancement than any other group. On the other hand, treatment differences were not obtained from females. At 96 hrs (maintenance of LTP), however, both neonatally isolated males and females showed significantly greater enhancement than either non-isolated siblings or unhandled controls. These results indicate that males and females exhibit different enhancement profiles with respect to both the magnitude and duration of LTP, and that neonatal isolation alters these profiles in a sex-specific manner.

  13. The Electrophysiological Effects of Qiliqiangxin on Cardiac Ventricular Myocytes of Rats

    PubMed Central

    Wei, Yidong; Liu, Xiaoyu; Wei, Haidong; Hou, Lei; Che, Wenliang; The, Erlinda; Li, Gang; Jhummon, Muktanand Vikash; Wei, Wanlin

    2013-01-01

    Qiliqiangxin, a Chinese herb, represents the affection in Ca channel function of cardiac myocytes. It is unknown whether Qiliqiangxin has an effect on Na current and K current because the pharmacological actions of this herb's compound are very complex. We investigated the rational usage of Qiliqiangxin on cardiac ventricular myocytes of rats. Ventricular myocytes were exposed acutely to 1, 10, and 50 mg/L Qiliqiangxin, and whole cell patch-clamp technique was used to study the acute effects of Qiliqiangxin on Sodium current (I Na), outward currents delayed rectifier outward K+ current (I K), slowly activating delayed rectifier outward K+ current (I Ks), transient outward K+ current (I to), and inward rectifier K+ current (I K1). Qiliqiangxin can decrease I Na by 28.53% ± 5.98%, and its IC50 was 9.2 mg/L. 10 and 50 mg/L Qiliqiangxin decreased by 37.2% ± 6.4% and 55.9% ± 5.5% summit current density of I to. 10 and 50 mg/L Qiliqiangxin decreased I Ks by 15.51% ± 4.03% and 21.6% ± 5.6%. Qiliqiangxin represented a multifaceted pharmacological profile. The effects of Qiliqiangxin on Na and K currents of ventricular myocytes were more profitable in antiarrhythmic therapy in the clinic. We concluded that the relative efficacy of Qiliqiangxin was another choice for the existing antiarrhythmic therapy. PMID:24250713

  14. Chronic nonocclusive coronary artery constriction in rats. Beta-adrenoceptor signal transduction and ventricular failure.

    PubMed Central

    Meggs, L G; Huang, H; Li, P; Capasso, J M; Anversa, P

    1991-01-01

    To determine the effects of chronic coronary artery constriction on the relationship between cardiac function and regulation of beta-adrenoceptor signal transduction, the left main coronary artery was narrowed in rats and the animals were killed 5 mo later. An average reduction in coronary luminal diameter of 44% was obtained and this change resulted in an increase in left ventricular end-diastolic pressure and a decrease in positive and negative dP/dt. Significant increases in left and right ventricular weights indicative of global cardiac hypertrophy were observed. Radioligand binding studies of beta-adrenoreceptors, agonist-stimulated adenylate cyclase activity, and ADP ribosylation of 45-kD substrate by cholera toxin were all depressed in the failing left ventricle. In contrast, in the hypertrophic non-failing right ventricle, beta-adrenoreceptor density was preserved and receptor antagonist affinity was increased. In spite of these findings at the receptor level, agonist stimulated cyclic AMP generation was reduced in the right ventricular myocardium. The quantity of the 45-kD substrate was also decreased. In conclusion, longterm nonocclusive coronary artery stenosis of moderate degree has profound detrimental effects on the contractile performance of the heart in association with marked attenuation of adrenergic support mechanisms. Images PMID:1661293

  15. Atelectasis causes vascular leak and lethal right ventricular failure in uninjured rat lungs.

    PubMed

    Duggan, Michelle; McCaul, Conán L; McNamara, Patrick J; Engelberts, Doreen; Ackerley, Cameron; Kavanagh, Brian P

    2003-06-15

    During mechanical ventilation, lung recruitment attenuates injury caused by high VT, improves oxygenation, and may optimize pulmonary vascular resistance (PVR). We hypothesized that ventilation without recruitment would induce injury in otherwise healthy lungs. Anesthetized rats were ventilated with conventional mechanical ventilation (VT 8 ml/kg; respiratory frequency 40 per minute) and 21% inspired oxygen, with or without a recruitment strategy consisting of recruitment maneuvers plus positive end-expiratory pressure, in the presence or absence of a laparotomy. Additional experiments examined the impact of atelectasis on right ventricular function using echocardiography, as well as functional residual capacity and PVR. Lack of recruitment resulted in reduced overall survival (59% nonrecruited vs. 100% recruited, p < 0.05), increased microvascular leak, greater impairment of oxygenation and lung compliance, increased PVR, and elevated plasma lactate. Echocardiography demonstrated that right ventricular dysfunction occurred in the absence of recruitment. Finally, samples from nonrecruited lungs demonstrated ultrastructural evidence of microvascular endothelial disruption. Although such effects clearly do not occur with comparable magnitude in the clinical context, the current data suggest novel mechanisms (microvascular leak, right ventricular dysfunction) whereby derecruitment may contribute to development of lung injury and adverse systemic outcome.

  16. [Effects of nicorandil on spontaneous beating and action potentials of cultured myocardial cells of neonatal rats].

    PubMed

    Wang, H X; Wang, W X

    1995-09-01

    To study the anti-arrhythmic mechanism of nicorandil (Nic). The myocardial cells of neonatal rats were cultured and effects of Nic on spontaneous beating and action potential of cultured myocardial cells were observed. Nic 32 mumol L-1 and 160 mumol L-1 decreased the spontaneous beating rates of cultured myocardial cells of neonatal rats. Nic 64 mumol L-1 prevented the beating rats induced by CaCl2 1 mmol L-1 and isoproterenol 2 mumol L-1. Nic 32 and 160 mumol L-1 reduced the amplitude, maximal rate of rise, and shortened APD50 and APD90 repolarization. Nic prolonged the spontaneous sinus cycle length. The antiarrhythmic mechanism of Nic is related to its direct effects on the myocardial cells.

  17. Neonatal exposure to phenobarbital potentiates schizophrenia-like behavioral outcomes in the rat.

    PubMed

    Bhardwaj, S K; Forcelli, P A; Palchik, G; Gale, K; Srivastava, L K; Kondratyev, A

    2012-06-01

    Previous work has indicated an association between seizures early in life and increased risk of psychiatric disorders, including schizophrenia. However, because early-life seizures are commonly treated with antiepileptic drugs (AEDs) such as phenobarbital, the possibility that drug treatment may affect later-life psychiatric outcomes needs to be evaluated. We therefore tested the hypothesis that phenobarbital exposure in the neonatal rat increases the risk of schizophrenia-like behavioral abnormalities in adulthood. Thus, in this study, we examined the effects of a single acute neonatal exposure to phenobarbital on adult behavioral outcomes in the rat neonatal ventral hippocampal (nVH) lesion model of schizophrenia. We compared these outcomes to those in rats a) without nVH lesions and b) with nVH lesions, without phenobarbital. The tasks used for behavioral evaluation were: amphetamine-induced locomotion, prepulse inhibition, elevated plus-maze, and novel object recognition task. We found that neonatal phenobarbital treatment (in the absence of nVH lesions) was sufficient to disrupt sensorimotor gating (as tested by prepulse inhibition) in adulthood to an extent equivalent to nVH lesions. Additionally, neonatal phenobarbital exposure enhanced the locomotor response to amphetamine in adult animals with and without nVH lesions. Our findings suggest that neonatal exposure to phenobarbital can predispose to schizophrenia-like behavioral abnormalities. Our findings underscore the importance of examining AED exposure early in life as a potential risk factor for later-life neuropsychiatric abnormalities in clinical populations. Copyright © 2012 Elsevier Ltd. All rights reserved.

  18. Long-acting calcium channel antagonist pranidipine prevents ventricular remodeling after myocardial infarction in rats.

    PubMed

    Takeuchi, K; Omura, T; Yoshiyama, M; Yoshida, K; Otsuka, R; Shimada, Y; Ujino, K; Yoshikawa, J

    1999-01-01

    The purpose of this study was to examine the effects of the long-acting calcium channel antagonist pranidipine on ventricular remodeling, systolic and diastolic cardiac function, circulating humoral factors, and cardiac mRNA expression in myocardial infarcted rats. Myocardial infarction (MI) was produced by ligation of the coronary artery in Wistar rats. Three mg/kg per day of pranidipine was randomly administered to the infarcted rats. Hemodynamic measurements, Doppler echocardiographic examinations, analyses of the plasma levels of humoral factors, and myocardial mRNA expression were performed at 4 weeks after myocardial infarction. Left ventricular end-diastolic pressure (LVEDP) and central venous pressure (CVP) increased to 24.2 +/- 1.2mmHg and 5.4 +/- 0.6 mmHg. Pranidipine reduced LVEDP and CVP to 13.6 +/- 1.4mmHg (P < 0.01) and 2.5 +/- 0.4mmHg (P < 0.01). The weight of the left and right ventricles in MI was significantly higher than in the sham-operated rats (sham, 2.02 +/- 0.04 and 0.47 +/- 0.02g/kg; MI, 2.18 +/- 0.05 and 0.79 +/- 0.04g/ kg; P < 0.01). Left ventricular end-diastolic dimension (LVDd) in MI increased to 10.3 +/- 0.3mm (P < 0.01) (sham, 6.4 +/- 0.3mm). Pranidipine prevented an increase in the weight of the left and right ventricles (2.02 +/- 0.04 and 0.6 +/- 0.03g/kg, P < 0.01) and LVDd (7.9 +/-0.2mm, P < 0.01 to MI). Plasma renin activity (PRA), and plasma epinephrine, norepinephrine, and dopamine concentrations in MI were higher than those of the sham-operated rats. Pranidipine decreased the PRA and plasma cathecolamine levels of the myocardial infarcted rats to the level of the sham-operated rats. Moreover, the rats in MI showed systolic dysfunction, shown by decreased fractional shortening (sham, 31 +/- 2% vs MI, 15 +/- 1%; P < 0.01) and diastolic dysfunction shown by the E-wave deceleration rate (sham, 12.8 +/- 1.1 m/s2; MI, 32.6 +/- 2.1 m/s2; P < 0.01). Pranidipine significantly prevented systolic and diastolic dysfunction. The increases

  19. Current-Voltage Relationship for Late Na(+) Current in Adult Rat Ventricular Myocytes.

    PubMed

    Clark, R B; Giles, W R

    2016-01-01

    It is now well established that the slowly inactivating component of the Na(+) current (INa-L) in the mammalian heart is a significant regulator of the action potential waveform. This insight has led to detailed studies of the role of INa-L in a number of important and challenging pathophysiological settings. These include genetically based ventricular arrhythmias (LQT 1, 2, and 3), ventricular arrhythmias arising from progressive cardiomyopathies (including diabetic), and proarrhythmic abnormalities that develop during local or global ventricular ischemia. Inhibition of INa-L may also be a useful strategy for management of atrial flutter and fibrillation. Many important biophysical parameters that characterize INa-L have been identified; and INa-L as an antiarrhythmia drug target has been studied extensively. However, relatively little information is available regarding (1) the ion transfer or current-voltage relationship for INa-L or (2) the time course of its reactivation at membrane potentials similar to the resting or diastolic membrane potential in mammalian ventricle. This chapter is based on our preliminary findings concerning these two very important physiological/biophysical descriptors for INa-L. Our results were obtained using whole-cell voltage clamp methods applied to enzymatically isolated rat ventricular myocytes. A chemical agent, BDF 9148, which was once considered to be a drug candidate in the Na(+)-dependent inotropic agent category has been used to markedly enhance INa-L current. BDF acts in a potent, selective, and reversible fashion. These BDF 9148 effects are compared and contrasted with the prototypical activator of INa-L, a sea anemone toxin, ATX II.

  20. Therapeutic Effect of Agaricus brasiliensis on Phenylhydrazine-Induced Neonatal Jaundice in Rats

    PubMed Central

    Zhang, Lan; Yuan, Bo; Wang, HuiPing; Gao, Ya

    2015-01-01

    The present study was designed to investigate the effect of Agaricus brasiliensis extract (ABE) on phenylhydrazine-induced neonatal jaundice in rats. Administration of ABE dose-dependently reduced the elevated bilirubin level induced by phenylhydrazine. It can be somewhat supported from the results of in vitro bilirubin degradation experiment. ABE treatment also reduced the total antioxidant status (TAOS), cascade O2−/SOD, level of NF-κB protein, and adrenomedullin (AM). Overall, the results of this study demonstrated that Agaricus brasiliensis extract may be beneficial to reducing bilirubin level without causing hepatotoxicity in neonatal jaundice. PMID:25883968

  1. Salubrinal attenuates right ventricular hypertrophy and dysfunction in hypoxic pulmonary hypertension of rats.

    PubMed

    He, Yun-Yun; Liu, Chun-Lei; Li, Xin; Li, Rui-Jun; Wang, Li-Li; He, Kun-Lun

    2016-12-01

    The phosphorylation of eukaryotic translation initiation factor 2 alpha (p-eIF2α) is essential for cell survival during hypoxia. The aim of this study was to investigate whether salubrinal, an inhibitor of p-eIF2α dephosphorylation could attenuate pulmonary arterial hypertension (PAH) and right ventricular (RV) hypertrophy in rats exposed to hypobaric hypoxia. PAH of rats was induced by hypobaric hypoxia. Salubrinal supplemented was randomized in either a prevention or a reversal protocol. At the end of the follow-up point, we measured echocardiography, hemodynamics, hematoxylin-eosin and Masson's trichrome stainings. RNA-seq analysis is explored to identify changes in gene expression associated with hypobaric hypoxia with or without salubrinal. Compared with vehicle-treatment rats exposed to hypobaric hypoxia, salubrinal prevented and partly reversed the increase of the mean pulmonary artery pressure and RV hypertrophy. What's more, salubrinal reduced the percentage wall thickness (WT%) of pulmonary artery and RV collagen volume fraction (CVF) in both prevention and reversal protocols. We also found that salubrinal was capable of reducing endoplasmic reticulum stress and oxidative stress. The result of RNA-seq analysis revealed that chronic hypoxia stimulated the differential expression of a series of genes involved in cell cycle regulation and ventricular hypertrophy and so on. Some of these genes could be ameliorated by salubrinal. These results indicate that salubrinal could prevent and reverse well-established RV remodeling, and restore the genes and pathways altered in the right ventricles of rats exposed to hypobaric hypoxia. Copyright © 2016. Published by Elsevier Inc.

  2. Neonatal Bladder Inflammation Produces Functional Changes and Alters Neuropeptide Content in Bladders of Adult Female Rats

    PubMed Central

    DeBerry, Jennifer; Randich, Alan; Shaffer, Amber D.; Robbins, Meredith T.; Ness, Timothy J.

    2009-01-01

    Neonatal bladder inflammation has been demonstrated to produce hypersensitivity to bladder re-inflammation as an adult. The purpose of this study was to investigate the effects of neonatal urinary bladder inflammation on adult bladder function and structure. Female Sprague-Dawley rats were treated on postnatal days 14-16 with intravesical zymosan or anesthesia alone. At 12-16 weeks of age, micturition frequency and cystometrograms were measured. Similarly treated rats had their bladders removed for measurement of plasma extravasation following intravesical mustard oil, for neuropeptide analysis (CGRP or SubP), or for detailed histological examination. Rats treated with zymosan as neonates exhibited increased micturition frequency, reduced micturition volume thresholds, greater extravasation of Evan's Blue following intravesical mustard oil administration, and greater total bladder content of CGRP and SubP. In contrast, there were no quantitative histological changes in the thickness, fibrosis or mast cells of bladder tissue due to neonatal zymosan treatments. Functional changes in urologic systems observed in adulthood, coupled with the increased neuropeptide content and neurogenic plasma extravasation in adult bladders, suggest that the neonatal bladder inflammation treatment enhanced the number, function and/or neurochemical content of primary afferent neurons. These data support the hypothesis that insults to the urologic system in infancy may contribute to the development of adult bladder hypersensitivity. Perspective Inflammation of the bladder early in life in the rat has multiple sequelae including laboratory measures that suggest an alteration of the neurophysiological substrates related to the bladder. Some painful bladder syndromes in humans have similar characteristics and so may be due to similar mechanisms. PMID:19945355

  3. Neuron-astrocyte interactions, pyruvate carboxylation and the pentose phosphate pathway in the neonatal rat brain.

    PubMed

    Morken, Tora Sund; Brekke, Eva; Håberg, Asta; Widerøe, Marius; Brubakk, Ann-Mari; Sonnewald, Ursula

    2014-01-01

    Glucose and acetate metabolism and the synthesis of amino acid neurotransmitters, anaplerosis, glutamate-glutamine cycling and the pentose phosphate pathway (PPP) have been extensively investigated in the adult, but not the neonatal rat brain. To do this, 7 day postnatal (P7) rats were injected with [1-(13)C]glucose and [1,2-(13)C]acetate and sacrificed 5, 10, 15, 30 and 45 min later. Adult rats were injected and sacrificed after 15 min. To analyse pyruvate carboxylation and PPP activity during development, P7 rats received [1,2-(13)C]glucose and were sacrificed 30 min later. Brain extracts were analysed using (1)H- and (13)C-NMR spectroscopy. Numerous differences in metabolism were found between the neonatal and adult brain. The neonatal brain contained lower levels of glutamate, aspartate and N-acetylaspartate but similar levels of GABA and glutamine per mg tissue. Metabolism of [1-(13)C]glucose at the acetyl CoA stage was reduced much more than that of [1,2-(13)C]acetate. The transfer of glutamate from neurons to astrocytes was much lower while transfer of glutamine from astrocytes to glutamatergic neurons was relatively higher. However, transport of glutamine from astrocytes to GABAergic neurons was lower. Using [1,2-(13)C]glucose it could be shown that despite much lower pyruvate carboxylation, relatively more pyruvate from glycolysis was directed towards anaplerosis than pyruvate dehydrogenation in astrocytes. Moreover, the ratio of PPP/glucose-metabolism was higher. These findings indicate that only the part of the glutamate-glutamine cycle that transfers glutamine from astrocytes to neurons is operating in the neonatal brain and that compared to adults, relatively more glucose is prioritised to PPP and pyruvate carboxylation. Our results may have implications for the capacity to protect the neonatal brain against excitotoxicity and oxidative stress.

  4. Intracellular calibration of the fluorescent Mg2+ indicator furaptra in rat ventricular myocytes.

    PubMed

    Watanabe, M; Konishi, M

    2001-04-01

    Single ventricular myocytes enzymatically isolated from rat hearts were loaded with the Mg2+ indicator furaptra, and the relationship between the fluorescence ratio signal (R) and the intracellular free concentration of Mg2+ ([Mg2+]i) was studied in situ at 25 degrees C. After the application of ionophores (ionomycin, monensin, nigericin and valinomycin), an immediate change in furaptra R was noted, followed by a slow change in R that reached a steady level in 2-4 h. The direction of the early change in R that accompanied rigor contraction was independent of the extracellular Mg2+ concentration ([Mg2+]o), and was consistent with the breakdown of ATP and release of bound Mg2+. The intracellular calibration curve was constructed from the steady levels of R obtained at various [Mg2+]o between 0 and 47 mM. The dissociation constant of intracellular furaptra was estimated to be 5.3 mM, which was 44% higher than that determined in salt solutions (3.7 mM). The basal [Mg2+]i of rat ventricular myocytes calculated with the intracellular curve averaged 0.91 mM.

  5. Toluene and benzene inhalation influences on ventricular arrhythmias in the rat.

    PubMed

    Magos, G A; Lorenzana-Jiménez, M; Vidrio, H

    1990-01-01

    We have previously found that toluene did not share the capacity of benzene for increasing the arrhythmogenic action of epinephrine in the rat, but appeared to elicit the opposite effect. The present experiments were carried out to verify this observation in rats subjected to more severe ventricular arrhythmias. In animals previously inhaling either air, toluene or benzene and anesthetized with pentobarbital, arrhythmias were produced by coronary ligation or aconitine. In both models, toluene decreased and benzene increased the number of ectopic ventricular beats in the 30 min following induction of arrhythmia. Gas chromatographic measurement of toluene levels in the heart during and after inhalation revealed essentially constant concentrations at the time of arrhythmia evaluation, equivalent to approximately one-third the peak levels observed at the end of inhalation. Although the mechanism of the effect of toluene on arrhythmia could not be ascertained, nonspecific membrane stabilization or central serotonergic stimulation were considered as possible explanations. Since both mechanisms could be operant also in the case of benzene, the opposite effects of the solvents on arrhythmia could not be readily accounted for.

  6. Immediate and enduring effects of neonatal isolation on maternal behavior in rats.

    PubMed

    Kosten, Therese A; Kehoe, Priscilla

    2010-02-01

    Previously, we showed that neonatal isolation (1-hisolation/day from dam, litter, and nest on PND 2-9) facilitates cocaine self-administration and increases extracellular dopamine responses in ventral striatum after stimulant administration in adulthood. Recent studies suggest that enduring alterations in neurobehavioral responses associated with early life manipulations reflect changes in maternal behavior. Thus, we sought to determine if neonatal isolation alters maternal care and if dams with neonatal isolation experience as pups showed differential maternal care towards their pups. In Experiment 1, litters were assigned to one of three conditions: neonatal isolation, handled (5-min separation of dam from litter), or non-handled (no separation). Maternal behaviors were rated on PND 2-9 for 60-min immediately following reunion of mother and litter. In Experiment 2, female rats with or without neonatal isolation experience were assigned to either the neonatal isolation or non-handled litter condition and maternal behaviors rated. Dams of isolated and handled litters spent more time licking pups and less time picking up pups to put outside the nest than dams of non-handled litters. Further, dams of isolated and handled vs. non-handled litters showed less non-maternal behaviors of burrowing and grooming. Neonatal isolation-experienced dams with isolated litters failed to increase pup-licking and decrease non-maternal behaviors. Rather, these dams picked up pups to place outside the nest more than non-handled-experienced dams. Neonatal isolation alters maternal behavior that, in turn, may shape neurobehavioral responses of offspring including effects on maternal care. Such changes may reflect epigenetic effects resulting from changes in maternal behavior.

  7. Suppression of oxidative stress and apoptosis in electrically stimulated neonatal rat cardiomyocytes by resveratrol and underlying mechanisms.

    PubMed

    Ge, Liqi; Wang, Zhirong; Li, Chengzong; Zhang, Yao; Chen, Lei

    2017-08-18

    We explored effects of resveratrol on oxidative stress in cardiomyocytes subjected to rapid electrical stimulation (RES) and also investigated underlying mechanisms. Neonatal rat ventricular myocytes cultured were subjected to RES at 4.0 Hz, with or without resveratrol, an NADPH oxidase inhibitor apocyanin (APO) or a Ca/calmodulin dependent protein kinase II (CaMKII) inhibitor autocamtide-2-inhibitory peptide (AIP). Cell counts, to optimize resveratrol concentration, and angiotensin II content were evaluated. Reactive oxygen species (ROS), intracellular Ca in cardiomyocytes and cardiomyocyte apoptosis were also assessed. Levels of methionine sulfoxide reductase A (MsrA), Nox, oxidative CaMKII (OX-CaMKII) and cleaved caspase-3 in cardiomyocytes were examined. Resveratrol treatment, as compared with APO and AIP, significantly decreased ROS levels, improved Ca amplitudes and intracellular Ca transient decay rates, and inhibited cardiomyocyte apoptosis. Resveratrol also increased MsrA protein levels. In cardiomyocytes subjected to RES, after pretreatment with resveratrol or APO, protein levels of Nox4, Nox2, OX-CaMKII and cleaved caspase-3 were decreased. In comparison, with AIP pretreatment, only Nox2, OX-CaMKII and cleaved caspase-3 were decreased. However, in the presence of DMSO, a competitive inhibitor of MsrA function, the decrease in cleaved caspase-3 did not occur. Resveratrol decreased ROS, partially through inhibition of NADPH oxidase activity and upregulation of MsrA expression.

  8. Targeted intracellular catalase delivery protects neonatal rat myocytes from hypoxia-reoxygenation and ischemia-reperfusion injury

    PubMed Central

    Undyala, Vishnu; Terlecky, Stanley R.; Vander Heide, Richard S.

    2010-01-01

    Hypoxia followed by reoxygenation (HR) and ischemia-reperfusion (IR) cause cell death in neonatal rat ventricular myocytes (NRVM) primarily through the generation of oxidative stress. Extracellular catalase (CAT) has not been effective in reducing or eliminating IR or HR-induced cell death due both to extracellular degradation and poor cellular uptake. Aims 1) to determine if a cell penetrating catalase derivative with enhanced peroxisome targeting efficiency (catalase-SKL) increases intracellular levels of the antioxidant enzyme in NVRM; and 2) to determine if catalase-SKL protects against both HR and IR injury. Methods NRVM were subjected to 3 or 6 hr of HR or 1 hr of IR. CAT concentration, activity, and subcellular distribution were determined using standard techniques. Reactive oxygen species (ROS) and related oxidative stress were visualized using 2’,7’-dichlorofluorescin diacetate. Cell death was measured using trypan blue exclusion or lactate dehydrogenase (LDH) release assays. Results CAT activity was higher in (catalase-SKL) transduced myocytes, was concentrated in a membranous cellular fraction, and potently inhibited oxidative stress. In contrast to non-transducible (unmodified) CAT, catalase-SKL-treated myocytes were protected against both HR and IR. Conclusions 1) catalase-SKL increased myocyte CAT content and activity and dramatically increased resistance to hydrogen peroxide-induced oxidation; 2) catalase-SKL protects against both HR and IR; 3) catalase-SKL may represent a new therapeutic approach to protect hearts against myocardial HR or IR. PMID:20708413

  9. Methanolic Extract of Ceplukan Leaf (Physalis minima L.) Attenuates Ventricular Fibrosis through Inhibition of TNF-α in Ovariectomized Rats.

    PubMed

    Lestari, Bayu; Permatasari, Nur; Rohman, Mohammad Saifur

    2016-01-01

    The increase of heart failure prevalence on menopausal women was correlated with the decrease of estrogen level. The aim of this study is to investigate the effects of ceplukan leaf (Physalis minima L.), which contains phytoestrogen physalin and withanolides, on ventricular TNF-α level and fibrosis in ovariectomized rats. Wistar rats were divided into six groups (control (-); OVX 5: 5-week ovariectomy (OVX); OVX 9: 9-week ovariectomy; treatments I, II, and III: 9-weeks OVX + 4-week ceplukan leaf's methanolic extract doses 500, 1500, and 2500 mg/kgBW, resp.). TNF-α levels were measured with ELISA. Fibrosis was counted as blue colored tissues percentage using Masson's Trichrome staining. This study showed that prolonged hypoestrogen increases ventricular fibrosis (p < 0.05). Ceplukan leaf treatment also resulted in a decrease of ventricular fibrosis and TNF-α level in dose dependent manner compared to without treatment group (p < 0.05). Furthermore, the TNF-α level was normalized in 2500 mg/kgBW Physalis minima L. (p < 0.05) treatment. The reduction of fibrosis positively correlated with TNF-α level (p < 0.05, r = 0.873). Methanolic extract of ceplukan leaf decreases ventricular fibrosis through the inhibition of ventricular TNF-α level in ovariectomized rats.

  10. Targeted ablation of cardiac sympathetic neurons reduces the susceptibility to ischemia-induced sustained ventricular tachycardia in conscious rats

    PubMed Central

    Lujan, Heidi L.; Palani, Gurunanthan; Zhang, Lijie

    2010-01-01

    The Cardiac Arrhythmia Suppression Trial demonstrated that antiarrhythmic drugs not only fail to prevent sudden cardiac death, but actually increase overall mortality. These findings have been confirmed in additional trials. The “proarrhythmic” effects of most currently available antiarrhythmic drugs makes it essential that we investigate novel strategies for the prevention of sudden cardiac death. Targeted ablation of cardiac sympathetic neurons may become a therapeutic option by reducing sympathetic activity. Thus cholera toxin B subunit (CTB) conjugated to saporin (a ribosomal inactivating protein that binds to and inactivates ribosomes; CTB-SAP) was injected into both stellate ganglia to test the hypothesis that targeted ablation of cardiac sympathetic neurons reduces the susceptibility to ischemia-induced, sustained ventricular tachycardia in conscious rats. Rats were randomly divided into three groups: 1) control (no injection); 2) bilateral stellate ganglia injection of CTB; and 3) bilateral stellate ganglia injection of CTB-SAP. CTB-SAP rats had a reduced susceptibility to ischemia-induced, sustained ventricular tachycardia. Associated with the reduced susceptibility to ventricular arrhythmias were a reduced number of stained neurons in the stellate ganglia and spinal cord (segments T1-T4), as well as a reduced left ventricular norepinephrine content and sympathetic innervation density. Thus CTB-SAP retrogradely transported from the stellate ganglia is effective at ablating cardiac sympathetic neurons and reducing the susceptibility to ventricular arrhythmias. PMID:20173045

  11. Methanolic Extract of Ceplukan Leaf (Physalis minima L.) Attenuates Ventricular Fibrosis through Inhibition of TNF-α in Ovariectomized Rats

    PubMed Central

    Lestari, Bayu; Permatasari, Nur; Rohman, Mohammad Saifur

    2016-01-01

    The increase of heart failure prevalence on menopausal women was correlated with the decrease of estrogen level. The aim of this study is to investigate the effects of ceplukan leaf (Physalis minima L.), which contains phytoestrogen physalin and withanolides, on ventricular TNF-α level and fibrosis in ovariectomized rats. Wistar rats were divided into six groups (control (—); OVX 5: 5-week ovariectomy (OVX); OVX 9: 9-week ovariectomy; treatments I, II, and III: 9-weeks OVX + 4-week ceplukan leaf's methanolic extract doses 500, 1500, and 2500 mg/kgBW, resp.). TNF-α levels were measured with ELISA. Fibrosis was counted as blue colored tissues percentage using Masson's Trichrome staining. This study showed that prolonged hypoestrogen increases ventricular fibrosis (p < 0.05). Ceplukan leaf treatment also resulted in a decrease of ventricular fibrosis and TNF-α level in dose dependent manner compared to without treatment group (p < 0.05). Furthermore, the TNF-α level was normalized in 2500 mg/kgBW Physalis minima L. (p < 0.05) treatment. The reduction of fibrosis positively correlated with TNF-α level (p < 0.05, r = 0.873). Methanolic extract of ceplukan leaf decreases ventricular fibrosis through the inhibition of ventricular TNF-α level in ovariectomized rats. PMID:26941790

  12. [Effects of neonatal fluvoxamine administration to white rats and their correction by semax treatment].

    PubMed

    Volodina, M A; Merchieva, S A; Sebentsova, E A; Glazova, N Iu; Manchenko, D M; Andreeva, L A; Levickaia, N G; Kamenskiĭ, A A; Miasoedov, N F

    2014-01-01

    The aim of this work was to study the delayed effects of chronic neonatal administration of the selective serotonin reuptake inhibitor fluvoxamine (FA) to white rat pups and to estimate the possibility to correct these effects by treatment with semax. Fluvoxamine was injected intraperitoneally at a dose of 10 mg/kg from postnatal days 1 to 14, and semax was injected intranasally at a dose of 0.05 mg/kg from postnatal days 15 to 28. It was shown that neonatal FA administration produced a significant delay in animal somatic growth. A loss in body weight was detected both during FA administration and 4-6 weeks after the last injection. Furthermore, FA administration increased the anxiety level and disturbed the learning ability of animals. The negative consequences of neonatal FA administration were largely compensated by Semax.

  13. Direct analysis of beta-adrenergic receptor subtypes on intact adult ventricular myocytes of the rat

    SciTech Connect

    Buxton, I.L.; Brunton, L.L.

    1985-01-01

    beta 1- and beta 2-Adrenergic receptors co-exist in the adult rat ventricle. Radioligand binding and cell purification techniques have been employed to determine the cellular origin of these receptors. The beta-adrenergic antagonist ligand (+/-)-(/sup 125/I) iodocyanopindolol binds to 2 X 10(5) receptors per purified adult rat cardiomyocyte, with a dissociation constant of 70 pM. The subtype-selective antagonists betaxolol (beta 1), practolol (beta 1), and zinterol (beta 2) compete for (/sup 125/I)iodocyanopindolol-binding sites on intact myocytes in monophasic manners with dissociation constants of 46, 845, and 923 nM, respectively. (/sup 125/I)iodocyanopindolol binding to membranes prepared from nonmyocyte elements of rat ventricle occurs with a dissociation constant of 43 pM and a capacity of 88 fmol/mg membrane protein. Computer analysis of competition of (/sup 125/I)iodocyanopindolol binding by betaxolol, practolol, and zinterol in nonmyocyte membranes demonstrates biphasic curves that comprise binding to both beta 1- and beta 2-receptors. These data demonstrate that purified adult ventricular myocytes possess only beta 1-receptors, and that the beta 2-receptors found in rat ventricle are located on nonmyocyte cell types.

  14. Long-term consequences of neonatal fluoxetine exposure in adult rats.

    PubMed

    Ko, Meng-Ching; Lee, Lukas Jyuhn-Hsiarn; Li, Yang; Lee, Li-Jen

    2014-10-01

    Serotonin (5-HT) plays important roles during neural development. Administration of selective serotonin reuptake inhibitor (SSRI)-type medication during gestation may influence the maturation of the fetal brain and subsequent brain functions. To mimic the condition of late-gestation SSRI exposure, we administered fluoxetine (FLX) in neonatal rats during the first postnatal week, which roughly corresponds to the third trimester period of human gestation. FLX-exposed adult male rats exhibited reduced locomotor activity and depression-like behaviors. Furthermore, sensorimotor gating capacity was also impaired. Interestingly, increased social interaction was noticed in FLX-exposed rats. When the levels of 5-HT and tryptophan hydroxylase were examined, no significant changes were found in FLX rats compared to control (CON) rats. The behavioral phenotypes of FLX rats suggested malfunction of the limbic system. Dendritic architectures of neurons in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) were examined. Layer II/III mPFC pyramidal neurons in FLX rats had exuberant dendritic branches with elongated terminal segments compared to those in CON rats. In BLA pyramidal neurons, the dendritic profiles were comparable between the two groups. However, in FLX rats, the density of dendritic spines was reduced in both mPFC and BLA. Together, our results demonstrated the long-lasting effects of early FLX treatment on emotional and social behaviors in adult rats in which impaired neuronal structure in the limbic system was also noticed. The risk of taking SSRI-type antidepressants during pregnancy should be considered.

  15. Coordination strategies for limb forces during weight-bearing locomotion in normal rats, and in rats spinalized as neonates

    PubMed Central

    Giszter, Simon F; Davies, Michelle R; Graziani, Virginia

    2010-01-01

    Some rats spinally transected as neonates (ST rats) achieve weight-supporting independent locomotion. The mechanisms of coordinated hindlimb weight support in such rats are not well understood. To examine these in such ST rats and normal rats, rats with better than 60% of weight supported steps on a treadmill as adults were trained to cross an instrumented runway. Ground reaction forces, coordination of hindlimb and forelimb forces and the motions of the center of pressure were assessed. Normal rats crossed the runway with a diagonal trot. On average hindlimbs bore about 80% of the vertical load carried by forelimbs, although this varied. Forelimbs and hindlimb acted synergistically to generate decelerative and propulsive rostrocaudal forces, which averaged 15% of body weight with maximums of 50% . Lateral forces were very small (<8% of body weight). Center of pressure progressed in jumps along a straight line with mean lateral deviations <1 cm. ST rats hindlimbs bore about 60% of the vertical load of forelimbs, significantly less compared to intact (p<0.05). ST rats showed similar mean rostrocaudal forces, but with significantly larger maximum fluctuations of up to 80% of body weight (p<0.05). Joint force-plate recordings showed forelimbs and hindlimb rostrocaudal forces in ST rats were opposing and significantly different from intact rats (p<0.05). Lateral forces were ~20% of body weight and significantly larger than in normal rats (p<0.05). Center of pressure zig-zagged, with mean lateral deviations of ~ 2cm and a significantly larger range (p<0.05). The haunches were also observed to roll more than normal rats. The locomotor strategy of injured rats using limbs in opposition was presumably less efficient but their complex gait was statically stable. Because forelimbs and hindlimbs acted in opposition, the trunk was held compressed. Force coordination was likely managed largely by the voluntary control in forelimbs and trunk. PMID:18612631

  16. Neonatal local noxious insult affects gene expression in the spinal dorsal horn of adult rats.

    PubMed

    Ren, Ke; Novikova, Svetlana I; He, Fang; Dubner, Ronald; Lidow, Michael S

    2005-09-22

    Neonatal noxious insult produces a long-term effect on pain processing in adults. Rats subjected to carrageenan (CAR) injection in one hindpaw within the sensitive period develop bilateral hypoalgesia as adults. In the same rats, inflammation of the hindpaw, which was the site of the neonatal injury, induces a localized enhanced hyperalgesia limited to this paw. To gain an insight into the long-term molecular changes involved in the above-described long-term nociceptive effects of neonatal noxious insult at the spinal level, we performed DNA microarray analysis (using microarrays containing oligo-probes for 205 genes encoding receptors and transporters for glutamate, GABA, and amine neurotransmitters, precursors and receptors for neuropeptides, and neurotrophins, cytokines and their receptors) to compare gene expression profiles in the lumbar spinal dorsal horn (LDH) of adult (P60) male rats that received neonatal CAR treatment within (at postnatal day 3; P3) and outside (at postnatal 12; P12) of the sensitive period. The data were obtained both without inflammation (at baseline) and during complete Freund's adjuvant induced inflammation of the neonatally injured paw. The observed changes were verified by real-time RT-PCR. This study revealed significant basal and inflammation-associated aberrations in the expression of multiple genes in the LDH of adult animals receiving CAR injection at P3 as compared to their expression levels in the LDH of animals receiving either no injections or CAR injection at P12. In particular, at baseline, twelve genes (representing GABA, serotonin, adenosine, neuropeptide Y, cholecystokinin, opioid, tachykinin and interleukin systems) were up-regulated in the bilateral LDH of the former animals. The baseline condition in these animals was also characterized by up-regulation of seven genes (encoding members of GABA, cholecystokinin, histamine, serotonin, and neurotensin systems) in the LDH ipsilateral to the neonatally-injured paw. The

  17. Alterations in cytochrome P-450 levels in adult rats following neonatal exposure to xenobiotics

    SciTech Connect

    Zangar, R.C. Pacific Northwest Laboratories, Richland, WA ); Springer, D.L. ); Buhler, D.R. )

    1993-01-01

    Neonatal exposure to certain xenobiotics has been shown to alter hepatic metabolism in adult rats in a manner that indicates long-term changes in enzyme regulation. Previously, the authors have observed changes in adult testosterone metabolism and in cytochrome P-450 (P-450) mRNA levels in animals neonatally exposed to phenobarbital (PB) or diethylstilbestrol (DES). In order to test for other enzyme alterations, they used Western blot procedures for specific P-450s to analyze hepatic microsomes from adult rats (24 wk old) that had been exposed neonatally to DES, PB, 7,12-dimethylbenz[a]anthracene (DMBA), or pregnenolone 16[alpha]-carbonitrile (PCN). The most striking effects were observed in the DES-treated males: P-4502C6 and an immunologically similar protein were increased 60 and 90%, respectively, relative to control values, but P-4503A2 was decreased by 44%. No changes were observed in the DES-treated males in levels of P-4502E1, P-4502B, or the male-specific P-4502C13. Adult males neonatally treated with PB had 150% increase in levels of anti-P4502B-reactive protein without significant changes in the other enzymes. The DES- and DMBA-treated females had increased levels of the female-specific P-4502C12 of 38 and 48%, respectively, but no other observed alterations. The results confirm that neonatal exposure to DES or PB can cause alterations in adult hepatic cytochrome P-450 levels but show that these chemicals act on different enzymes. Neonatal DMBA resulted in changes in adult females similar to those produced by the synthetic estrogen DES, but did so at about two-thirds lower dose. 37 refs., 5 figs.

  18. Neonatal nociception elevated baseline blood pressure and attenuated cardiovascular responsiveness to noxious stress in adult rats.

    PubMed

    Chu, Ya-Chun; Yang, Cheryl C H; Lin, Ho-Tien; Chen, Pin-Tarng; Chang, Kuang-Yi; Yang, Shun-Chin; Kuo, Terry B J

    2012-10-01

    Neonatal nociception has significant long-term effects on sensory perception in adult animals. Although neonatal adverse experience affect future responsiveness to stressors is documented, little is known about the involvement of early nociceptive experiences in the susceptibility to subsequent nociceptive stress exposure during adulthood. The aim of this study is to explore the developmental change in cardiovascular regulating activity in adult rats that had been subjected to neonatal nociceptive insults. To address this question, we treated neonatal rats with an intraplantar injection of saline (control) or carrageenan at postnatal day 1. The carrageenan-treated rats exhibited generalized hypoalgesia at basal state, and localized hyperalgesia after re-nociceptive challenge induced by intraplantar injections of complete Freund's adjuvant (CFA) as adults. Then we recorded baseline cardiovascular variables and 24-h responsiveness to an injection of CFA in the free-moving adult rats with telemetric technique. The carrageenan-treated rats showed significantly higher basal blood pressures (110.3±3.16 vs. control 97.0±4.28 mmHg). In control animals, baroreceptor reflex sensitivity (BRS) decreased, sympathetic vasomotor activity increased, and parasympathetic activity was inhibited after CFA injection. Blood pressure elevation was evident (107.0±2.75 vs. pre-injection 97.0±4.28 mmHg). Comparatively, the carrageenan-treated rats showed a higher BRS (BrrLF 1.03±0.09 vs. control 0.70±0.06 ms/mmHg) and higher parasympathetic activity [0.93±0.17 vs. control 0.32±0.02 ln(ms²)] after CFA injection. The change in blood pressure is negligible (111.9±4.05 vs. pre-injection 110.3±3.16 mmHg). Our research has shown that neonatal nociception alters future pain sensation, raises basal blood pressure level, and attenuates cardiovascular responsiveness to nociceptive stress in adult rats. Copyright © 2012 ISDN. Published by Elsevier Ltd. All rights reserved.

  19. Simultaneous measurement of arterial and left ventricular pressure in conscious freely moving rats by telemetry.

    PubMed

    Segreti, Jason A; Polakowski, James S; Blomme, Eric A; King, Andrew J

    2016-01-01

    Comprehensive cardiovascular assessment in conscious rodents by utilizing telemetry has been limited by the restriction of current devices to one pressure channel. The purpose of this study was to test and validate a dual pressure transmitter that allows the simultaneous measurement of arterial pressure (AP) and left ventricular pressure (LVP) in conscious freely moving rats. Six rats were surgically implanted with dual pressure transmitters. Baseline hemodynamics and circadian rhythm were observed to return within 7days. AP, heart rate (HR), LVP and indices of left ventricular contractility were stable and demonstrated a prominent circadian rhythm over a two-week period of uninterrupted recordings. Administration of the vasodilator nifedipine produced the anticipated dose-dependent decrease in AP which was accompanied by a baroreflex mediated increase in HR and cardiac contractility. The negative inotrope verapamil produced the expected dose-dependent decreases in AP and cardiac contractility. Finally, a terminal validation of the dual pressure transmitter was performed under anesthesia by measuring AP and LVP simultaneously via telemetry and from a fluid filled arterial catheter and an intraventricular Millar catheter, respectively. A range of pressures and cardiac contractility were studied by administering sequential intravenous infusions of the positive inotrope dobutamine followed by verapamil. Linear regression analysis revealed a high level of agreement between pressures measured by the dual pressure transmitter and the exteriorized catheters. Histopathologic analysis of the heart revealed mild peri-catheter fibrosis. In conclusion, the simultaneous measurement of AP and LVP offers the potential for more detailed cardiovascular assessment in conscious rats. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Arrhythmogenic substrate in hearts of rats with monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy

    PubMed Central

    Benoist, David; Stones, Rachel; Drinkhill, Mark; Bernus, Olivier

    2011-01-01

    Mechanisms associated with right ventricular (RV) hypertension and arrhythmias are less understood than those in the left ventricle (LV). The aim of our study was to investigate whether and by what mechanisms a proarrhythmic substrate exists in a rat model of RV hypertension and hypertrophy. Rats were injected with monocrotaline (MCT; 60 mg/kg) to induce pulmonary artery hypertension or with saline (CON). Myocardial levels of mRNA for genes expressing ion channels were measured by real-time RT-PCR. Monophasic action potential duration (MAPD) was recorded in isolated Langendorff-perfused hearts. MAPD restitution was measured, and arrhythmias were induced by burst stimulation. Twenty-two to twenty-six days after treatment, MCT animals had RV hypertension, hypertrophy, and decreased ejection fractions compared with CON. A greater proportion of MCT hearts developed sustained ventricular tachycardias/fibrillation (0.83 MCT vs. 0.14 CON). MAPD was prolonged in RV and less so in the LV of MCT hearts. There were decreased levels of mRNA for K+ channels. Restitution curves of MCT RV were steeper than CON RV or either LV. Dispersion of MAPD was greater in MCT hearts and was dependent on stimulation frequency. Computer simulations based on ion channel gene expression closely predicted experimental changes in MAPD and restitution. We have identified a proarrhythmic substrate in the hearts of MCT-treated rats. We conclude that steeper RV electrical restitution and rate-dependant RV-LV action potential duration dispersion may be contributing mechanisms and be implicated in the generation of arrhythmias associated with in RV hypertension and hypertrophy. PMID:21398591

  1. Effects of anesthesia on echocardiographic assessment of left ventricular structure and function in rats.

    PubMed

    Stein, Adam B; Tiwari, Sumit; Thomas, Paul; Hunt, Greg; Levent, Cemil; Stoddard, Marcus F; Tang, Xian-Liang; Bolli, Roberto; Dawn, Buddhadeb

    2007-01-01

    Echocardiography is an essential diagnostic tool for accurate noninvasive assessment of cardiac structure and function in vivo. However, the use of anesthetic agents during echocardiographic studies is associated with alterations in cardiac anatomical and functional parameters. We sought to systematically compare the effects of three commonly used anesthetic agents on echocardiographic measurements of left ventricular (LV) systolic and diastolic function, LV dimensions, and LV mass in rats. Adult male Fischer 344 rats underwent echocardiographic studies under pentobarbital (PB, 25 mg/kg i.p.) (group I, n = 25), inhaled isoflurane (ISF, 1.5%) (group II, n = 25),or ketamine/xylazine (K/X, 37 mg/kg ketamine and 7 mg/kg xylazine i.p.) (group III, n = 25) anesthesia in a cross-over design. Echocardiography was also performed in an additional group of unanesthetized conscious rats (group IV, n = 5). Postmortem studies were performed to validate echocardiographic assessment of LV dimension and mass. Rats in group I exhibited significantly higher LV ejection fraction, fractional shortening, fractional area change, velocity of circumferential fiber shortening corrected for heart rate, and heart rate as compared with groups II and III. LV end-diastolic volume, end-diastolic diameter, and cross-sectional area in diastole were significantly smaller in group I compared with groups II and III. Cardiac output was significantly lower in group III compared with groups I and II. Postmortem LV mass measurements correlated well with echocardiographic estimation of LV mass for all anesthetic agents, and the correlation was best with PB anesthesia. Limited echocardiographic data obtained in conscious rats were similar to those obtained under PB anesthesia. We conclude that compared with ISF and K/X anesthesia, PB anesthesia at a lower dose yields echocardiographic LV structural and functional data similar to those obtained in conscious rats. In addition, PB anesthesia also facilitates

  2. Neonatal Parathion Exposure Disrupts Serotonin and Dopamine Synaptic Function in Rat Brain Regions

    PubMed Central

    Slotkin, Theodore A.; Wrench, Nicola; Ryde, Ian T.; Lassiter, T. Leon; Levin, Edward D.; Seidler, Frederic J.

    2009-01-01

    The consequences of exposure to developmental neurotoxicants are influenced by environmental factors. In the present study, we examined the role of dietary fat intake. We administered parathion to neonatal rats and then evaluated whether a high-fat diet begun in adulthood could modulate the persistent effects on 5HT and DA systems. Neonatal rats received parathion on postnatal days 1-4 at 0.1 or 0.2 mg/kg/day, straddling the cholinesterase inhibition threshold. In adulthood, half the animals in each exposure group were given a high-fat diet for 8 weeks. We assessed 5HT and DA concentrations and turnover in brain regions containing their respective cell bodies and projections. In addition, we monitored 5HT1A and 5HT2 receptor binding and the concentration of 5HT presynaptic transporters. Neonatal parathion exposure evoked widespread increases in neurotransmitter turnover, indicative of presynaptic hyperactivity, further augmented by 5HT receptor upregulation. In control rats, consumption of a high-fat diet recapitulated many of the changes seen with neonatal parathion exposure; the effects represented convergent mechanisms, since the high-fat diet often obtunded further increases caused by parathion. Neonatal parathion exposure causes lasting hyperactivity of 5HT and DA systems accompanied by 5HT receptor upregulation, consistent with “miswiring” of neuronal projections. A high-fat diet obtunds the effect of parathion, in part by eliciting similar changes itself. Thus, dietary factors may produce similar synaptic changes as do developmental neurotoxicants, potentially contributing to the increasing incidence in neurodevelopmental disorders. PMID:19616088

  3. Therapeutic effects of hypercapnia on chronic lung injury and vascular remodeling in neonatal rats.

    PubMed

    Masood, Azhar; Yi, Man; Lau, Mandy; Belcastro, Rosetta; Shek, Samuel; Pan, Jingyi; Kantores, Crystal; McNamara, Patrick J; Kavanagh, Brian P; Belik, Jaques; Jankov, Robert P; Tanswell, A Keith

    2009-11-01

    Permissive hypercapnia, achieved using low tidal volume ventilation, has been an effective protective strategy in patients with acute respiratory distress syndrome. To date, no such protective effect has been demonstrated for the chronic neonatal lung injury, bronchopulmonary dysplasia. The objective of our study was to determine whether evolving chronic neonatal lung injury, using a rat model, is resistant to the beneficial effects of hypercapnia or simply requires a less conservative approach to hypercapnia than that applied clinically to date. Neonatal rats inhaled air or 60% O2 for 14 days with or without 5.5% CO2. Lung parenchymal neutrophil and macrophage numbers were significantly increased by hyperoxia alone, which was associated with interstitial thickening and reduced secondary crest formation. The phagocyte influx, interstitial thickening, and impaired alveolar formation were significantly attenuated by concurrent hypercapnia. Hyperoxic pups that received 5.5% CO2 had a significant increase in alveolar number relative to air-exposed pups. Increased tyrosine nitration, a footprint for peroxynitrite-mediated reactions, arteriolar medial wall thickening, and both reduced small peripheral pulmonary vessel number and VEGF and angiopoietin-1 (Ang-1) expression, which were observed with hyperoxia, was attenuated by concurrent hypercapnia. We conclude that evolving chronic neonatal lung injury in a rat model is responsive to the beneficial effects of hypercapnia. Inhaled 5.5% CO2 provided a significant degree of protection against parenchymal and vascular injury in an animal model of chronic neonatal lung injury likely due, at least in part, to its inhibition of a phagocyte influx.

  4. Elevated vertebrobasilar artery resistance in neonatal spontaneously hypertensive rats.

    PubMed

    Cates, Matthew J; Steed, Peter W; Abdala, Ana P L; Langton, Philip D; Paton, Julian F R

    2011-07-01

    There is a strong correlation between increased vertebral artery resistance and arterial blood pressure in humans. The reasons for this increased resistance at high systemic pressure remain unknown, but may include raised sympathetic activity. With the recent finding that prehypertensive spontaneously hypertensive (PHSH) rats, which have raised sympathetic nerve activity, but a blood pressure comparable to normotensive rat strains, we hypothesized that its vertebrobasilar vascular resistance would already be raised and, as a consequence, would exhibit a more responsive Cushing response (e.g., brain ischemia evoked sympathoexcitation and a pressor response). We report that PHSH rats exhibited a remodeling of the basilar artery (i.e., increased wall thickness and lower lumen-to-wall thickness ratio) that occurred before the onset of hypertension. In a novel in vitro vascularly isolated, arterially perfused brain stem preparation of PHSH rats of 4-5 wk of age, brain stem vascular resistance was raised by ∼35% relative to age- and sex-matched normotensive rats (P < 0.05). In the in situ arterial perfused working heart-brain stem preparation, occlusion of both vertebral arteries in the PHSH rat resulted in a significantly greater increase in sympathetic activity (57 vs. 20%, PHSH vs. control; P < 0.01) that triggered a greater increase in arterial perfusion pressure (8 vs. 3 mmHg, PHSH vs. control; P < 0.01) compared with normotensive rats. These data indicate raised vertebrobasilar artery resistance before the onset of hypertension in the PHSH rat. With the raised responsiveness of the Cushing response in the PHSH rat, we discuss the possibility of brain stem perfusion as a central nervous system determinant of the set point of vasomotor sympathetic tone in the hypertensive condition.

  5. Elevated vertebrobasilar artery resistance in neonatal spontaneously hypertensive rats

    PubMed Central

    Cates, Matthew J.; Steed, Peter W.; Abdala, Ana P. L.; Langton, Philip D.

    2011-01-01

    There is a strong correlation between increased vertebral artery resistance and arterial blood pressure in humans. The reasons for this increased resistance at high systemic pressure remain unknown, but may include raised sympathetic activity. With the recent finding that prehypertensive spontaneously hypertensive (PHSH) rats, which have raised sympathetic nerve activity, but a blood pressure comparable to normotensive rat strains, we hypothesized that its vertebrobasilar vascular resistance would already be raised and, as a consequence, would exhibit a more responsive Cushing response (e.g., brain ischemia evoked sympathoexcitation and a pressor response). We report that PHSH rats exhibited a remodeling of the basilar artery (i.e., increased wall thickness and lower lumen-to-wall thickness ratio) that occurred before the onset of hypertension. In a novel in vitro vascularly isolated, arterially perfused brain stem preparation of PHSH rats of 4–5 wk of age, brain stem vascular resistance was raised by ∼35% relative to age- and sex-matched normotensive rats (P < 0.05). In the in situ arterial perfused working heart-brain stem preparation, occlusion of both vertebral arteries in the PHSH rat resulted in a significantly greater increase in sympathetic activity (57 vs. 20%, PHSH vs. control; P < 0.01) that triggered a greater increase in arterial perfusion pressure (8 vs. 3 mmHg, PHSH vs. control; P < 0.01) compared with normotensive rats. These data indicate raised vertebrobasilar artery resistance before the onset of hypertension in the PHSH rat. With the raised responsiveness of the Cushing response in the PHSH rat, we discuss the possibility of brain stem perfusion as a central nervous system determinant of the set point of vasomotor sympathetic tone in the hypertensive condition. PMID:21493719

  6. Soybean oil increases SERCA2a expression and left ventricular contractility in rats without change in arterial blood pressure

    PubMed Central

    2010-01-01

    Background Our aim was to evaluate the effects of soybean oil treatment for 15 days on arterial and ventricular pressure, myocardial mechanics and proteins involved in calcium handling. Methods Wistar rats were divided in two groups receiving 100 μL of soybean oil (SB) or saline (CT) i.m. for 15 days. Ventricular performance was analyzed in male 12-weeks old Wistar rats by measuring left ventricle diastolic and systolic pressure in isolated perfused hearts according to the Langendorff technique. Protein expression was measured by Western blot analysis. Results Systolic and diastolic arterial pressures did not differ between CT and SB rats. However, heart rate was reduced in the SB group. In the perfused hearts, left ventricular isovolumetric systolic pressure was higher in the SB hearts. The inotropic response to extracellular Ca2+ and isoproterenol was higher in the soybean-treated animals than in the control group. Myosin ATPase and Na+-K+ATPase activities, the expression of sarcoplasmic reticulum calcium pump (SERCA2a) and sodium calcium exchanger (NCX) were increased in the SB group. Although the phosfolamban (PLB) expression did not change, its phosphorylation at Ser16 was reduced while the SERCA2a/PLB ratio was increased. Conclusions In summary, soybean treatment for 15 days in rats increases the left ventricular performance without affecting arterial blood pressure. These changes might be associated with an increase in the myosin ATPase activity and SERCA2a expression. PMID:20504316

  7. Impact of neonatal anoxia on adult rat hippocampal volume, neurogenesis and behavior.

    PubMed

    Takada, Silvia Honda; Motta-Teixeira, Lívia Clemente; Machado-Nils, Aline Vilar; Lee, Vitor Yonamine; Sampaio, Carlos Alberto; Polli, Roberson Saraiva; Malheiros, Jackeline Moraes; Takase, Luiz Fernando; Kihara, Alexandre Hiroaki; Covolan, Luciene; Xavier, Gilberto Fernando; Nogueira, Maria Inês

    2016-01-01

    Neonates that suffer oxygen deprivation during birth can have long lasting cognitive deficits, such as memory and learning impairments. Hippocampus, one of the main structures that participate in memory and learning processes, is a plastic and dynamic structure that conserves during life span the property of generating new cells which can become neurons, the so-called neurogenesis. The present study investigated whether a model of rat neonatal anoxia, that causes only respiratory distress, is able to alter the hippocampal volume, the neurogenesis rate and has functional implications in adult life. MRI analysis revealed significant hippocampal volume decrease in adult rats who had experienced neonatal anoxia compared to control animals for rostral, caudal and total hippocampus. In addition, these animals also had 55.7% decrease of double-labelled cells to BrdU and NeuN, reflecting a decrease in neurogenesis rate. Finally, behavioral analysis indicated that neonatal anoxia resulted in disruption of spatial working memory, similar to human condition, accompanied by an anxiogenic effect. The observed behavioral alterations caused by oxygen deprivation at birth might represent an outcome of the decreased hippocampal neurogenesis and volume, evidenced by immunohistochemistry and MRI analysis. Therefore, based on current findings we propose this model as suitable to explore new therapeutic approaches. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Sodium Pyruvate Reduced Hypoxic-Ischemic Injury to Neonatal Rat Brain

    PubMed Central

    Pan, Rui; Rong, Zhihui; She, Yun; Cao, Yuan; Chang, Li-Wen; Lee, Wei-Hua

    2013-01-01

    Background Neonatal hypoxia-ischemia (HI) remains a major cause of severe brain damage and is often associated with high mortality and lifelong disability. Immature brains are extremely sensitive to hypoxia-ischemia, shown as prolonged mitochondrial neuronal death. Sodium pyruvate (SP), a substrate of the tricarboxylic acid cycle and an extracellular antioxidant, has been considered as a potential treatment for hypoxic-ischemic encephalopathy (HIE), but its effects have not been evaluated in appropriate animal models for hypoxic-ischemic encephalopathy (HIE). Methods This investigation employed primary cortical neuron cultures derived from neonatal rats subjected to oxygen and glucose deprivation (OGD) and a well-established neonatal rat hypoxia-ischemia model. Results HI caused brain tissue loss and impaired sensorimotor function and spatial memory while SP significantly reduced brain damage and improved neurological performance. These neuroprotective effects of SP are likely the result of improved cerebral metabolism as demonstrated by maintaining ATP levels and preventing an increase in intracellular reactive oxygen species (ROS) levels. SP treatment also decreased levels of Bax, a death signal for immature neurons, blocked caspases-3 activation, and activated a key survival signaling kinase, Akt, both in vitro and in vivo. Conclusion SP protected neonatal brain from hypoxic-ischemic injury through maintaining cerebral metabolism and mitochondrial function. PMID:22885415

  9. A paradigm of undernourishing and neonatal rehabilitation in the newborn rat.

    PubMed

    Perez-Torrero, Esther; Torrerob, Carmen; Collado, Paloma; Salas, Manuel

    2003-04-01

    Perinatal undernutrition as a deficiency of nutrient availability, affects body and brain developmental processes and promotes recurrent health problems. Thus, altered mother-litter bonds and deficient environmental interactions may interfere with the brain pluripotential capabilities of the newborn. To gather information concerning the mechanisms underlying perinatal undernutrition we designed a paradigm of undernutrition and neonatal rehabilitation in the rat. An underfed group came from pregnant Wistar rats fed with 50% of the diet from G6 to G12 and with 60% from G13 until G21. After birth, pups were daily undernourished during 12 h daily by rotating a pair of lactating well-nourished dams which had one of their nipples subcutaneously ligated. The rehabilitated animals were undernourished pups neonatally fed by a pair of normally lactating dams. Controls received plenty of food during the pre- and neonatal periods. Pups were sacrificed at 12, 20 and 30 days of age. Perinatal underfeeding significantly reduced body and brain weights and neuronal morphometric parameters. Normal neonatal feeding in the newborn ameliorated the damages associated to food deprivation. The current undernourishing paradigm may be helpful to assess brain development alterations, as well as to study the compensatory mechanisms associated to salutary epigenetic influences.

  10. Selective effects of neonatal handling on rat brain N-methyl-D-aspartate receptors.

    PubMed

    Stamatakis, A; Toutountzi, E; Fragioudaki, K; Kouvelas, E D; Stylianopoulou, F; Mitsacos, A

    2009-12-29

    Neonatal handling, an experimental model of early life experiences, is known to affect the hypothalamic-pituitary-adrenal axis function thus increasing adaptability, coping with stress, cognitive abilities and in general brain plasticity-related processes. A molecule that plays a most critical role in such processes is the N-methyl-D-aspartate (NMDA) receptor, a tetramer consisting of two obligatory, channel forming NR1 subunits and two regulatory subunits, usually a combination of NR2A and NR2B. Since the subunit composition of the NMDA receptor affects brain plasticity, in the present study we investigated the effect of neonatal handling on NR1, NR2A and NR2B mRNA levels using in situ hybridization, and on NR2B binding sites, using autoradiography of in vitro binding of [(3)H]-ifenprodil, in adult rat limbic brain areas. We found that neonatal handling specifically increased NR2B mRNA and binding sites, while it had no effect on the NR1 and NR2A subunits. More specifically, neonatally handled animals, both males and females, had higher NR2B mRNA and binding sites in the dorsal CA1 hippocampal area, as well as the prelimbic, the anterior cingulate and the somatosensory cortex, compared to the non-handled. Moreover NR2B binding sites were increased in the dorsal CA3 area of handled animals of both sexes. Furthermore, neonatal handling had a sexually dimorphic effect, increasing NR2B mRNA and binding sites in the central and medial amygdaloid nuclei only of the females. The neonatal handling-induced increase in the NR2B subunit of the NMDA receptor could underlie the higher brain plasticity, which neonatally handled animals exhibit.

  11. Effects of neonatal handling on the basal forebrain cholinergic system of adult male and female rats.

    PubMed

    Pondiki, S; Stamatakis, A; Fragkouli, A; Philippidis, H; Stylianopoulou, F

    2006-10-13

    Neonatal handling is an early experience which results in improved function of the hypothalamic-pituitary-adrenal axis, increased adaptability and coping as a response to stress, as well as better cognitive abilities. In the present study, we investigated the effect of neonatal handling on the basal forebrain cholinergic system, since this system is known to play an important role in cognitive processes. We report that neonatal handling results in increased number of choline-acetyl transferase immunopositive cells in the septum/diagonal band, in both sexes, while no such effect was observed in the other cholinergic nuclei, such as the magnocellular preoptic nucleus and the nucleus basalis of Meynert. In addition, neonatal handling resulted in increased M1 and M2 muscarinic receptor binding sites in the cingulate and piriform cortex of both male and female rats. A handling-induced increase in M1 muscarinic receptor binding sites was also observed in the CA3 and CA4 (fields 3 and 4 of Ammon's horn) areas of the hippocampus. Furthermore, a handling-induced increase in acetylcholinesterase staining was found only in the hippocampus of females. Our results thus show that neonatal handling acts in a sexually dimorphic manner on one of the cholinergic parameters, and has a beneficial effect on BFCS function, which could be related to the more efficient and adaptive stress response and the superior cognitive abilities of handled animals.

  12. Network mechanisms of spindle-burst oscillations in the neonatal rat barrel cortex in vivo.

    PubMed

    Minlebaev, Marat; Ben-Ari, Yehezkel; Khazipov, Rustem

    2007-01-01

    Early in development, cortical networks generate particular patterns of activity that participate in cortical development. The dominant pattern of electrical activity in the neonatal rat neocortex in vivo is a spatially confined spindle-burst. Here, we studied network mechanisms of generation of spindle-bursts in the barrel cortex of neonatal rats using a superfused cortex preparation in vivo. Both spontaneous and sensory-evoked spindle-bursts were present in the superfused barrel cortex. Pharmacological analysis revealed that spindle-bursts are driven by glutamatergic synapses with a major contribution of AMPA/kainate receptors, but slight participation of NMDA receptors and gap junctions. Although GABAergic synapses contributed minimally to the pacing the rhythm of spindle-burst oscillations, surround GABAergic inhibition appeared to be crucial for their compartmentalization. We propose that local spindle-burst oscillations, driven by glutamatergic synapses and spatially confined by GABAergic synapses, contribute to the development of barrel cortex during the critical period of developmental plasticity.

  13. Neonatal sciatic nerve transection induces TUNEL labeling of neurons in the rat spinal cord and DRG.

    PubMed

    Oliveira, A L; Risling, M; Deckner, M; Lindholm, T; Langone, F; Cullheim, S

    1997-09-08

    Transection of a peripheral nerve in neonatal rats induces an extensive death of axotomized neurons. We demonstrate here that spinal motoneurons and sensory dorsal root ganglia neurons become TUNEL-labeled after sciatic nerve transection in neonatal rats, thus indicating that apoptotic mechanisms are involved in the death process. Interestingly, there is also a profound increase of TUNEL-labeled interneurons in the deep dorsal horn. This location suggests that an intact afferent input and/or contact with target cells is essential for interneuronal survival. Death of motoneurons and sensory neurons could be a result of the injury per se and/or the deprivation of neurotrophic substances, secondary to the loss of contact with target cells.

  14. Neonatal low-dose gamma irradiation-induced impaired fertility in mature rats.

    PubMed

    Freud, A; Canfi, A; Sod-Moriah, U A; Chayoth, R

    1990-11-01

    The reproductive capacity of mature rats at the age of 8 days was studied following neonatal exposure to 0.06 Gy dose of gamma-radiation. Decreased litter size and reduced body weight of the pups on weaning day, but not at parturition, were observed in female rats. The reduced litter size was not associated with impaired ovulation, impaired uterine implantation or mortality in utero, but resulted from increased death rate or at near parturition. Of the neonatally irradiated males 29% were found to be sterile and had degenerated or necrotic testes. The testicular damage and the reduced growth rate of the offspring of the irradiated females demonstrate the extreme sensitivity of the immature reproductive system to ionizing radiation, even at very low doses.

  15. Neonatal pinealectomy in rats - a simple micro-suction technique.

    PubMed

    Pawlicki, Bohdan; Henry, Brandon Michael; Tomaszewski, Krzysztof A; Gajda, Mariusz; Brzozowska, Iwona; Walocha, Jerzy A; Skowron-Cendrzak, Anna

    2017-01-01

    To determine the role of the pineal gland and its secretory product melatonin on various aspects of the functioning of the organism, the gland can be easily surgically removed in rats within 18 hours after birth. We performed pinealectomy in rats in a state of deep hypothermia under an operating microscope, using a micro-suction device of our own construction. The rats were induced into a state of suspended animation by placing them in the freezing compartment at minus 20 Celsius degrees. The cessation of respiration and heart beat lasted for about 15 minutes. During that time the pinealectomy was performed. In some cases there was minor hemorrhage that was easily controlled. There were no major side effects or mortality following surgery. All rats recovered within 15 minutes after the end of the procedure. The pinealectomy procedure described in this study is simple, rapid, effective and safe, and can be easily performed with instruments commonly available in most laboratories.

  16. Establishment and identification of a hypoxia-ischemia brain damage model in neonatal rats

    PubMed Central

    YAO, DAN; ZHANG, WEIRAN; HE, XUE; WANG, JINHU; JIANG, KEWEN; ZHAO, ZHENGYAN

    2016-01-01

    The present study was designed to set up a reliable model of severe hypoxia-ischemia brain damage (HIBD) in neonatal rats and several methods were used to identify whether the model was successful. A total of 40 healthy 7-day-old Sprague-Dawley rats were randomly divided into 2 groups: The sham-surgery group (n=18) and the HIBD model group (n=22). The HIBD model was produced according to the traditional Rice method. The rats were anesthetized with ethyl ether. The left common carotid artery (CCA) was exposed, ligated and cut. Following this, the rats were exposed to hypoxia in a normobaric chamber filled with 8% oxygen and 92% nitrogen for 2 h. In the sham-surgery group, the left CCA was exposed but was not ligated, cut or exposed to hypoxia. The neurobehavioral changes of the rats were observed in the 24 h after HIBD. The brains were collected after 72 h to observe the pathological morphological changes of the brain tissue. The behavioral ability and neurobehavioral changes were studied in each group. The water maze test was used for evaluating the learning-memory ability when the rats were 28 days old. Compared with the sham-surgery group, all the HIBD model rats had a lag of motor development. The rats had evident changes in anatomy and Nissl staining, and cognitive impairment was shown through the result of the water maze. Therefore, the model of HIBD in neonatal rats is feasible and provides a reliable model for subsequent studies. PMID:27073628

  17. Hypothermia decreased the expression of heat shock proteins in neonatal rat model of hypoxic ischemic encephalopathy.

    PubMed

    Lee, Byong Sop; Jung, Euiseok; Lee, Yeonjoo; Chung, Sung-Hoon

    2017-03-11

    Hypothermia (HT) is a well-established neuroprotective strategy against neonatal hypoxic ischemic encephalopathy (HIE). The overexpression of heat shock proteins (HSP) has been shown to provide neuroprotection in animal models of stroke. We aimed to investigate the effect of HT on HSP70 and HSP27 expression in a neonatal rat model of HIE. Seven-day-old rat pups were exposed to hypoxia for 90 min to establish the Rice-Vannucci model and were assigned to the following four groups: hypoxic injury (HI)-normothermia (NT, 36 °C), HI-HT (30 °C), sham-NT, and sham-HT. After temperature intervention for 24 h, the mRNA and protein expression of HSP70 and HSP27 were measured. The association between HSP expression and brain injury severity was also evaluated. The brain infarct size was significantly smaller in the HI-HT group than in the HI-NT group. The mRNA and protein expression of both HSPs were significantly greater in the two HI groups, compared to those in the two sham groups. Moreover, among the rat pups subjected to HI, HT significantly reduced the mRNA and protein expression of both HSPs. The mRNA expression level of the HSPs was proportional to the brain injury severity. Post-ischemic HT, i.e., a cold shock attenuated the expression of HSP70 and HSP27 in a neonatal rat model of HIE. Our study suggests that neither HSP70 nor HSP27 expression is involved in the neuroprotective mechanism through which prolonged HT protects against neonatal HIE.

  18. Bax inhibiting peptide reduces apoptosis in neonatal rat hypoxic-ischemic brain damage

    PubMed Central

    Sun, Meng-Ya; Cui, Kai-Jie; Yu, Mao-Min; Zhang, Hui; Peng, Xiang-Li; Jiang, Hong

    2015-01-01

    Neonatal hypoxic ischemic encephalopathy (HIE) has been reported to induce apoptosis in neonates. We, therefore, analyzed the ability of Bax-inhibiting peptide (BIP) to provide neuroprotective effects during hypoxic-ischemic brain damage (HIBD). Seven-day-old wistar rat pups (n = 198) were randomly divided into a sham-operated group (Group S, n = 18), saline group (Group C, n = 90) and BIP group (Group B, n = 90). Pathological changes in the cerebral tissues of rat pups were analyzed using hematoxylin and eosin stain, TUNEL and Western blot. The expression of cytochrome c and caspase-3 was determined using western blot technique. Rat pups demonstrated neurobehavioral alteration in Groups C and B. TUNEL-positive cells in the left hippocampus were significantly increased in Group C and Group B after HIBD (P < 0.01) when compared with Group S. There was a marked reduction in TUNEL positive cells in subgroups B1 through B4 when compared with the respective subgroups C1 through C5. Compared with Group S, the expression of caspase-3 and cytochrome c was significantly increased in Groups C and B (P < 0.01). The difference in expression of caspase-3 and cytochrome c between subgroups B1 through B4 and C1 through C4 was significant (P < 0.01). In conclusions, the neuro-protective effect of BIP was due to a reduction of nerve cell apoptosis in our neonatal HIE rat model. We propose that BIP has potential as a neuro-protective drug in neonatal HIE cases. PMID:26823794

  19. Do early MRI signals predict lesion size in a neonatal stroke rat model?

    PubMed

    Fau, S; Po, C; Goyenvalle, C; Meric, P; Charriaut-Marlangue, C

    2013-07-01

    In this study, we compared lesion size by using VADC and VT2 at 0, 2, 5, 24, and 48 hours and histologic lesions at 48 hours in a P7 rat stroke model. The best correlation between VHISTO and VADC was at H0, and between VHISTO and VT2, at H2-H5. Early MR imaging signals allowed excluding "no-lesion" and "no-reflow" animals to help standardize this neonatal stroke model and predict lesion size.

  20. Incidence and natural history of neonatal isolated ventricular septal defects: Do we know everything? A 6-year single-center Italian experience follow-up.

    PubMed

    Cresti, Alberto; Giordano, Raffaele; Koestenberger, Martin; Spadoni, Isabella; Scalese, Marco; Limbruno, Ugo; Falorini, Susanna; Stefanelli, Stefania; Picchi, Andrea; De Sensi, Francesco; Malandrino, Angela; Cantinotti, Massimiliano

    2017-08-30

    Despite ventricular septal defects (VSDs) are the most common congenital heart diseases (CHDs) in the neonatal period, their incidence and natural history are still debated and their follow-up and management strategies remain controversial. Our aim was to evaluate the incidence and natural history of isolated VSDs. From January 1996 to December 2015 all neonates with a CHD suspicion were referred to the Cardiological Department of Grosseto Misericordia Hospital. Only newborns with confirmed isolated VSD were enrolled in this study and followed for 6 years. Our 343 newborns with an isolated VSD (incidence of 10.45/1000/births) account for 64% of all detected CHDs. VSDs location were as follows: muscular (73.8%), perimembranous (11.3%), inlet (1%), and outlet (0.8%). Of the located VSDs, 90% were small, 7.5% moderate, and 2.5% large, respectively. Spontaneous closure was observed in 96 (29.2%) of the VSD patients at 6-month, 198 (60.2%) at 1-year, 261 (79.3%) at 2-year, and in 302 (91.8%) at 6-year follow-up. Risk factors for defect persistence were a perimembranous location (P = .001; HR: 0.508, CI: 0.342-0.755), detection of multiple defects (P = .043; HR: 0.728, CI: 0.536-0.990), and male gender (P < .048; HR: 0.783, CI: 0.615-0.998), respectively. We here provide an incidence and natural history of neonatal isolated VSDs in a neonatal Caucasian population. These data may be useful for the development of expert consensus/standard recommendation guidelines for the follow-up and VSD management, data that are currently lacking. © 2017 Wiley Periodicals, Inc.

  1. Neonatal exposure to genistein ameliorates high-fat diet-induced non-alcoholic steatohepatitis in rats.

    PubMed

    Huang, Chengfei; Qiao, Xubai; Dong, Bing

    2011-07-01

    Non-alcoholic steatohepatitis (NASH) is becoming a prevalent disease in developing countries with no effective therapy. Isoflavones such as genistein have been shown to prevent NASH in a rat model, but the effects of neonatal exposure to genistein on lipid metabolism have been rarely studied. In the present study, three doses of genistein (30, 300 or 1200 μg/rat per d) were injected (subcutaneously) into neonatal male Sprague-Dawley rats at postnatal days 1-5. After weaning, these rats were allowed free access to a high-fat diet for 6 weeks. The results demonstrate that NASH was induced by high fat feeding in the control rats, whereas genistein-treated rats displayed smaller body weight, and lower hepatic inflammation and steatosis. The mid dose of genistein was most effective. Neonatal exposure to genistein also resulted in a lower incidence of apoptotic cells in the liver. Additionally, neonatal genistein-treated rats showed lower hepatic expression of fatty acid synthase and sterol regulatory element-binding protein-1, but higher expression of PPARα, indicative of lower rates of lipid synthesis and higher rates of β-oxidation. These results indicate that neonatal treatment with genistein has a prolonged effect on hepatic lipid metabolism that is maintained post-weaning, offering a potential approach for the prevention of hepatic steatosis and NASH.

  2. Long-lasting neonatal inflammation enhances pain responses to subsequent inflammation, but not peripheral nerve injury in adult rats.

    PubMed

    Lim, Eun Jeong; Back, Seung Keun; Kim, Myung Ah; Li, Chengjin; Lee, Jaehee; Jeong, Keun Yeong; Na, Heung Sik

    2009-05-01

    The early postnatal period has been suggested to be the vulnerable time for structural and functional reorganization of sensory systems, and painful stimuli at this time may alter neuronal circuits, thereby leading to changes in an individual's response to pain later in life. In the present study, we examined whether inflammatory experience in the early life can affect pain responses to subsequent noxious insults later in life. The two groups of neonatal rats, treated with an inflammatory irritant and untreated, were subjected to inflammation and peripheral nerve injury in adulthood. Neonatal inflammation was induced by injection of complete Freund's adjuvant (CFA, 25 microl) into the hindpaw or tail of newborn rat pups. Adult rats which had suffered from neonatal paw inflammation at P0 were subjected to re-injection of CFA into the paw neonatally exposed to CFA or L5 spinal nerve ligation. Paw thickness and histology of inflamed paw were examined to assess the neonatal inflammation. Adult animals whose tail had been subjected to CFA injection on P3 received tail-innervating nerve injury. The results showed that the neonatal CFA-treated rats suffered from chronic inflammation, confirmed by persistent increase of paw thickness and histological result of inflamed paw. These animals showed enhanced pain responses to re-inflammatory challenge by injection of CFA (200 microl) into the neonatally inflamed paw 8 weeks after birth compared with the neonatally untreated animals. However, neuropathic pain on the hindpaw and the tail which had been induced by peripheral nerve injury in the neonatal CFA-treated group were not different from those of the untreated group. The present data suggest that early neonatal long-lasting inflammation differentially affects pain responses later in life, depending on the types of subsequent noxious insults.

  3. Enhanced acquisition of cocaine self-administration in adult rats with neonatal isolation stress experience.

    PubMed

    Kosten, T A; Miserendino, M J; Kehoe, P

    2000-09-01

    That stress enhances the behavioral effects of cocaine is well-documented in adult rats, but whether early life stress endures into adulthood to affect responsivity to cocaine is less clear. We now report that neonatal isolation stress (1 h per day isolation on postnatal days 2-9) enhances acquisition of cocaine self-administration in adult rats. This effect was specific to cocaine and not due to learning or performance differences. Neither acquisition of operant responding for food nor locomotor activity differed between groups. These results have important implications for the role of early childhood stress in vulnerability to cocaine addiction.

  4. Caffeine in the neonatal period induces long-lasting changes in sleep and breathing in adult rats.

    PubMed

    Montandon, Gaspard; Horner, Richard L; Kinkead, Richard; Bairam, Aida

    2009-11-15

    Caffeine is commonly used clinically to treat apnoeas and unstable breathing associated with premature birth. Caffeine antagonizes adenosine receptors and acts as an efficient respiratory stimulant in neonates. Owing to its persistent effects on adenosine receptor expression in the brain, neonatal caffeine administration also has significant effects on maturation of the respiratory control system. However, since adenosine receptors are critically involved in sleep regulation, and sleep also modulates breathing, we tested the hypothesis that neonatal caffeine treatment disrupts regulation of sleep and breathing in the adult rat. Neonatal caffeine treatment (15 mg kg(-1) day(-1)) was administered from postnatal days 3-12. At adulthood (8-10 weeks old), sleep and breathing were measured with a telemetry system and whole-body plethysmography respectively. In adult rats treated with caffeine during the neonatal period, sleep time was reduced, sleep onset latency was increased, and non-rapid eye movement (non-REM) sleep was fragmented compared to controls. Ventilation at rest was higher in caffeine-treated adult rats compared to controls across sleep/wake states. Hypercapnic ventilatory responses were significantly reduced in caffeine-treated rats compared to control rats across sleep/wake states. Additional experiments in adult anaesthetized rats showed that at similar levels of arterial blood gases, phrenic nerve activity was enhanced in caffeine-treated rats. This study demonstrates that administration of caffeine in the neonatal period alters respiratory control system activity in awake and sleeping rats, as well as in the anaesthetized rats, and also has persistent disrupting effects on sleep that are apparent in adult rats.

  5. NGF induces neonatal rat sensory neurons to extend dendrites in culture after removal of satellite cells.

    PubMed

    De Koninck, P; Carbonetto, S; Cooper, E

    1993-02-01

    Vertebrate sensory neurons have a pseudo-unipolar morphology; their somata are covered by satellite cells and lack dendrites or synaptic contacts. However, when neonatal rat sensory neurons from the nodose ganglia develop in culture in absence of satellite cells and with NGF, they form synapses among themselves. In this study, we investigated whether neonatal rat nodose neurons express dendrites under the same culture conditions. We show by Lucifer yellow injection that nodose neurons remain typically unipolar when cocultured with their ganglionic satellite cells. However, when these neurons are cultured without satellite cells, virtually all neurons acquire a multipolar morphology. Moreover, when NGF is added to satellite cell-free cultures, several neurons extend dendrites; these processes stain positively for microtubule-associated protein-2. NGF induces a 17-fold increase in dendritic outgrowth after 3 weeks but has little effect on axon number. In addition, we find that the ability of nodose neurons to extend dendrites is developmentally regulated. Furthermore, in a combined morphological and electrophysiological study, using whole-cell voltage-clamp technique with Lucifer yellow in the recording solution, we demonstrate a positive correlation between the extent of dendritic outgrowth and the density of ACh currents, suggesting that these dendrites have ACh receptors. Our results indicate that neonatal rat nodose neurons are capable of extending dendrites and that extrinsic factors can induce or suppress their extension. In addition, the results suggest that these dendrites may act as principal post-synaptic structures for synapse formation that occurs in these cultures.

  6. Lithium Treatment Prevents Apoptosis in Neonatal Rat Hippocampus Resulting from Sevoflurane Exposure.

    PubMed

    Zhou, Xue; da Li, Wen-; Yuan, Bao-Long; Niu, Li-Jun; Yang, Xiao-Yu; Zhou, Zhi-Bin; Chen, Xiao-Hui; Feng, Xia

    2016-08-01

    We aimed to observe the therapeutic effects of lithium on inhalational anesthetic sevoflurane-induced apoptosis in immature brain hippocampus. From postnatal day 5 (P5) to P28, male Sprague-Dawley pups were intraperitoneally injected with lithium chloride or 0.9 % sodium chloride. On P7 after the injection, pups were exposed to 2.3 % sevoflurane or air for 6 h. Brain tissues were harvested 12 h and 3 weeks after exposure. Cleaved caspase-3, nNOS protein, GSK-3β,p-GSK-3β were assessed by Western blot, and histopathological changes were assessed using Nissl stain and TUNEL stain. From P28, we used the eight-arm radial maze test and step-through test to evaluate the influence of sevoflurane exposure on the learning and memory of juvenile rats. The results showed that neonatal sevoflurane exposure induced caspase-3 activation and histopathological changes in hippocampus can be attenuated by lithium chloride. Sevoflurane increased GSK-3β activity while pretreatment of lithium decreased GSK-3β activity. Moreover, sevoflurane showed possibly slight but temporal influence on the spatial learning and the memory of juvenile rats, and chronic use of lithium chloride might have the therapeutic effect. Our current study suggests that lithium attenuates sevoflurane induced neonatal hippocampual damage by GSK-3β pathway and might improve learning and memory deficits in rats after neonatal exposure.

  7. Sildenafil Improves Brain Injury Recovery following Term Neonatal Hypoxia-Ischemia in Male Rat Pups.

    PubMed

    Yazdani, Armin; Khoja, Zehra; Johnstone, Aaron; Dale, Laura; Rampakakis, Emmanouil; Wintermark, Pia

    2016-01-01

    Term asphyxiated newborns remain at risk of developing brain injury despite available neuropreventive therapies such as hypothermia. Neurorestorative treatments may be an alternative. This study investigated the effect of sildenafil on brain injury induced by neonatal hypoxia-ischemia (HI) at term-equivalent age. Neonatal HI was induced in male Long-Evans rat pups at postnatal day 10 (P10) by left common carotid ligation followed by a 2-hour exposure to 8% oxygen; sham-operated rat pups served as the control. Both groups were randomized to oral sildenafil or vehicle twice daily for 7 consecutive days. Gait analysis was performed on P27. At P30, the rats were sacrificed, and their brains were extracted. The surfaces of both hemispheres were measured on hematoxylin and eosin-stained brain sections. Mature neurons and endothelial cells were quantified near the infarct boundary zone using immunohistochemistry. HI caused significant gait impairment and a reduction in the size of the left hemisphere. Treatment with sildenafil led to an improvement in the neurological deficits as measured by gait analysis, as well as an improvement in the size of the left hemisphere. Sildenafil, especially at higher doses, also caused a significant increase in the number of neurons near the infarct boundary zone. In conclusion, sildenafil administered after neonatal HI may improve brain injury recovery by promoting neuronal populations.

  8. Immune response to lentiviral bilirubin UDP-glucuronosyltransferase gene transfer in fetal and neonatal rats.

    PubMed

    Seppen, J; van Til, N P; van der Rijt, R; Hiralall, J K; Kunne, C; Elferink, R P J Oude

    2006-04-01

    Gene therapy for inherited disorders might cause an immune response to the therapeutic protein. A solution would be to introduce the gene in the fetal or neonatal period, which should lead to tolerization. Lentiviral vectors mediate long-term gene expression, and are well suited for gene therapy early in development. A model for fetal or neonatal gene therapy is the inherited disorder of bilirubin metabolism, Crigler-Najjar disease (CN). The absence of bilirubin UDP-glucoronyltransferase (UGT1A1) activity in CN patients causes high serum levels of unconjugated bilirubin and brain damage in infancy. CN is attractive for the development of gene therapy because the mutant Gunn rat closely mimics the human disease. Injection of UGT1A1 lentiviral vectors corrected the hyperbilirubinemia for more than a year in rats injected as fetuses and for up to 18 weeks in rats injected the day of birth. UGT1A1 gene transfer was confirmed by the presence of bilirubin glucuronides in bile. All animals injected with UGT1A1 lentiviral vectors developed antibodies to UGT1A1. Animals injected with green fluorescent protein (GFP) lentiviral vectors did not develop antibodies to GFP. Our results indicate that fetal and neonatal gene therapy with immunogenic proteins such as UGT1A1 does not necessarily lead to tolerization.

  9. RAGE/NF-κB signaling mediates lipopolysaccharide induced acute lung injury in neonate rat model.

    PubMed

    Li, Yuhong; Wu, Rong; Tian, Yian; Yu, Min; Tang, Yun; Cheng, Huaipin; Tian, Zhaofang

    2015-01-01

    Lipopolysaccharide (LPS) is known to induce acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Accumulating data suggest the crucial role of RAGE in the pathogenesis of ALI/ARDS. However, the mechanism by which RAGE mediates inflammatory lung injury in the neonates remains elusive. In this study we established LPS-induced ALI model in neonate rats, and investigated the role of RAGE/NF-κB signaling in mediating ALI. We found that RAGE antibody or bortezomib reduced LPS-induced histopathological abnormalities in the lung and lung damage score. RAGE antibody or bortezomib also reduced TNF-α level in both serum and BALF of the rats. Furthermore, RAGE antibody or bortezomib significantly reduced LPS-induced upregulation of RAGE and NF-κB expression in the lung. In conclusion, we established ALI model in neonate rats to demonstrate that LPS induced inflammatory lung injury via RAGE/NF-κB signaling. Interference with RAGE/NF-κB signaling is a potential approach to prevent and treat sepsis-related ALI/ARDS.

  10. Dopaminergic neuronal injury in the adult rat brain following neonatal exposure to lipopolysaccharide and the silent neurotoxicity

    PubMed Central

    Fan, Lir-Wan; Tien, Lu-Tai; Zheng, Baoying; Pang, Yi; Lin, Rick C. S.; Simpson, Kimberly L.; Ma, Tangeng; Rhodes, Philip G.; Cai, Zhengwei

    2010-01-01

    Our previous studies have shown that neonatal exposure to lipopolysaccharide (LPS) resulted in motor dysfunction and dopaminergic neuronal injury in the juvenile rat brain. To further examine whether neonatal LPS exposure has persisting effects in adult rats, motor behaviors were examined from postnatal day 7 (P7) to P70 and brain injury was determined in P70 rats following an intracerebral injection of LPS (1 mg/kg) in P5 Sprague-Dawley male rats. Although neonatal LPS exposure resulted in hyperactivity in locomotion and stereotyped tasks, and other disturbances of motor behaviors, the impaired motor functions were spontaneously recovered by P70. On the other hand, neonatal LPS-induced injury to the dopaminergic system such as the loss of dendrites and reduced tyrosine hydroxylase immunoreactivity in the substantia nigra persisted in P70 rats. Neonatal LPS exposure also resulted in sustained inflammatory responses in the P70 rat brain, as indicated by an increased number of activated microglia and elevation of interleukin-1β and interleukin-6 content in the rat brain. In addition, when challenged with methamphetamine (METH, 0.5 mg/kg) subcutaneously, rats with neonatal LPS exposure had significantly increased responses in METH-induced locomotion and stereotypy behaviors as compared to those without LPS exposure. These results indicate that although neonatal LPS-induced neurobehavioral impairment is spontaneously recoverable, the LPS exposure-induced persistent injury to the dopaminergic system and the chronic inflammation may represent the existence of silent neurotoxicity. Our data further suggest that the compromised dendritic mitochondrial function might contribute, at least partially, to the silent neurotoxicity. PMID:20875849

  11. Formation of binucleated myocardial cells in the neonatal rat. An index for growth hypertrophy

    SciTech Connect

    Clubb, F.J. Jr.; Bishop, S.P.

    1984-05-01

    The purposes of this study were to characterize myocardial cell growth in neonatal rats and investigate the mechanism of binucleation in myocardial cells. To test the hypothesis that binucleated myocardial cells result from karyokinesis without cytokinesis, experiments were designed to measure the rate of DNA synthesis and the percentage of binucleated myocardial cells in neonatal rats during growth. Estimates of myocardial cell nuclear divisions were obtained from rats pulsed with tritiated thymidine at 17 days of gestation. Autoradiograms were prepared from isolated myocardial cells of rats killed at various ages postpartum, and the number of developed silver halide grains over myocardial cell nuclei was calculated. This estimated the mitotic activity of nuclei. To determine myocardial cell DNA synthesis postpartum, another set of rats were injected at various time periods with 4 hourly doses of tritiated thymidine, and hearts were fixed by perfusion 1 hour later. Labeling index of myocardial cells was calculated (labeled/total myocardial cells) from autoradiograms. Results indicated that the growth of myocardial cells in period can be divided into three phases: (a) a hyperplastic phase, (b) a transitional phase, and (c) a hypertrophic phase. Binucleation of myocardial cells was not due to fusion of mononucleated cells.

  12. Carnosine pretreatment protects against hypoxia-ischemia brain damage in the neonatal rat model.

    PubMed

    Zhang, Xiangmin; Song, Lili; Cheng, Xiuyong; Yang, Yi; Luan, Bin; Jia, Liting; Xu, Falin; Zhang, Zhan

    2011-09-30

    Perinatal hypoxia-ischemia brain injury is a major cause of mortality and morbidity in neonates and lacks an effective treatment thus far. Carnosine has been demonstrated to play a neuroprotective role in the adult brain injuries. However, there is no information available concerning its neuroprotective role in the immature brains after hypoxia-ischemia insults. Therefore, we investigated whether carnosine could also confer neuroprotective effects in a neonatal rat hypoxia-ischemia model. Hypoxia-ischemia was induced in rats on postnatal day 7 (P7). Carnosine (250 mg/kg) was administered intraperitoneally, 30 min prior to hypoxia-ischemia induction. Morphological brain injury and biochemical markers of apoptosis and oxidative stress were evaluated 24 h after hypoxia-ischemia induction. Cognitive performance was evaluated by the Morris Water Maze test on P28-P33. We found that pretreatment with carnosine significantly reduced the infarct volume and the number of terminal-deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells in the hypoxia-ischemia brain. Carnosine also inhibited mRNA expression of apoptosis-inducing factor(AIF) and caspase-3, which was accompanied by an increase in superoxide dismutase(SOD)activity and a decrease in the malondialdehyde(MDA)level in carnosine-treated rats. Furthermore, carnosine also improved the spatial learning and memory abilities of rats declined due to hypoxia-ischemia. These results demonstrate that carnosine can protect rats against hypoxia-ischemia-induced brain damage by antioxidation.

  13. Neonatal handling affects learning, reversal learning and antioxidant enzymes activities in a sex-specific manner in rats.

    PubMed

    Noschang, Cristie; Krolow, Rachel; Arcego, Danusa Mar; Toniazzo, Ana Paula; Huffell, Ana Paula; Dalmaz, Carla

    2012-06-01

    Early life experiences have profound influences on behavior and neurochemical parameters in adult life. The aim of this study is to verify neonatal handling-induced sex specific differences on learning and reversal learning as well as oxidative stress parameters in the prefrontal cortex and striatum of adult rats. Litters of rats were non-handled or handled (10 min/day, days 1-10 after birth). In adulthood, learning and reversal learning were evaluated using a Y maze associated with palatable food in male and female rats. Morris water maze reversal learning was verified in males. Oxidative stress parameters were evaluated in both genders. Male neonatal handled animals had a worse performance in the Y maze reversal learning compared to non-handled ones and no difference was observed in the water maze reversal learning task. Regarding females, neonatal handled rats had a better performance during the Y maze learning phase compared to non-handled ones. In addition, neonatal handled female animals showed a decreased SOD/CAT ratio in the PFC compared to non-handled females. We conclude that neonatal handling effects on learning and memory in adult rats are sex and task specific. The sex specific differences are also observed in the evaluation of antioxidant enzymes activities with neonatal handling affecting only females. Copyright © 2012 ISDN. Published by Elsevier Ltd. All rights reserved.

  14. Decreased transient outward K+ current in ventricular myocytes from acromegalic rats.

    PubMed

    Xu, X P; Best, P M

    1991-03-01

    Cardiac hypertrophy and heart failure are common to acromegalic patients who have abnormally high serum growth hormone (GH). While the function of cardiac muscle is clearly affected by chronically elevated GH, the electrical activity of myocytes from hearts with GH-dependent hypertrophy has not been studied. We used adult, female Wistar-Furth rats with induced GH-secreting tumors to study the effect of excessive GH on ion channels of cardiac myocytes. GH-secreting tumors were induced by subcutaneous inoculation of GH3 cells. Eight weeks after inoculation, the rats had doubled their body weight and heart size compared with age-matched controls. There were no differences in either action potential amplitude or resting potential of right ventricular myocytes from control and tumor-bearing rats. However, action potential duration increased significantly in tumor-bearing rats; the time to 50% repolarization was 23 +/- 14 ms (n = 10) compared with 6.6 +/- 1.5 ms (n = 14) in controls. The prolongation of the action potential was mainly due to a decrease in density of a transient outward current (It,o) carried by K+. The normalized conductance for It,o decreased from 0.53 +/- 0.10 nS/pF (n = 25) in controls to 0.33 +/- 0.09 nS/pF (n = 26) in tumor-bearing rats. The decrease in It,o) and increase in heart weight occurred with a similar time course. The increased action potential duration prolongs Ca2+ influx through L-type Ca2+ channels in the tumor-bearing animals; this may be important in cardiovascular adaptation.

  15. Progressive development of pulmonary hypertension leading to right ventricular hypertrophy assessed by echocardiography in rats.

    PubMed

    Kato, Yosuke; Iwase, Mitsunori; Kanazawa, Hiroaki; Kawata, Natsuki; Yoshimori, Yukie; Hashimoto, Katsunori; Yokoi, Toyoharu; Noda, Akiko; Takagi, Kenzo; Koike, Yasuo; Nishizawa, Takao; Nishimura, Masahiko; Yokota, Mitsuhiro

    2003-07-01

    The present study aimed to evaluate the development of pulmonary hypertension by serial echocardiography, including measurements of pulmonary artery (PA) flow velocities, and correlate echocardiographic indices with pathological findings in rats administered monocrotaline (MCT). MCT (60 mg/kg body weight) or physiologic saline was administered to a total of 9 male Wistar rats at the age of 4 weeks (MCT group: n = 4, control group: n = 5, respectively). Echocardiography was performed serially until the age of 8 weeks. The ratio of right ventricular (RV) outflow tract dimensions to aortic dimensions increased progressively in the MCT group and became significantly greater than that of the control group after the age of 6 weeks. Peak PA velocity (Peak V) in the MCT group was significantly less than that of the control group at the ages of 7 and 8 weeks. The ratio of acceleration time to ejection time (AT/ET) in PA flow waveforms declined progressively and was significantly less than that of the control group after the age of 6 weeks. The ratio of RV weight to body weight (RVW/BW) in the MCT group was significantly greater than that of the control group. Both AT/ET ratio and Peak V were significantly inversely correlated with RVW/BW ratio. Furthermore, these echocardiographic findings were also significantly inversely correlated with the mean cross-sectional RV myocyte area. In conclusion, the progressive development of pulmonary hypertension leading to RV hypertrophy can be evaluated appropriately by echocardiography including PA flow Doppler indices in rats.

  16. Temporal evaluation of left ventricular remodeling and function in rats with chronic volume overload.

    PubMed

    Brower, G L; Henegar, J R; Janicki, J S

    1996-11-01

    The left ventricle (LV) significantly dilates and hypertrophies in response to chronic volume overload. However, the temporal responses in LV mass, volume, and systolic/diastolic function secondary to chronic volume overload induced by an infrarenal arteriovenous (A-V) fistula in rats have not been well characterized. To this end, LV end-diastolic pressure, size, and function (i.e., isovolumetric pressure-volume relationships in the blood-perfused isolated heart) were assessed at 1, 2, 3, 5, and 8 wk post-A-V fistula and compared with age-matched control animals. Progressive hypertrophy (192% at 8 wk), ventricular dilatation (172% at 8 wk), and a decrease in ventricular stiffness (257% at 8 wk) occurred in the fistula groups. LV end-diastolic pressure increased from a control value of 4.2 +/- 3.1 mmHg to a peak value of 15.7 +/- 3.6 mmHg after 3 wk of volume overload. A subsequent decline in LVEDP to 11.0 +/- 6.0 mmHg together with further LV dilation (169%) corresponded to a significant decrease in LV stiffness (222%) at 5 wk post-A-V fistula. Myocardial contractility, as assessed by the isovolumetric pressure-volume relationship, was significantly reduced in all A-V fistula groups; however, the compensatory remodeling induced by 8 wk of chronic biventricular volume overload tended to preserve systolic function.

  17. The Effects of Puerarin on Rat Ventricular Myocytes and the Potential Mechanism

    PubMed Central

    Xu, Hao; Zhao, Manxi; Liang, Shenghui; Huang, Quanshu; Xiao, Yunchuan; Ye, Liang; Wang, Qinyi; He, Longmei; Ma, Lanxiang; Zhang, Hua; Zhang, Li; Jiang, Hui; Ke, Xiao; Gu, Yuchun

    2016-01-01

    Puerarin, a known isoflavone, is commonly found as a Chinese herb medicine. It is widely used in China to treat cardiac diseases such as angina, cardiac infarction and arrhythmia. However, its cardioprotective mechanism remains unclear. In this study, puerarin significantly prolonged ventricular action potential duration (APD) with a dosage dependent manner in the micromolar range on isolated rat ventricular myocytes. However, submicromolar puerarin had no effect on resting membrane potential (RMP), action potential amplitude (APA) and maximal velocity of depolarization (Vmax) of action potential. Only above the concentration of 10 mM, puerarin exhibited more aggressive effect on action potential, and shifted RMP to the positive direction. Millimolar concentrations of puerarin significantly inhibited inward rectified K+ channels in a dosage dependent manner, and exhibited bigger effects upon Kir2.1 vs Kir2.3 in transfected HEK293 cells. As low as micromolar range concentrations of puerarin significantly inhibited Kv7.1 and IKs. These inhibitory effects may due to the direct inhibition of puerarin upon channels not via the PKA-dependent pathway. These results provided direct preclinical evidence that puerarin prolonged APD via its inhibitory effect upon Kv7.1 and IKs, contributing to a better understanding the mechanism of puerarin cardioprotection in the treatment of cardiovascular diseases. PMID:27762288

  18. Deferoxamine prevents cerebral glutathione and vitamin E depletions in asphyxiated neonatal rats: role of body temperature.

    PubMed

    Kletkiewicz, Hanna; Nowakowska, Anna; Siejka, Agnieszka; Mila-Kierzenkowska, Celestyna; Woźniak, Alina; Caputa, Michał; Rogalska, Justyna

    2016-01-01

    Hypoxic-ischaemic brain injury involves increased oxidative stress. In asphyxiated newborns iron deposited in the brain catalyses formation of reactive oxygen species. Glutathione (GSH) and vitamin E are key factors protecting cells against such agents. Our previous investigation has demonstrated that newborn rats, showing physiological low body temperature as well as their hyperthermic counterparts injected with deferoxamine (DF) are protected against iron-mediated, delayed neurotoxicity of perinatal asphyxia. Therefore, we decided to study the effects of body temperature and DF on the antioxidant status of the brain in rats exposed neonatally to critical anoxia. Two-day-old newborn rats were exposed to anoxia in 100% nitrogen atmosphere for 10 min. Rectal temperature was kept at 33 °C (physiological to rat neonates), or elevated to the level typical of healthy adult rats (37 °C), or of febrile adult rats (39 °C). Half of the rats exposed to anoxia under extremely hyperthermic conditions (39 °C) were injected with DF. Cerebral concentrations of malondialdehyde (MDA, lipid peroxidation marker) and the levels of GSH and vitamin E were determined post-mortem, (1) immediately after anoxia, (2) 3 days, (3) 7 days, and (4) 2 weeks after anoxia. There were no post-anoxic changes in MDA, GSH and vitamin E concentrations in newborn rats kept at body temperature of 33 °C. In contrast, perinatal anoxia at elevated body temperatures intensified oxidative stress and depleted the antioxidant pool in a temperature-dependent manner. Both the depletion of antioxidants and lipid peroxidation were prevented by post-anoxic DF injection. The data support the idea that hyperthermia may extend perinatal anoxia-induced brain lesions.

  19. Trypsin and alpha-chymotrypsin treatment abolishes glibenclamide sensitivity of KATP channels in rat ventricular myocytes.

    PubMed

    Nichols, C G; Lopatin, A N

    1993-03-01

    Cytoplasmic trypsin-treatment of voltage-sensitive potassium channels has been shown to cleave domains of the channel responsible for inactivation of the channel. Trypsin has also been reported to remove slow, irreversible inactivation, or run-down in ATP-sensitive potassium (KATP) channels. Cytoplasmic treatment of rat ventricular KATP channels with either crude, or pure trypsin (1-2 mg/ml) failed to prevent a slow run-down of channel activity. However, trypsin (porcine pancreatic type IX, or type II (Sigma Chem. Co.), or alpha-chymotrypsin (Sigma Chem. Co.) rapidly and irreversibly removed, or substantiallly decreased glibenclamide and tolbutamide-sensitivity of the channels without removing sensitivity to ATP. We conclude that glibenclamide must bind to either a separate protein, or to a separate domain on the channel in order to effect channel inhibition, and this domain is functionally disconnected from the channel by trypsin-, or alpha-chymotrypsin treatment.

  20. Agonists of MAS oncogene and angiotensin II type 2 receptors attenuate cardiopulmonary disease in rats with neonatal hyperoxia-induced lung injury.

    PubMed

    Wagenaar, Gerry T M; Laghmani, El Houari; Fidder, Melissa; Sengers, Rozemarijn M A; de Visser, Yvonne P; de Vries, Louwe; Rink, Rick; Roks, Anton J M; Folkerts, Gert; Walther, Frans J

    2013-09-01

    Stimulation of MAS oncogene receptor (MAS) or angiotensin (Ang) receptor type 2 (AT2) may be novel therapeutic options for neonatal chronic lung disease (CLD) by counterbalancing the adverse effects of the potent vasoconstrictor angiotensin II, consisting of arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH) and pulmonary inflammation. We determined the cardiopulmonary effects in neonatal rats with CLD of daily treatment during continuous exposure to 100% oxygen for 10 days with specific ligands for MAS [cyclic Ang-(1-7); 10-50 μg·kg(-1)·day(-1)] and AT2 [dKcAng-(1-7); 5-20 μg·kg(-1)·day(-1)]. Parameters investigated included lung and heart histopathology, fibrin deposition, vascular leakage, and differential mRNA expression in the lungs of key genes involved in the renin-angiotensin system, inflammation, coagulation, and alveolar development. We investigated the role of nitric oxide synthase inhibition with N(ω)-nitro-l-arginine methyl ester (25 mg·kg(-1)·day(-1)) during AT2 agonist treatment. Prophylactic treatment with agonists for MAS or AT2 for 10 days diminished cardiopulmonary injury by reducing alveolar septum thickness and medial wall thickness of small arterioles and preventing RVH. Both agonists attenuated the pulmonary influx of inflammatory cells, including macrophages (via AT2) and neutrophils (via MAS) but did not reduce alveolar enlargement and vascular alveolar leakage. The AT2 agonist attenuated hyperoxia-induced fibrin deposition. In conclusion, stimulation of MAS or AT2 attenuates cardiopulmonary injury by reducing pulmonary inflammation and preventing PAH-induced RVH but does not affect alveolar and vascular development in neonatal rats with experimental CLD. The beneficial effects of AT2 activation on experimental CLD were mediated via a NOS-independent mechanism.

  1. A Computational Model of Cytosolic and Mitochondrial [Ca2+] in Paced Rat Ventricular Myocytes

    PubMed Central

    Choi, Seong Woo; Jang, Chang Han; Kim, Hyoung Kyu; Leem, Chae Hun; Kim, Nari; Han, Jin

    2011-01-01

    We carried out a series of experiment demonstrating the role of mitochondria in the cytosolic and mitochondrial Ca2+ transients and compared the results with those from computer simulation. In rat ventricular myocytes, increasing the rate of stimulation (1~3 Hz) made both the diastolic and systolic [Ca2+] bigger in mitochondria as well as in cytosol. As L-type Ca2+ channel has key influence on the amplitude of Ca2+-induced Ca2+ release, the relation between stimulus frequency and the amplitude of Ca2+ transients was examined under the low density (1/10 of control) of L-type Ca2+ channel in model simulation, where the relation was reversed. In experiment, block of Ca2+ uniporter on mitochondrial inner membrane significantly reduced the amplitude of mitochondrial Ca2+ transients, while it failed to affect the cytosolic Ca2+ transients. In computer simulation, the amplitude of cytosolic Ca2+ transients was not affected by removal of Ca2+ uniporter. The application of carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) known as a protonophore on mitochondrial membrane to rat ventricular myocytes gradually increased the diastolic [Ca2+] in cytosol and eventually abolished the Ca2+ transients, which was similarly reproduced in computer simulation. The model study suggests that the relative contribution of L-type Ca2+ channel to total transsarcolemmal Ca2+ flux could determine whether the cytosolic Ca2+ transients become bigger or smaller with higher stimulus frequency. The present study also suggests that cytosolic Ca2+ affects mitochondrial Ca2+ in a beat-to-beat manner, however, removal of Ca2+ influx mechanism into mitochondria does not affect the amplitude of cytosolic Ca2+ transients. PMID:21994480

  2. SKF-96365 strongly inhibits voltage-gated sodium current in rat ventricular myocytes.

    PubMed

    Chen, Kui-Hao; Liu, Hui; Yang, Lei; Jin, Man-Wen; Li, Gui-Rong

    2015-06-01

    SKF-96365 (1-(beta-[3-(4-methoxy-phenyl) propoxy]-4-methoxyphenethyl)-1H-imidazole hydrochloride) is a general TRPC channel antagonist commonly used to characterize the potential functions of TRPC channels in cardiovascular system. Recent reports showed that SKF-96365 induced a reduction in cardiac conduction. The present study investigates whether the reduced cardiac conduction caused by SKF-96365 is related to the blockade of voltage-gated sodium current (I Na) in rat ventricular myocytes using the whole-cell patch voltage-clamp technique. It was found that SKF-96365 inhibited I Na in rat ventricular myocytes in a concentration-dependent manner. The compound (1 μM) negatively shifted the potential of I Na availability by 9.5 mV, increased the closed-state inactivation of I Na, and slowed the recovery of I Na from inactivation. The inhibition of cardiac I Na by SKF-96365 was use-dependent and frequency-dependent, and the IC₅₀ was decreased from 1.36 μM at 0.5 Hz to 1.03, 0.81, 0.61, 0.56 μM at 1, 2, 5, 10 Hz, respectively. However, the selective TRPC3 antagonist Pyr3 decreased cardiac I Na by 8.5% at 10 μM with a weak use and frequency dependence. These results demonstrate that the TRPC channel antagonist SKF-96365 strongly blocks cardiac I Na in use-dependent and frequency-dependent manners. Caution should be taken for interpreting the alteration of cardiac electrical activity when SKF-96365 is used in native cells as a TRPC antagonist.

  3. Alpha 1-adrenergic agonists selectively suppress voltage-dependent K+ current in rat ventricular myocytes.

    PubMed Central

    Apkon, M; Nerbonne, J M

    1988-01-01

    The effects of alpha 1-adrenergic agonists on the waveforms of action potentials and voltage-gated ionic currents were examined in isolated adult rat ventricular myocytes by the whole-cell patch-clamp recording technique. After "puffer" applications of either of two alpha 1 agonists, phenylephrine and methoxamine, action-potential durations were increased. In voltage-clamped cells, phenylephrine (5-20 microM) or methoxamine (5-10 microM) reduced the amplitudes of Ca2+-independent voltage-activated outward K+ currents (Iout); neither the kinetics nor the voltage-dependent properties of Iout were significantly affected. The effects of phenylephrine or methoxamine on Iout were larger and longer-lasting at higher concentrations and after prolonged or repeated exposures; in all experiments, however, Iout recovered completely when puffer applications were discontinued. The suppression of Iout is attributed to the activation of alpha 1-adrenergic receptors, as neither beta- nor alpha 2-adrenergic agonists had measurable effects on Iout; in addition, the effect of phenylephrine was attenuated in the presence of the alpha antagonist phentolamine (10 microM), but not in the presence of the beta antagonist propranolol (10 microM). Voltage-gated Ca2+ currents, in contrast, were not altered measurably by phenylephrine or methoxamine and no currents were activated directly by these agents. Suppression of Iout was also observed during puffer applications of either of two protein kinase C activators, phorbol 12-myristate 13-acetate (10 nM-1 microM) and 1-oleoyl-2-acetylglycerol (60 microM). We conclude that the activation of alpha 1-adrenergic receptors in adult rat ventricular myocytes leads to action-potential prolongation as a result of the specific suppression of Iout and that this effect may be mediated by activation of protein kinase C. PMID:2903506

  4. Neuroprotective effects of NGF, BDNF, NT-3 and GDNF on axotomized extraocular motoneurons in neonatal rats.

    PubMed

    Morcuende, S; Muñoz-Hernández, R; Benítez-Temiño, B; Pastor, A M; de la Cruz, R R

    2013-10-10

    Neurotrophic factors delivered from target muscles are essential for motoneuronal survival, mainly during development and early postnatal maturation. It has been shown that the disconnection between motoneurons and their innervated muscle by means of axotomy produces a vast neuronal death in neonatal animals. In the present work, we have evaluated the effects of different neurotrophic factors on motoneuronal survival after neonatal axotomy, using as a model the motoneurons innervating the extraocular eye muscles. With this purpose, neonatal rats were monocularly enucleated at the day of birth (postnatal day 0) and different neurotrophic treatments (NGF, BDNF, NT-3, GDNF and the mixture of BDNF+GDNF) were applied intraorbitally by means of a Gelfoam implant (a single dose of 5 μg of each factor). We first demonstrated that extraocular eye muscles of neonatal rats expressed these neurotrophic factors and therefore constituted a natural source of retrograde delivery for their innervating motoneurons. By histological and immunocytochemical methods we determined that all treatments significantly rescued extraocular motoneurons from axotomy-induced cell death. For the dose used, NGF and GDNF were the most potent survival factors for these motoneurons, followed by BDNF and lastly by NT-3. The simultaneous administration of BDNF and GDNF did not increase the survival-promoting effects above those obtained by GDNF alone. Interestingly, the rescue effects of all neurotrophic treatments persisted even 30 days after lesion. The administration of these neurotrophic factors, with the exception of NT-3, also prevented the loss of the cholinergic phenotype observed by 10 days after axotomy. At the dosage applied, NGF and GDNF were revealed again as the most effective neuroprotective agents against the axotomy-induced decrease in ChAT. Two remarkable findings highlighted in the present work that contrasted with other motoneuronal types after neonatal axotomy: first, the extremely

  5. Maternal-fetal carnitine relationship and neonatal ketosis in the rat.

    PubMed

    Robles-Valdes, C; McGarry, J D; Foster, D W

    1976-10-10

    The concentration of ketone bodies in plasma and of carnitine in various maternal, fetal, and neonatal tissues was examined during the developmental period in rats. Plasma ketone levels were low in the fetus, increased 10-fold during the first 24 h postpartom, and thereafter gradually declined such that normal values were found at the end of the suckling period. An almost identical profile was observed for liver carnitine concentrations in the baby rats. The converse was true for heart tissue, the carnitine content of which was low at birth and steadily increased to adult levels with the time of suckling. The primary source of carnitine in neonatal tissues, at least during the first 2 to 3 days postpartum, was shown to be the mother rat whose liver and milk carnitine content was very high at this time and fell as nursing continued. Experiments in which the fate of [14C]butyrobetaine, the immediate precursor of carnitine, was followed after injection into nursing mother rats indicated movement of carnitine from maternal liver leads to maternal plasma leads to milk leads to neonatal tissues. The above findings support the view expressed earlier that one prerequisite for the development of a high ketogenic profile in liver may be an elevation in the tissue carnitine concentration. Additional factors, however, are clearly involved as evidenced by the observation that in the fed state perfused livers from nursing mother rats synthesized ketone bodies from oleic acid at low rates compared with those seen after a 24 h fast, despite the fact that tissue carnitine levels were equally elevated in both groups. This paradox is likely related to the fact that in the fed state such livers also contained large quantities of glycogen, depletion of which through fasting was accompanied by marked acceleration of ketogenesis from oleate. The data indicate, therefore, that maximal ketogenic capacity of the liver requires for its induction an increase in carnitine coupled with a

  6. Neonatal stress alters LTP in freely moving male and female adult rats.

    PubMed

    Kehoe, P; Bronzino, J D

    1999-01-01

    We previously reported that neonatal isolation stress significantly changes measures of hippocampal long-term potentiation (LTP) in male and female juvenile rats, i.e., at 30 days of age. The changes in dentate granule population measures, i.e., excitatory postsynaptic potential (EPSP) and population spike amplitude (PSA), evoked by tetanization of the medial perforant pathway, indicated that juvenile rats exposed to neonatal isolation exhibit different enhancement profiles with respect to both the magnitude and duration of LTP in a sex-specific manner. Isolated males showed a significantly greater enhancement of LTP, while female "isolates" showed significantly longer LTP duration when compared to all other groups. The present study was designed to determine whether the effects of the neonatal isolation stress paradigm endures into adulthood. Rats isolated from their mothers for 1 h per day during postnatal days 2-9 were surgically prepared at 70-90 days of age, with stimulating and recording electrodes placed in the medial perforant pathway and the hippocampal dentate gyrus, respectively. Prior to tetanization, no significant effect of sex or treatment was obtained for baseline measures of EPSP slope or PSA. In order to rule out baseline differences in hippocampal cell excitability in female adult rats, we measured the response of dentate granule cells for one estrus cycle and found no pretetanization enhancement in the evoked response in either controls or previously stressed rats. Following tetanization, there was a significant treatment and sex effect. During the induction of LTP, PSA values were significantly enhanced in both isolated males and females and had significantly longer LTP duration when compared to the unhandled control group. Additionally, we observed that females took longer to reach baseline levels than males. Taken together, these results indicate that repeated infant isolation stress enhances LTP induction and duration in both males and

  7. Neonatal hyperthyroidism on rat heart: interrelation with nitric oxide and sex.

    PubMed

    Rodríguez, L; Detomaso, F; Braga, P; Prendes, M; Perosi, F; Cernadas, G; Balaszczuk, A; Fellet, A

    2015-06-01

    To clarify the mechanism mediating the effect of hyperthyroidism on cardiac function during the second month of life in rats. Male and female Sprague-Dawley rats were assigned to a control or to a triiodothyronine (T3)-treated group. Treatment of each group was started on the third day after birth. Control rats (Eut) received 0.9 NaCl [0.1 ml/100 g body weight (BW)] every second day during 60 days and T3-treated rats (Hyper) received subcutaneous (SC) T3 injections every second day during 60 days. Hyperthyroidism decreased left ventricle volume only in male rats. Female euthyroid rats presented higher atrial nitric oxide synthase (NOS) activity than male rats and hormonal treatment decreased this enzyme's activity in both sexes. Euthyroid male and female rats had similar atrial NOS protein levels, but females had higher caveolin (cav) 3 protein levels. T3 treatment increased this protein only in males. Female rats had lower ventricular NOS activity than male rats; hyperthyroidism increased NOS activity in both sexes but this effect was associated with lower cav 3 protein levels. Hyperthyroidism did not change cav 1 protein levels in both male and female rats. The results of this study demonstrating clinically relevant sex-related differences in the pathophysiology of the hyperthyroid heart have raised new questions regarding the mechanisms responsible for the observed differences. This study suggests that sex-related intrinsic factors such as nitric oxide may modulate the response to hyperthyroidism that leads to cardiovascular dysfunction.

  8. PRENATAL WINDOW OF SUSCEPTIBILITY TO PERFLUOROOCTANE SULFONATE-INDUCED NEONATAL MORTALITY IN THE SPRAGUE-DAWLEY RAT

    EPA Science Inventory

    Abstract
    The critical period for increased neonatal mortality induced by PFOS exposure was evaluated in the rat . Timed-pregnant Sprague-Dawley rats were treated by oral gavage with 25 mg/kg/d PFOS/K+ on four consecutive days during gestation (gestation days (GD) 2-5, 6-9, 1...

  9. Acetylcholine esterase activity and behavioral response in hypoxia induced neonatal rats: effect of glucose, oxygen and epinephrine supplementation.

    PubMed

    Chathu, Finla; Krishnakumar, Amee; Paulose, Cheramadathikudyil S

    2008-10-01

    Brain damage due to an episode of hypoxia remains a major problem in infants causing deficit in motor and sensory function. Hypoxia leads to neuronal functional failure, cerebral palsy and neuro-developmental delay with characteristic biochemical and molecular alterations resulting in permanent or transitory neurological sequelae or even death. During neonatal hypoxia, traditional resuscitation practices include the routine administration of 100% oxygen, epinephrine and glucose. In the present study, we assessed the changes in the cholinergic system by measuring the acetylcholinesterase (AChE) activity and the behavioral responses shown by hypoxia induced neonatal rats and hypoxic rats supplemented with glucose, oxygen and epinephrine using elevated plus-maze and open-field test. The acetylcholine esterase enzyme activity showed a significant decrease in cerebral cortex, whereas it increased significantly in the muscle of experimental rats when compared to control. Hypoxic rats supplemented with glucose, glucose and oxygen showed a reversal to the control status. Behavioral studies were carried out in experimental rats with elevated plus-maze test and open-field test. Hypolocomotion and anxiogenic behavioral responses were observed in all experimental rats when compared to control, hypoxic rats supplemented with glucose, glucose and oxygen. Thus, our results suggest that brain damage due to hypoxia, oxygen and epinephrine supplementation in the neonatal rats cause acetylcholine-neuromuscular-defect leading to hypolocomotion and anxiogenic behavioral response. Glucose and glucose with oxygen supplementation to hypoxic neonates protect the brain damage for a better functional status in the later life.

  10. NEONATAL LOW- AND HIGH-DOSE EXPOSURE TO ESTRADIOL BENZOATE IN THE MALE RAT: I. EFFECTS ON THE PROSTATE GLAND

    EPA Science Inventory

    Neonatal Low- And High-Dose Exposure To Estradiol Benzoate In The Male Rat: 1. Effects On The Prostate Gland. Oliver Putz, Christian B. Schwartz, Steve Kim, Gerald A. LeBlanc Ralph L. Cooper, Gail S. Prins

    ABSTRACT
    Brief exposure of rats to high doses of natural estro...

  11. PRENATAL WINDOW OF SUSCEPTIBILITY TO PERFLUOROOCTANE SULFONATE-INDUCED NEONATAL MORTALITY IN THE SPRAGUE-DAWLEY RAT

    EPA Science Inventory

    Abstract
    The critical period for increased neonatal mortality induced by PFOS exposure was evaluated in the rat . Timed-pregnant Sprague-Dawley rats were treated by oral gavage with 25 mg/kg/d PFOS/K+ on four consecutive days during gestation (gestation days (GD) 2-5, 6-9, 1...

  12. NEONATAL LOW- AND HIGH-DOSE EXPOSURE TO ESTRADIOL BENZOATE IN THE MALE RAT: I. EFFECTS ON THE PROSTATE GLAND

    EPA Science Inventory

    Neonatal Low- And High-Dose Exposure To Estradiol Benzoate In The Male Rat: 1. Effects On The Prostate Gland. Oliver Putz, Christian B. Schwartz, Steve Kim, Gerald A. LeBlanc Ralph L. Cooper, Gail S. Prins

    ABSTRACT
    Brief exposure of rats to high doses of natural estro...

  13. Effect of paroxetine on left ventricular remodeling in an in vivo rat model of myocardial infarction.

    PubMed

    Lassen, Thomas Ravn; Nielsen, Jan Møller; Johnsen, Jacob; Ringgaard, Steffen; Bøtker, Hans Erik; Kristiansen, Steen Buus

    2017-05-01

    Left ventricular (LV) remodeling following a myocardial infarction (MI) involves formation of reactive oxygen species (ROS). Paroxetine, a selective serotonin reuptake inhibitor, has an antioxidant effect in the vascular wall. We investigated whether paroxetine reduces myocardial ROS formation and LV remodeling following a MI. In a total of 32 Wistar rats, MI was induced by a 30-min ligation of the left anterior descending artery followed by 7- or 28-day reperfusion. During the 28 days of reperfusion, LV remodeling was evaluated by magnetic resonance imaging (MRI) and echocardiography (n = 20). After 28 days of reperfusion, the susceptibility to ventricular tachycardia was evaluated prior to sacrifice and histological assessment of myocyte cross-sectional area, fibrosis, and presence of myofibroblasts. Myocardial ROS formation was measured with dihydroethidium after 7 days of reperfusion in separate groups (n = 12). Diastolic LV volume, evaluated by MRI (417 ± 60 vs. 511 ± 64 µL, p < 0.05), and echocardiography (515 ± 80 vs. 596 ± 83 µL, p < 0.05) as well as diastolic LV internal diameter evaluated with echocardiography (7.2 ± 0.6 vs. 8.1 ± 0.7 mm, p < 0.05) were lower in the paroxetine group than in controls. Furthermore, myocyte cross-sectional area was reduced in the paroxetine group compared with controls (277 ± 26 vs. 354 ± 23 mm(3), p < 0.05) and ROS formation was reduced in the remote myocardium (0.415 ± 0.19 normalized to controls, p < 0.05). However, no differences in the presence of fibrosis or myofibroblasts were observed. Finally, paroxetine reduced the susceptibility to ventricular tachycardia (induced in 2/11 vs. 6/8 rats, p < 0.05). Paroxetine treatment following MI decreases LV remodeling and susceptibility to arrhythmias, probably by reducing ROS formation.

  14. Exercise induces cortical plasticity after neonatal spinal cord injury in the rat

    PubMed Central

    Kao, T; Shumsky, JS; Murray, M; Moxon, KA

    2009-01-01

    Exercise-induced cortical plasticity is associated with improved functional outcome after brain or nerve injury. Exercise also improves functional outcomes after spinal cord injury, but its effects on cortical plasticity are not known. The goal of this investigation was to study the effect of moderate exercise (treadmill locomotion, 3 min/day, 5days/week) on the somatotopic organization of forelimb and hindlimb somatosensory cortex (SI) after neonatal thoracic transection. We used adult rats spinalized as neonates because some of these animals develop weight-supported stepping and, therefore, the relationship between cortical plasticity and stepping could also be examined. Acute, single-neuron mapping was used to determine the percentage of cortical cells responding to cutaneous forelimb stimulation in normal, spinalized, and exercised spinalized rats. Multiple single neuron recording from arrays of chronically implanted microwires examined the magnitude of response of these cells in normal and exercised spinalized rats. Our results show that exercise not only increased the percentage of responding cells in the hindlimb SI, but also increased the magnitude of the response of these cells. This increase in response magnitude was correlated with behavioral outcome measures. In the forelimb SI, neonatal transection reduced the percentage of responding cells to forelimb stimulation but exercise reversed this loss. This restoration in the percentage of responding cells after exercise was accompanied by an increase in their response magnitude. Therefore, the increase in responsiveness of hindlimb SI to forelimb stimulation after neonatal transection and exercise may be due, in part, to the effect of exercise on the forelimb SI. PMID:19515923

  15. Activity and social behavior in a complex environment in rats neonatally exposed to alcohol.

    PubMed

    Boschen, Karen E; Hamilton, Gillian F; Delorme, James E; Klintsova, Anna Y

    2014-09-01

    Environmental complexity (EC) is a powerful, stimulating paradigm that engages animals through a variety of sensory and motor pathways. Exposure to EC (30 days) following 12 days of wheel running preserves hippocampal neuroplasticity in male rats neonatally exposed to alcohol during the third-trimester equivalent (binge-like exposure on postnatal days [PD] 4-9). The current experiment investigates the importance of various components of EC (physical activity, exploration, social interaction, novelty) and examines whether neonatal alcohol exposure affects how male rats interact with their environment and other male rats. Male pups were assigned to 1 of 3 neonatal conditions from PD 4-9: suckle control (SC), sham-intubated (SI), or alcohol-exposed (AE, 5.25 g/kg/day). From PD 30-42 animals were housed with 24-h access to a voluntary running wheel. The animals were then placed in EC from PD 42-72 (9 animals/cage, counterbalanced by neonatal condition). During EC, the animals were filmed for five 30-min sessions (PD 42, 48, 56, 64, 68). For the first experiment, the videos were coded for distance traveled in the cage, overall locomotor activity, time spent near other animals, and interaction with toys. For the second experiment, the videos were analyzed for wrestling, mounting, boxing, grooming, sniffing, and crawling over/under. AE animals were found to be less active and exploratory and engaged in fewer mounting behaviors compared to control animals. Results suggest that after exposure to wheel running, AE animals still have deficits in activity and social behaviors while housed in EC compared to control animals with the same experience.

  16. Activity and Social Behavior in a Complex Environment in Rats Neonatally Exposed to Alcohol

    PubMed Central

    Boschen, Karen E.; Hamilton, Gillian F.; Delorme, James E.; Klintsova, Anna Y.

    2014-01-01

    Environmental complexity (EC) is a powerful, stimulating paradigm that engages animals through a variety of sensory and motor pathways. Exposure to EC (30 days) following 12 days of wheel running preserves hippocampal neuroplasticity in male rats neonatally exposed to alcohol during the third-trimester equivalent (binge-like exposure on postnatal days [PD] 4–9). The current experiment investigates the importance of various components of EC (physical activity, exploration, social interaction, novelty) and examines whether neonatal alcohol exposure affects how male rats interact with their environment and other male rats. Male pups were assigned to 1 of 3 neonatal conditions from PD 4–9: suckle control (SC), sham-intubated (SI), or alcohol-exposed (AE, 5.25 g/kg/day). From PD 30–42 animals were housed with 24-h access to a voluntary running wheel. The animals were then placed in EC from PD 42–72 (9 animals/cage, counterbalanced by neonatal condition). During EC, the animals were filmed for five 30-min sessions (PD 42, 48, 56, 64, 68). For the first experiment, the videos were coded for distance traveled in the cage, overall locomotor activity, time spent near other animals, and interaction with toys. For the second experiment, the videos were analyzed for wrestling, mounting, boxing, grooming, sniffing, and crawling over/under. AE animals were found to be less active and exploratory and engaged in fewer mounting behaviors compared to control animals. Results suggest that after exposure to wheel running, AE animals still have deficits in activity and social behaviors while housed in EC compared to control animals with the same experience. PMID:25150044

  17. Effects of Sleep Deprivation on Action Potential and Transient Outward Potassium Current in Ventricular Myocytes in Rats

    PubMed Central

    Fang, Zhou; Ren, Yi-Peng; Lu, Cai-Yi; Li, Yang; Xu, Qiang; Peng, Li; Fan, Yong-Yan

    2015-01-01

    Background Sleep deprivation contributes to the development and recurrence of ventricular arrhythmias. However, the electrophysiological changes in ventricular myocytes in sleep deprivation are still unknown. Material/Methods Sleep deprivation was induced by modified multiple platform technique. Fifty rats were assigned to control and sleep deprivation 1, 3, 5, and 7 days groups, and single ventricular myocytes were enzymatically dissociated from rat hearts. Action potential duration (APD) and transient outward current (Ito) were recorded using whole-cell patch clamp technique. Results Compared with the control group, the phases of APD of ventricular myocytes in 3, 5, and 7 days groups were prolonged and APD at 20% and 50% level of repolarization (APD20 and APD50) was significantly elongated (The APD20 values of control, 1, 3, 5, and 7 days groups: 5.66±0.16 ms, 5.77±0.20 ms, 8.28±0.30 ms, 11.56±0.32 ms, 13.24±0.56 ms. The APD50 values: 50.66±2.16 ms, 52.77±3.20 ms, 65.28±5.30 ms, 83.56±7.32 ms, 89.24±5.56 ms. P<0.01, n=18). The current densities of Ito significantly decreased. The current density-voltage (I–V) curve of Ito was vitally suppressed downward. The steady-state inactivation curve and steady-state activation curve of Ito were shifted to left and right, respectively, in sleep deprivation rats. The inactivation recovery time of Ito was markedly retarded and the time of closed-state inactivation was markedly accelerated in 3, 5, and 7 days groups. Conclusions APD of ventricular myocytes in sleep deprivation rats was significantly prolonged, which could be attributed to decreased activation and accelerated inactivation of Ito. PMID:25694200

  18. Effects of sleep deprivation on action potential and transient outward potassium current in ventricular myocytes in rats.

    PubMed

    Fang, Zhou; Ren, Yi-Peng; Lu, Cai-Yi; Li, Yang; Xu, Qiang; Peng, Li; Fan, Yong-Yan

    2015-02-19

    Sleep deprivation contributes to the development and recurrence of ventricular arrhythmias. However, the electrophysiological changes in ventricular myocytes in sleep deprivation are still unknown. Sleep deprivation was induced by modified multiple platform technique. Fifty rats were assigned to control and sleep deprivation 1, 3, 5, and 7 days groups, and single ventricular myocytes were enzymatically dissociated from rat hearts. Action potential duration (APD) and transient outward current (Ito) were recorded using whole-cell patch clamp technique. Compared with the control group, the phases of APD of ventricular myocytes in 3, 5, and 7 days groups were prolonged and APD at 20% and 50% level of repolarization (APD20 and APD50) was significantly elongated (The APD20 values of control, 1, 3, 5, and 7 days groups: 5.66±0.16 ms, 5.77±0.20 ms, 8.28±0.30 ms, 11.56±0.32 ms, 13.24±0.56 ms. The APD50 values: 50.66±2.16 ms, 52.77±3.20 ms, 65.28±5.30 ms, 83.56±7.32 ms, 89.24±5.56 ms. P<0.01, n=18). The current densities of Ito significantly decreased. The current density-voltage (I-V) curve of Ito was vitally suppressed downward. The steady-state inactivation curve and steady-state activation curve of Ito were shifted to left and right, respectively, in sleep deprivation rats. The inactivation recovery time of Ito was markedly retarded and the time of closed-state inactivation was markedly accelerated in 3, 5, and 7 days groups. APD of ventricular myocytes in sleep deprivation rats was significantly prolonged, which could be attributed to decreased activation and accelerated inactivation of Ito.

  19. The calcium-frequency response in the rat ventricular myocyte: an experimental and modelling study.

    PubMed

    Gattoni, Sara; Røe, Åsmund Treu; Frisk, Michael; Louch, William E; Niederer, Steven A; Smith, Nicolas P

    2016-08-01

    In the majority of species, including humans, increased heart rate increases cardiac contractility. This change is known as the force-frequency response (FFR). The majority of mammals have a positive force-frequency relationship (FFR). In rat the FFR is controversial. We derive a species- and temperature-specific data-driven model of the rat ventricular myocyte. As a measure of the FFR, we test the effects of changes in frequency and extracellular calcium on the calcium-frequency response (CFR) in our model and three altered models. The results show a biphasic peak calcium-frequency response, due to biphasic behaviour of the ryanodine receptor and the combined effect of the rapid calmodulin buffer and the frequency-dependent increase in diastolic calcium. Alterations to the model reveal that inclusion of Ca(2+) /calmodulin-dependent protein kinase II (CAMKII)-mediated L-type channel and transient outward K(+) current activity enhances the positive magnitude calcium-frequency response, and the absence of CAMKII-mediated increase in activity of the sarco/endoplasmic reticulum Ca(2+) -ATPase induces a negative magnitude calcium-frequency response. An increase in heart rate affects the strength of cardiac contraction by altering the Ca(2+) transient as a response to physiological demands. This is described by the force-frequency response (FFR), a change in developed force with pacing frequency. The majority of mammals, including humans, have a positive FFR, and cardiac contraction strength increases with heart rate. However, the rat and mouse are exceptions, with the majority of studies reporting a negative FFR, while others report either a biphasic or a positive FFR. Understanding the differences in the FFR between humans and rats is fundamental to interpreting rat-based experimental findings in the context of human physiology. We have developed a novel model of rat ventricular electrophysiology and calcium dynamics, derived predominantly from experimental data

  20. Latent inhibition in rats neonatally treated chronically with MK-801: differential effects on conditioned taste aversion and conditioned emotional response.

    PubMed

    Niikura, Ryo; Nozawa, Takashi; Yamada, Kazuo; Kato, Katsunori; Ichitani, Yukio

    2015-04-15

    Chronic neonatal blockade of N-methyl-d-aspartate (NMDA) receptors produces various abnormal behaviors in adulthood animals. This study investigated the effects of neonatal treatment chronically with MK-801 in rats on the preexposure-induced retardation of CS-US association, i.e. latent inhibition (LI), of two aversive classical conditioning tasks in adulthood. In conditioned taste aversion (CTA) using sucrose taste and LiCl, neonatal chronic MK-801 (0.4 mg/kg twice/day) treatment attenuated the inhibitory effect of sucrose preexposure on the aversive conditioning, although the treatment did not affect CTA conditioning itself. On the other hand, in conditioned emotional response (CER) using tone and electrical foot shock, rats neonatally treated with MK-801 showed the same degree of inhibitory effect of tone preexposure on the aversive conditioning compared with neonatally vehicle-treated rats, and also showed the same level of CER conditioning itself. Thus, the effect of chronic neonatal blockade of NMDA receptors on the LI of classical conditioning in adulthood was differentiated by the task employed. Results suggest that LI of CTA paradigm compared with that of CER is more sensitive to abnormal development after chronic neonatal blockade of NMDA receptors as an index of cognitive/attentional deficits caused by the treatment.

  1. [Intervention of systolic pressure and left ventricular hypertrophy in rats under cold stress].

    PubMed

    Sun, C F; Wang, S G; Peng, Y G; Shi, Y; Du, Y P; Shi, G X; Wen, T; Wang, Y K; Su, H

    2016-06-20

    To investigate the effects of different drugs on systolic blood pressure (SBP) and left ventricular hypertrophy (LVH) in spontaneously hypertensive rats under cold stress. A total of 40 male spontaneously hypertensive rats aged 10 weeks (160~200 g) were given adaptive feeding for 7 days at a temperature of 20±1°C and then randomly divided into control group, cold stress group, metoprolol group, amlodipine group, and benazepril group, with 8 rats in each group. SBP, body weight, and heart rate were measured once a week. After the rats were sacrificed by exsanguination, left ventricular weight (LVW) was measured, and left ventricular weight index (LVWI; mg/g) was calculated. Radioimmunoassay was used to measure the concentrations of endothelin-1 (ET-1) and angiotensin-II (Ang-II) in plasma and myocardium, and the chemical method was used to measure the concentrations of nitric oxide (NO) in plasma and myocardium. RT-PCR was used to measure the mRNA expression of endothelin-A receptor. Compared with the cold stress group, all medication groups showed significant reductions in SBP since week 5 (P<0.05). The cold stress group showed a significant increase in LVWI compared with the control group (3.38±0.27 mg/g vs 2.89±0.19 mg/g, P<0.05). The amlodipine group showed a significant reduction in LVWI compared with the cold stress group (2.98±0.28 mg/g vs 3.38±0.27 mg/g, P<0.05). The cold stress group showed a significant reduction in plasma NO concentration compared with the control group (104.9±19.5 μmol/L vs 129.3±17.8 μmol/L, P<0.05) ; compared with the cold stress group, all the medication groups showed significant increases in blood NO concentration (P<0.05). The cold stress group showed a significant increase in myocardial ET-1 concentration compared with the control group (6.3±1.5 pg/100 mg vs 4.5±1.9 pg/100 mg, P<0.05) ; compared with the cold stress group, the amlodipine group showed a significant reduction in myocardial ET-1 concentration (4.4±1.0 pg

  2. Schisandra chinensis reverses visceral hypersensitivity in a neonatal-maternal separated rat model.

    PubMed

    Yang, Jia-Ming; Xian, Yan-Fang; Ip, Paul S P; Wu, Justin C Y; Lao, Lixing; Fong, Harry H S; Sung, Joseph J Y; Berman, Brian; Yeung, John H K; Che, Chun-Tao

    2012-03-15

    Visceral hypersensitivity is an important characteristic feature of functional gastrointestinal disorders, such as irritable bowel syndrome (IBS). This study evaluated the effect of Schisandra chinensis on visceral hyperalgesia induced by neonatal maternal separation (NMS) in an IBS rat model. The visceromotor responses to colorectal balloon distension (CRD) were measured by abdominal withdrawal reflex (AWR) and electromyographic (EMG) activities. NMS control rats (receiving vehicle) underwent aggravated visceral pain in response to CRD as compared to normal rats, evidenced by the reduced pain threshold, enhanced AWR scores and EMG responses. Treatment with a 70% ethanol extract of S. chinensis (0.3g/kg and 1.5g/kg/day) for 7 days resulted in an increase in the pain threshold (NMS control: 19.1±1.0mmHg vs low-dose: 24.8±1.3mmHg and high-dose: 25.2±1.8mmHg, p<0.01), and abolished the elevated AWR and EMG responses to CRD in NMS rats (AUC values of EMG response curve were: 1952±202 in NMS control group vs 1074±90 in low-dose group and 1145±92 in high-dose group, p<0.001), indicating that S. chinensis could reverse the visceral hypersensitivity induced by early-life stress event. The result of ELSA measurement shows that the elevated serotonin (5-HT) level in the distal colon of NMS rats returned to normal level after treatment with S. chinensis. Moreover, the increase in pain threshold in rats treated with S. chinensis was associated with a decline of the mRNA level of 5-HT(3) receptor in the distal colon. All available results demonstrate that S. chinensis can reverse visceral hypersensitivity induced by neonatal-maternal separation, and the effect may be mediated through colonic 5-HT pathway in the rat.

  3. Schisandra chinensis reverses visceral hypersensitivity in a neonatal-maternal separated rat model

    PubMed Central

    Yang, Jia-Ming; Xian, Yan-Fang; Ip, Paul SP; Wu, Justin CY; Lao, Lixing; Fong, Harry HS; Sung, Joseph JY; Berman, Brian; Yeung, John HK; Che, Chun-Tao

    2012-01-01

    Visceral hypersensitivity is an important characteristic feature of functional gastrointestinal disorders, such as irritable bowel syndrome (IBS). This study evaluated the effect of Schisandra chinensis on visceral hyperalgesia induced by neonatal maternal separation (NMS) in an IBS rat model. The visceromotor responses to colorectal balloon distension (CRD) were measured by abdominal withdrawal reflex (AWR) and electromyographic activities (EMG). NMS control rats (receiving vehicle) underwent aggravated visceral pain in response to CRD as compared to normal rats, evidenced by the reduced pain threshold, enhanced AWR scores and EMG responses. Treatment with a 70% ethanol extract of S. chinensis (0.3 g/kg and 1.5 g/kg per day) for seven days resulted in an increase in the pain threshold (NMS control: 19.1 ± 1.0 mmHg vs low-dose: 24.8 ± 1.3 mmHg and high-dose: 25.2 ± 1.8 mmHg, p<0.01), and abolished the elevated AWR and EMG responses to CRD in NMS rats (AUC values of EMG response curve were: 1952 ± 202 in NMS control group vs 1074 ± 90 in low-dose group and 1145 ± 92 in high-dose group, p<0.001), indicating that S. chinensis could reverse the visceral hypersensitivity induced by early-life stress event. The result of ELSA measurement shows that the elevated serotonin (5-HT) level in the distal colon of NMS rats returned to normal level after treatment with S. chinensis. Moreover, the increase in pain threshold in rats treated with S. chinensis was associated with a decline of the mRNA level of 5-HT3 receptor in the distal colon. All available results demonstrate that S. chinensis can reverse visceral hypersensitivity induced by neonatal-maternal separation, and the effect may be mediated through colonic 5-HT pathway in the rat. PMID:22230486

  4. Krill oil attenuates left ventricular dilatation after myocardial infarction in rats

    PubMed Central

    2011-01-01

    Background In the western world, heart failure (HF) is one of the most important causes of cardiovascular mortality. Supplement with n-3 polyunsaturated fatty acids (PUFA) has been shown to improve cardiac function in HF and to decrease mortality after myocardial infarction (MI). The molecular structure and composition of n-3 PUFA varies between different marine sources and this may be of importance for their biological effects. Krill oil, unlike fish oil supplements, contains the major part of the n-3 PUFA in the form of phospholipids. This study investigated effects of krill oil on cardiac remodeling after experimental MI. Rats were randomised to pre-treatment with krill oil or control feed 14 days before induction of MI. Seven days post-MI, the rats were examined with echocardiography and rats in the control group were further randomised to continued control feed or krill oil feed for 7 weeks before re-examination with echocardiography and euthanization. Results The echocardiographic evaluation showed significant attenuation of LV dilatation in the group pretreated with krill oil compared to controls. Attenuated heart weight, lung weight, and levels of mRNA encoding classical markers of LV stress, matrix remodeling and inflammation reflected these findings. The total composition of fatty acids were examined in the left ventricular (LV) tissue and all rats treated with krill oil showed a significantly higher proportion of n-3 PUFA in the LV tissue, although no difference was seen between the two krill oil groups. Conclusions Supplement with krill oil leads to a proportional increase of n-3 PUFA in myocardial tissue and supplement given before induction of MI attenuates LV remodeling. PMID:22206454

  5. Effects of acute intravenous iloprost on right ventricular hemodynamics in rats with chronic pulmonary hypertension

    PubMed Central

    Bachman, Timothy N.; El-Haddad, Hazim; Champion, Hunter C.

    2014-01-01

    Abstract The inotropic effects of prostacyclins in chronic pulmonary arterial hypertension (PAH) are unclear and may be important in directing patient management in the acute setting. We sought to study the effects of an acute intravenous (IV) infusion of iloprost on right ventricular (RV) contractility in a rat model of chronic PAH. Rats were treated with monocrotaline, 60 mg/kg intraperitoneally, to induce PAH. Six weeks later, baseline hemodynamic assessment was performed with pressure-volume and Doppler flow measurements. In one group of animals, measurements were repeated 10–15 minutes after IV infusion of a fixed dose of iloprost (20 μg/kg). A separate group of rats underwent dose-response assessment. RV contractility and RV–pulmonary artery coupling were assessed by the end-systolic pressure-volume relationship (ESPVR) and end-systolic elastance/effective arterial elastance (Ees/Ea). RV cardiomyocytes were isolated, and intracellular cAMP (cyclic adenosine monophosphate) concentration was measured with a cAMP-specific enzyme immunoassay kit. Animals had evidence of PAH and RV hypertrophy. Right ventricle/(left ventricle + septum) weight was 0.40 ± 0.03. RV systolic pressure (RVSP) was 39.83 ± 1.62 mmHg. Administration of iloprost demonstrated an increase in the slope of the ESPVR from 0.29 ± 0.02 to 0.42 ± 0.05 (P < .05). Ees/Ea increased from 0.63 ± 0.07 to 0.82 ± 0.06 (P < .05). The RV contractility index (max dP/dt normalized for instantaneous pressure) increased from 94.11 to 114.5/s (P < .05), as did the RV ejection fraction, from 48.0% to 52.5% (P < .05). This study suggests a positive inotropic effect of iloprost on a rat model of chronic PAH. PMID:25610597

  6. Intralipid prevents and rescues fatal pulmonary arterial hypertension and right ventricular failure in rats.

    PubMed

    Umar, Soban; Nadadur, Rangarajan D; Li, Jingyuan; Maltese, Federica; Partownavid, Parisa; van der Laarse, Arnoud; Eghbali, Mansoureh

    2011-09-01

    Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling leading to right ventricular (RV) hypertrophy and failure. Intralipid (ILP), a source of parenteral nutrition for patients, contains γ-linolenic acid and soy-derived phytoestrogens that are protective for lungs and heart. We, therefore, investigated the therapeutic potential of ILP in preventing and rescuing monocrotaline-induced PAH and RV dysfunction. PAH was induced in male rats with monocrotaline (60 mg/kg). Rats then received daily ILP (1 mL of 20% ILP per day IP) from day 1 to day 30 for prevention protocol or from day 21 to day 30 for rescue protocol. Other monocrotaline-injected rats were left untreated to develop severe PAH by day 21 or RV failure by approximately day 30. Saline or ILP-treated rats served as controls. Significant increase in RV pressure and decrease in RV ejection fraction in the RV failure group resulted in high mortality. Therapy with ILP resulted in 100% survival and prevented PAH-induced RV failure by preserving RV pressure and RV ejection fraction and preventing RV hypertrophy and lung remodeling. In preexisting severe PAH, ILP attenuated most lung and RV abnormalities. The beneficial effects of ILP in PAH seem to result from the interplay of various factors, among which preservation and/or stimulation of angiogenesis, suppression and/or reversal of inflammation, fibrosis and hypertrophy, in both lung and RV, appear to be major contributors. In conclusion, ILP not only prevents the development of PAH and RV failure but also rescues preexisting severe PAH.

  7. The Physiologic Effects of Isoflurane, Sevoflurane, and Hypothermia Used for Anesthesia in Neonatal Rats (Rattus norvegicus)

    PubMed Central

    Huss, Monika K; Chum, Helen H; Chang, Angela G; Jampachairsi, Katechan; Pacharinsak, Cholawat

    2016-01-01

    Information regarding effective anesthetic regimens for neonatal rat pups is limited. Here we investigated whether isoflurane or sevoflurane anesthesia maintains physiologic parameters more consistently than does hypothermia anesthesia in neonatal rat pups. Rat pups (age, 4 d) were randomly assigned to receive isoflurane, sevoflurane, or hypothermia. Physiologic parameters monitored at 1, 5, 10, and 15 min included heart rate (HR), respiratory rate (RR), and oxygen saturation (%SpO2). Other parameters evaluated were loss and return of righting reflex, paw withdrawal reflex, and maternal acceptance. Corticosterone and glucose were sampled at 20 min and 24 h after anesthesia induction. Once a surgical plane of anesthesia was achieved, a skin incision was made on the right lateral thigh. After the procedure, all pups were accepted and cared for by their dam. Isoflurane- and sevoflurane-treated pups maintained higher HR, RR, %SpO2, and glucose levels than did hypothermia-treated pups. For both the isoflurane and sevoflurane groups, HR and RR were significantly lower at 10 and 15 min after anesthesia than at 1 min. Compared with hypothermia, isoflurane and sevoflurane anesthesia provided shorter times to loss of and return of the righting reflex. Although corticosterone did not differ among the groups, glucose levels were higher at 20 min after anesthesia induction than at 24 h in all anesthetic groups. We conclude that both isoflurane and sevoflurane anesthesia maintain physiologic parameters (HR, RR, %SpO2) more consistently than does hypothermia anesthesia in 4-d-old rat pups. PMID:26817984

  8. The Physiologic Effects of Isoflurane, Sevoflurane, and Hypothermia Used for Anesthesia in Neonatal Rats (Rattus norvegicus).

    PubMed

    Huss, Monika K; Chum, Helen H; Chang, Angela G; Jampachairsi, Katechan; Pacharinsak, Cholawat

    2016-01-01

    Information regarding effective anesthetic regimens for neonatal rat pups is limited. Here we investigated whether isoflurane or sevoflurane anesthesia maintains physiologic parameters more consistently than does hypothermia anesthesia in neonatal rat pups. Rat pups (age, 4 d) were randomly assigned to receive isoflurane, sevoflurane, or hypothermia. Physiologic parameters monitored at 1, 5, 10, and 15 min included heart rate (HR), respiratory rate (RR), and oxygen saturation (%SpO2). Other parameters evaluated were loss and return of righting reflex, paw withdrawal reflex, and maternal acceptance. Corticosterone and glucose were sampled at 20 min and 24 h after anesthesia induction. Once a surgical plane of anesthesia was achieved, a skin incision was made on the right lateral thigh. After the procedure, all pups were accepted and cared for by their dam. Isoflurane- and sevoflurane-treated pups maintained higher HR, RR, %SpO2, and glucose levels than did hypothermia-treated pups. For both the isoflurane and sevoflurane groups, HR and RR were significantly lower at 10 and 15 min after anesthesia than at 1 min. Compared with hypothermia, isoflurane and sevoflurane anesthesia provided shorter times to loss of and return of the righting reflex. Although corticosterone did not differ among the groups, glucose levels were higher at 20 min after anesthesia induction than at 24 h in all anesthetic groups. We conclude that both isoflurane and sevoflurane anesthesia maintain physiologic parameters (HR, RR, %SpO2) more consistently than does hypothermia anesthesia in 4-d-old rat pups.

  9. Mechanisms of noradrenaline-induced vasorelaxation in isolated femoral arteries of the neonatal rat.

    PubMed

    Nishina, H; Ozaki, T; Hanson, M A; Poston, L

    1999-06-01

    Isolated arteries from the femoral circulation of Wistar rats mounted on a small vessel myograph demonstrated age related tension development to noradrenaline (NA, 1 x 10(-8) - 5 x 10(-5) M) day 20 greater than day 10 (P<0.005); day 100 greater than day 20 (P<0.001) and depolarizing potassium (125 mM) buffer day 20 greater than day 10 (P<0.001). NA evoked dilatation in femoral arteries from neonatal rats (10 days) when added to unstimulated vessels or to those preconstricted with the thromboxane mimetic, U46619. Relaxation to NA was inhibited by L-NAME (0.1 mM) (P<0.001), endothelial removal (P<0.001) and the alpha2-adrenoceptor antagonist, yohimbine (0.1 microM) (P<0.001). Alpha1- or beta-adrenoceptor antagonism was without effect. Relaxation was evoked in femoral arteries of the 10-day-old rats by the alpha2-adrenoceptor agonist UK14304 (1 x 10(-8) - 5 x 10(-5) M). This relaxation was also abolished by L-NAME (0.1 mM) (P<0.001) or endothelial removal (P<0.001). Alpha2-adrenoceptor-mediated vasorelaxation was the predominant response to NA stimulation in femoral arteries of the neonatal rat. These responses were endothelium-dependent and were NO-mediated.

  10. Environmental Enrichment Decreases Asphyxia-Induced Neurobehavioral Developmental Delay in Neonatal Rats

    PubMed Central

    Kiss, Peter; Vadasz, Gyongyver; Kiss-Illes, Blanka; Horvath, Gabor; Tamas, Andrea; Reglodi, Dora; Koppan, Miklos

    2013-01-01

    Perinatal asphyxia during delivery produces long-term disability and represents a major problem in neonatal and pediatric care. Numerous neuroprotective approaches have been described to decrease the effects of perinatal asphyxia. Enriched environment is a popular strategy to counteract nervous system injuries. The aim of the present study was to investigate whether enriched environment is able to decrease the asphyxia-induced neurobehavioral developmental delay in neonatal rats. Asphyxia was induced in ready-to-deliver mothers by removing the pups by caesarian section after 15 min of asphyxia. Somatic and neurobehavioral development was tested daily and motor coordination weekly. Our results show that rats undergoing perinatal asphyxia had a marked developmental delay and worse performance in motor coordination tests. However, pups kept in enriched environment showed a decrease in the developmental delay observed in control asphyctic pups. Rats growing up in enriched environment did not show decrease in weight gain after the first week and the delay in reflex appearance was not as marked as in control rats. In addition, the development of motor coordination was not as strikingly delayed as in the control group. Short-term neurofunctional outcome are known to correlate with long-term deficits. Our results thus show that enriched environment could be a powerful strategy to decrease the deleterious developmental effects of perinatal asphyxia. PMID:24232451

  11. Effects of Neonatal Overfeeding on Juvenile and Adult Feeding and Energy Expenditure in the Rat

    PubMed Central

    Stefanidis, Aneta; Spencer, Sarah J.

    2012-01-01

    Overfeeding during perinatal life leads to an overweight phenotype that persists throughout the juvenile stage and into adulthood, however, the mechanim(s) underlying this effect are poorly understood. We hypothesized that obesity due to neonatal overfeeding is maintained by changes in energy expenditure and that these changes differ between males and females. We investigated feeding, physical activity, hormonal and metabolic alterations that occur in adult rats made obese by having been nursed in small litters (SL) compared with those from control litters (CL). There were no differences in absolute food intake between the groups, and juvenile and adult SL rats ate less chow per gram body weight than the CL did in the dark (active) phase. Juvenile, but not adult SL rats did have reduced whole body energy expenditure, but there were no differences between the groups by the time they reached adulthood. Adult SL females (but not males) had reduced brown adipose tissue (BAT) temperatures compared with CL in the first half of the dark phase. Our results indicate a persistent overweight phenotype in rats overfed as neonates is not associated with hyperphagia at any stage, but is reflected in reduced energy expenditure into the juvenile phase. The reduced dark phase BAT activity in adult SL females is not sufficient to reduce total energy expenditure at this stage of life and there is an apparently compensatory effect that prevents SL and CL from continuing to diverge in weight that appears between the juvenile and adult stages. PMID:23251693

  12. Osteogenic potential of osteoblasts from neonatal rats born to mothers treated with caffeine throughout pregnancy.

    PubMed

    Reis, Amanda Maria Sena; Ribeiro, Lorena Gabriela Rocha; Ocarino, Natália de Melo; Goes, Alfredo Miranda; Serakides, Rogéria

    2015-02-04

    Caffeine is an active alkaloid that can cause damage to bones in formation during prenatal life into adulthood. This compound can pass across the placenta and into the mother's milk, causing a reduction in bone formation, growth and mass. The objective of this study was to examine the osteogenic potential of osteoblasts extracted from neonatal rats born to mothers treated with caffeine throughout pregnancy. Twenty-four adult Wistar rats were randomly divided into four groups, consisting of one control group and three groups that were treated with 25, 50, or 100 mg/kg of caffeine by an oral-gastric probe throughout the duration of the experimental period (pregnancy). At birth, three puppies from each dam in each group were euthanized, and osteoblasts were extracted from the calvaria of these pups for in vitro testing. The osteoblasts extracted from the pups of rats that received 50 mg/kg caffeine during pregnancy exhibited increased expression of osteocalcin, osteopontin, sialoprotein, runx-2, alkaline phosphatase and type I collagen transcripts, resulting in increased synthesis of mineralization nodules. Neonates from rats treated with 50 mg/kg caffeine during pregnancy contained osteoblasts with a higher osteogenic potential characterized by increased expression of osteocalcin, osteopontin, sialoprotein, runx-2, alkaline phosphatase and type I collagen and increased synthesis of mineralization nodules.

  13. The effect of exposure to hypergravity on pregnant rat dams, pregnancy outcome and early neonatal development

    NASA Astrophysics Data System (ADS)

    Ladd, B.; Nguon, K.; Sajdel-Sulkowska, E. M.

    2006-01-01

    We previously reported that hypergravity exposure affects food intake and mass gain during pregnancy. In the present study, we explored the hypothesis that changes in maternal body mass in hypergravity-exposed pregnant rat dams affect pregnancy outcome and early offspring development. Furthermore, we hypothesized that the changes observed at 1.5G will be magnified at higher gravity and by exposure during critical developmental periods. To test this hypothesis, we compared maternal body mass gain, food consumption, birth outcome and early offspring development between Sprague Dawley rat dams exposed to graded (1.5 1.75G) chronic hypergravity (HG) or rotation (rotational control, RC) on a 24-ft centrifuge for 22.5 h starting on gestational day (G) 10 with dams housed under identical conditions but not exposed to hypergravity (SC). We also compared maternal body mass, food consumption, birth outcome and early offspring development between rat dams exposed to 1.65G during different stages of pregnancy and nursing. Exposure to hypergravity resulted in transient loss in body mass and prolonged decrease in food consumption in HG dams, but the changes observed at 1.5G were not magnified at 1.65G or 1.75G. On the other hand RC dams gained more mass and consumed more food than SC dams. Exposure to hypergravity also affected pregnancy outcome as evidenced by decreased litter size, lowered neonatal mass at birth, and higher neonatal mortality; pregnancy outcome was not affected in RC dams. Neonatal changes evidenced by impaired righting response observed at 1.5G was magnified at higher gravity and was dependent on the period of hypergravity exposure. On the other hand, righting response was improved in RC neonates. Hypergravity exposure during early postpartum affected the food consumption of nursing mothers and affected early survival of their offspring. The changes observed in dams and neonates appear to be due to hypergravity exposure since animals exposed to the rotation

  14. Development of insulation in neonatal cotton rats (Sigmodon hispidus)

    SciTech Connect

    McClure, P.A.; Porter, W.P.

    1983-01-01

    Data on environmental temperatures, skin temperature, animal size, the depth of fur, density of hairs in fur, hair length, and diameter of hair shafts were used to calculate fur thermal conductivity and heat loss, using a porous medium model modified for that of Kowalski and Mitchell. The total thermal conductivity of fur changed little with respect to the age of the animal, but calculated heat loss per unit area decreased because of a decrease in the thermal gradient across the fur caused by an increase in fur depth. A sensitivity analysis of the model showed that skin, air, and radiant environmental temperatures were most important in determining heat loss in all sizes of animals. Fur depth is the only important property of fur determining heat loss in nestling rats, but in adults, all the properties of fur exert significant effects on heat loss. The diameter of animals is a significant variable in all sizes of rats.

  15. Human Connexin43E42K mutation from a sudden infant death victim leads to impaired ventricular activation and neonatal death in mice.

    PubMed

    Lübkemeier, Indra; Bosen, Felicitas; Kim, Jung-Sun; Sasse, Philipp; Malan, Daniela; Fleischmann, Bernd K; Willecke, Klaus

    2015-02-01

    Sudden infant death syndrome (SIDS) describes the sudden, unexplained death of a baby during its first year of age and is the third leading cause of infant mortality. It is assumed that ≤20% of all SIDS cases are because of cardiac arrhythmias resulting from mutations in ion channel proteins. Besides ion channels also cardiac gap junction channels are important for proper conduction of cardiac electric activation. In the mammalian heart Connexin43 (Cx43) is the major gap junction protein expressed in ventricular cardiomyocytes. Recently, a novel Connexin43 loss-of-function mutation (Cx43E42K) was identified in a 2-month-old SIDS victim. We have generated Cx43E42K-expressing mice as a model for SIDS. Heterozygous cardiac-restricted Cx43E42K-mutated mice die neonatally without major cardiac morphological defects. Electrocardiographic recordings of embryonic Cx43+/E42K mice reveal severely disturbed ventricular activation, whereas immunohistochemical analyses show normal localization and expression patterns of gap junctional Connexin43 protein in the Cx43E42K-mutated newborn mouse heart. Because we did not find heterogeneous gap junction loss in Cx43E42K mouse hearts, we conclude that the Cx43E42K gap junction channel creates an arrhythmogenic substrate leading to lethal ventricular arrhythmias. The strong cardiac phenotype of Cx43E42K expressing mice supports the association between the human Cx43E42K mutation and SIDS and indicates that Connexin43 mutations should be considered in future studies when SIDS cases are to be molecularly explained. © 2014 American Heart Association, Inc.

  16. Neonatal magnetocardiography.

    PubMed

    Anastasiadis, P G; Anninos, P; Kotini, A; Koutlaki, N; Garas, A; Galazios, G

    2001-01-01

    The aim of the present study was to test the validity of magnetocardiography (MCG) in the estimation of neonatal cardiac rhythm using a single channel superconductive quantum interference device (SQUID). Our study population consisted of 50 neonates who were delivered normally between 37-41 weeks of gestation from clinically uncomplicated pregnancies. There was also a neonate included in the study in which the diagnosis of "hypoplastic left heart syndrome" was demonstrated by U/S Doppler examination. Maternal age ranged from 18 to 39 years (mean=29.15, SD=6.13). Our study results revealed 44 neonates with normal cardiac rhythm, four with ventricular tachycardia (VT), one with ventricular tachycardia (VT) and extrasystolic beats and one with bradycardia. The neonate with the hypoplastic left heart syndrome presented frequent episodes of ventricular bigeminy in the magnetocardiographic trace. M-mode echocardiography confirmed the diagnosis of the seven cases of arrhythmia in our study group. Results gained from the study lead us to believe that MCG could provide clinical practice with a non-invasive, rapid and easy to perform method, which could be used as an adjunct to conventional methods for the evaluation of neonatal cardiac rhythm.

  17. Lithium ameliorates autistic-like behaviors induced by neonatal isolation in rats

    PubMed Central

    Wu, Xiaoyan; Bai, Yanrui; Tan, Tao; Li, Hongjie; Xia, Shuting; Chang, Xinxia; Zhou, Zikai; Zhou, Weihui; Li, Tingyu; Wang, Yu Tian; Dong, Zhifang

    2014-01-01

    Neonatal isolation is a widely accepted model to study the long-term behavioral changes produced by the early life events. However, it remains unknown whether neonatal isolation can induce autistic-like behaviors, and if so, whether pharmacological treatment can overcome it. Here, we reported that newborn rats subjected to individual isolations from their mother and nest for 1 h per day from postnatal days 1–9 displayed apparent autistic-like symptoms including social deficits, excessive repetitive self-grooming behavior, and increased anxiety- and depressive-like behaviors tested in young adult (postnatal days 42–56) compared to normal reared controls. Furthermore, these behavioral changes were accompanied by impaired adult hippocampal neurogenesis and reduced the ratio of excitatory/inhibitory synaptic transmissions, as reflected by an increase in spontaneous inhibitory postsynaptic current (sIPSC) and normal spontaneous excitatory postsynaptic current (sEPSC) in the hippocampal CA1 pyramidal neuron. More importantly, chronic administration of lithium, a clinically used mood stabilizer, completely overcame neonatal isolation-induced autistic-like behaviors, and restored adult hippocampal neurogenesis as well as the balance between excitatory and inhibitory activities to physiological levels. These findings indicate that neonatal isolation may produce autistic-like behaviors, and lithium may be a potential therapeutic agent against autism spectrum disorders (ASD) during development. PMID:25018711

  18. Hippocampal synaptic plasticity: effects of neonatal stress in freely moving adult male rats.

    PubMed

    Petrosino, M; Bronzino, J D; Pizzuti, G P

    1999-01-01

    The present study examines the effects of neonatal isolation on hippocampal LTP in adult male rats. Changes in dentate granule cell population measures, i.e., EPSP slope and population spike amplitude (PSA), evoked by tetanization of the medial perforant pathway were used to assess the effects of neonatal isolation on LTP over a period of 96 h. Following tetanization significant group differences were obtained for input/output (I/O) response measures of EPSP slope and PSA, with isolated males showing consistently higher values than in the other two groups. Comparisons made at 1 h post-tetanization (establishment of LTP) indicated that isolated males showed significantly greater enhancement than any other group. At 96 h (maintenance of LTP), however, neonatally isolated males showed significantly greater enhancement than either non-isolated siblings or unhandled controls. Additionally, isolation resulted in prolonging the duration of enhancement obtained from males. Thus, males show different enhancement profiles with respect to both the magnitude and duration of LTP and neonatal isolation alters these profiles in profound manner.

  19. Subplate neurons promote spindle bursts and thalamocortical patterning in the neonatal rat somatosensory cortex

    PubMed Central

    Tolner, Else A.; Sheikh, Aminah; Yukin, Alexey Y.; Kaila, Kai; Kanold, Patrick

    2012-01-01

    Patterned neuronal activity such as spindle bursts in the neonatal cortex is likely to promote the maturation of cortical synapses and neuronal circuits. Previous work on cats has shown that removal of subplate neurons, a transient neuronal population in the immature cortex, prevents the functional maturation of thalamocortical and intracortical connectivity. Here we studied the effect of subplate removal in the neonatal rat somatosensory cortex (S1). Using intracortical EEG we show that after selective removal of subplate neurons in the limb region of S1, endogenous and sensory evoked spindle burst activity is largely abolished. Consistent with the reduced in vivo activity in the S1 limb region, we find by in vitro recordings that thalamocortical inputs to layer 4 neurons are weak. In addition, we find that removal of subplate neurons in the S1 barrel region prevents the development of the characteristic histological barrel-like appearance. Thus, subplate neurons are crucially involved in the generation of particular types of early network activity in the neonatal cortex, which are an important feature of cortical development. The altered EEG pattern following subplate damage could be applicable in the neurological assessment of human neonates. PMID:22238105

  20. Striatal cholinergic functional alterations in hypoxic neonatal rats: role of glucose, oxygen, and epinephrine resuscitation.

    PubMed

    Anju, T R; Paulose, C S

    2013-10-01

    Molecular processes regulating cholinergic functions play an important role in the control of respiration under hypoxia. Cholinergic alterations and its further complications in respiration due to hypoxic insult in neonatal rats and the effect of glucose, oxygen, and epinephrine resuscitation was evaluated in the present study. Receptor binding and gene expression studies were done in the corpus striatum to analyse the changes in total muscarinic receptors, muscarinic M1, M2, M3 receptors, and the enzymes involved in acetylcholine metabolism, choline acetyltransferase and acetylcholinesterase. Neonatal hypoxia decreased total muscarinic receptors with reduced expression of muscarinic M1, M2, and M3 receptor genes. The reduction in acetylcholine metabolism is indicated by the downregulated choline acetyltransferase and upregulated acetyl cholinesterase expression. These cholinergic disturbances were reversed to near control in glucose-resuscitated hypoxic neonates. The adverse effects of immediate oxygenation and epinephrine administration are also reported. The present findings points to the cholinergic alterations due to neonatal hypoxic shock and suggests a proper resuscitation method to ameliorate these striatal changes.

  1. Behavioral and Neurochemical Deficits in Aging Rats with Increased Neonatal Iron Intake: Silibinin’s Neuroprotection by Maintaining Redox Balance

    PubMed Central

    Chen, Hanqing; Wang, Xijin; Wang, Meihua; Yang, Liu; Yan, Zhiqiang; Zhang, Yuhong; Liu, Zhenguo

    2015-01-01

    Aging is a critical risk factor for Parkinson’s disease. Silibinin, a major flavonoid in Silybum marianum, has been suggested to display neuroprotective properties against various neurodegenerative diseases. In the present study, we observed that neonatal iron (120 μg/g body weight) supplementation resulted in significant abnormality of behavior and depletion of striatal dopamine (DA) in the aging male and female rats while it did not do so in the young male and female rats. No significant change in striatal serotonin content was observed in the aging male and female rats with neonatal supplementation of the same dose of iron. Furthermore, we found that the neonatal iron supplementation resulted in significant increase in malondialdehyde (MDA) and decrease in glutathione (GSH) in the substantia nigra (SN) of the aging male and female rats. No significant change in content of MDA and GSH was observed in the cerebellum of the aging male and female rats with the neonatal iron supplementation. Interestingly, silibinin (25 and 50 mg/kg body weight) treatment significantly and dose-dependently attenuated depletion of striatal DA and improved abnormality of behavior in the aging male and female rats with the neonatal iron supplementation. Moreover, silibinin significantly reduced MDA content and increased GSH content in the SN of the aging male and female rats. Taken together, our results indicate that elevated neonatal iron supplementation may result in neurochemical and behavioral deficits in the male and female rats with aging and silibinin may exert dopaminergic neuroprotection by maintaining redox balance. PMID:26578951

  2. Neonatal sensory deprivation promotes development of absence seizures in adult rats with genetic predisposition to epilepsy.

    PubMed

    Sitnikova, Evgenia

    2011-03-04

    Absence epilepsy has age-related onset. In a WAG/Rij rat genetic model, absence seizures appear after puberty and they are increased with age. It is known that (1) epileptic activity in WAG/Rij rats is initiated at the perioral area in the somatosensory cortex; (2) sensory deprivation, i.e., whisker trimming during the critical period of development, could enhance excitatory activity in the somatosensory cortex. It is hypothesized that the cortex may become more excitable after neonatal vibrissae removal, and this may precipitate absence seizures in adult rats. We found that whisker trimming during the first postnatal weeks caused more rapid development of EEG seizure activity in adult WAG/Rij rats. Epileptic discharges in the trimmed rats were more numerous (vs control), showed longer duration and often appeared in desynchronized and drowsy EEG. The number of absence-like spindle-shaped EEG events (spike-wave spindles) in the whisker-trimmed rats was higher than in control, especially during the intermediate sleep state. An age-dependent increase of intermediate sleep state was found in the trimmed rats, but not in the intact animals. We discuss epigenetic factors that can modulate absence epilepsy in genetically prone subjects.

  3. Time course of myosin heavy chain transitions in neonatal rats: importance of innervation and thyroid state

    NASA Technical Reports Server (NTRS)

    Adams, G. R.; McCue, S. A.; Zeng, M.; Baldwin, K. M.

    1999-01-01

    During the postnatal period, rat limb muscles adapt to weight bearing via the replacement of embryonic (Emb) and neonatal (Neo) myosin heavy chains (MHCs) by the adult isoforms. Our aim was to characterize this transition in terms of the six MHC isoforms expressed in skeletal muscle and to determine the importance of innervation and thyroid hormone status on the attainment of the adult MHC phenotype. Neonatal rats were made hypothyroid via propylthiouracil (PTU) injection. In normal and PTU subgroups, leg muscles were unilaterally denervated at 15 days of age. The MHC profiles of plantaris (PLN) and soleus (Sol) muscles were determined at 7, 14, 23, and 30 days postpartum. At day 7, the Sol MHC profile was 55% type I, 30% Emb, and 10% Neo; in the PLN, the pattern was 60% Neo and 25% Emb. By day 30 the Sol and PLN had essentially attained an adult MHC profile in the controls. PTU augmented slow MHC expression in the Sol, whereas in the PLN it markedly repressed IIb MHC by retaining neonatal MHC expression. Denervation blunted the upregulation of IIb in the PLN and of Type I in the Sol and shifted the pattern to greater expression of IIa and IIx MHCs in both muscles. In contrast to previous observations, these findings collectively suggest that both an intact thyroid and innervation state are obligatory for the attainment of the adult MHC phenotype, particularly in fast-twitch muscles.

  4. Time course of myosin heavy chain transitions in neonatal rats: importance of innervation and thyroid state

    NASA Technical Reports Server (NTRS)

    Adams, G. R.; McCue, S. A.; Zeng, M.; Baldwin, K. M.

    1999-01-01

    During the postnatal period, rat limb muscles adapt to weight bearing via the replacement of embryonic (Emb) and neonatal (Neo) myosin heavy chains (MHCs) by the adult isoforms. Our aim was to characterize this transition in terms of the six MHC isoforms expressed in skeletal muscle and to determine the importance of innervation and thyroid hormone status on the attainment of the adult MHC phenotype. Neonatal rats were made hypothyroid via propylthiouracil (PTU) injection. In normal and PTU subgroups, leg muscles were unilaterally denervated at 15 days of age. The MHC profiles of plantaris (PLN) and soleus (Sol) muscles were determined at 7, 14, 23, and 30 days postpartum. At day 7, the Sol MHC profile was 55% type I, 30% Emb, and 10% Neo; in the PLN, the pattern was 60% Neo and 25% Emb. By day 30 the Sol and PLN had essentially attained an adult MHC profile in the controls. PTU augmented slow MHC expression in the Sol, whereas in the PLN it markedly repressed IIb MHC by retaining neonatal MHC expression. Denervation blunted the upregulation of IIb in the PLN and of Type I in the Sol and shifted the pattern to greater expression of IIa and IIx MHCs in both muscles. In contrast to previous observations, these findings collectively suggest that both an intact thyroid and innervation state are obligatory for the attainment of the adult MHC phenotype, particularly in fast-twitch muscles.

  5. Neonatal anoxia in rats: hippocampal cellular and subcellular changes related to cell death and spatial memory.

    PubMed

    Takada, S H; dos Santos Haemmerle, C A; Motta-Teixeira, L C; Machado-Nils, A V; Lee, V Y; Takase, L F; Cruz-Rizzolo, R J; Kihara, A H; Xavier, G F; Watanabe, I-S; Nogueira, M I

    2015-01-22

    Neonatal anoxia in rodents has been used to understand brain changes and cognitive dysfunction following asphyxia. This study investigated the time-course of cellular and subcellular changes and hippocampal cell death in a non-invasive model of anoxia in neonatal rats, using Terminal deoxynucleotidyl transferase-mediated dUTP Nick End Labeling (TUNEL) to reveal DNA fragmentation, Fluoro-Jade® B (FJB) to show degenerating neurons, cleaved caspase-3 immunohistochemistry (IHC) to detect cells undergoing apoptosis, and transmission electron microscopy (TEM) to reveal fine ultrastructural changes related to cell death. Anoxia was induced by exposing postnatal day 1 (P1) pups to a flow of 100% gaseous nitrogen for 25 min in a chamber maintained at 37 °C. Control rats were similarly exposed to this chamber but with air flow instead of nitrogen. Brain changes following anoxia were evaluated at postnatal days 2, 14, 21 and 60 (P2, P14, P21 and P60). In addition, spatial reference memory following anoxia and control treatments was evaluated in the Morris water maze, starting at P60. Compared to their respective controls, P2 anoxic rats exhibited (1) higher TUNEL labeling in cornus ammonis (CA) 1 and the dentate gyrus (DG), (2) higher FJB-positive cells in the CA2-3, and (3) somato-dendritic swelling, mitochondrial injury and chromatin condensation in irregular bodies, as well as other subcellular features indicating apoptosis, necrosis, autophagy and excitotoxicity in the CA1, CA2-3 and DG, as revealed by TEM. At P14, P21 and P60, both groups showed small numbers of TUNEL-positive and FJB-positive cells. Stereological analysis at P2, P14, P21 and P60 revealed a lack of significant differences in cleaved caspase-3 IHC between anoxic and control subjects. These results suggest that the type of hippocampal cell death following neonatal anoxia is likely independent of caspase-3 activation. Neonatal anoxia induced deficits in acquisition and performance of spatial reference

  6. Lower trunk of brachial plexus injury in the neonate rat: effects of timing repair.

    PubMed

    Lauretti, Liverana; Pallini, Roberto; Romani, Rossana; Di Rocco, Federico; Ciampini, Alessandro; Gangitano, Carlo; Del Fa, Aurora; Fernandez, Eduardo

    2009-06-01

    After lesion of a peripheral nerve in neonatal mammals, motoneurons undergo a cell death. We wanted to ascertain if early surgery could influence such post-axotomy motoneuronal death and improve the functional outcome. In this study, we investigated the functional and anatomical results after immediate and delayed repair of the lower trunk of brachial plexus (BP) sectioned at birth in rats. In neonate rats, the lower trunk of the left BP was cut. This nerve trunk was repaired either immediately [immediately-reconstructed group of rats (IR), or 30 days after, tardy reconstructed group of rats (TR)]; in the third group of animals, the nerve was not repaired (noreconstructed group of rats, NoR). In each group of animals, functional studies were performed at 90 days of age using the grooming test and the walking tracks analysis. Histologic studies of the C7-T1 spinal cord and lower trunk of BP were performed at 30 and 90 days of age; the numbers of motoneuron and axon were counted. Functional recovery was related to the difference in motoneuron number between the injured and the uninjured sides of the spinal cord of the operated animals. On the one side, only in the rats in which the inferior trunk was immediately repaired, the difference in motoneuron number between the two sides of the spinal cord was not statistically significant; these animals showed a good axonal regeneration and function recovery. On the other side, in the rats in which the inferior trunk was left unrepaired or tardy repaired, the decrease in motoneuron number in the injured side compared with the uninjured side of the spinal cord was statistically significant; these animals showed no axonal regeneration and no function recovery. The results cited above suggest that an important role in restoration of good neurological function after section of the lower trunk of BP in neonate rats is played by early nerve repair. Good neurological function was related more to a quite numerical balance of

  7. Cholesterol depletion impairs contractile machinery in neonatal rat cardiomyocytes

    PubMed Central

    Hissa, Barbara; Oakes, Patrick W.; Pontes, Bruno; Ramírez-San Juan, Guillermina; Gardel, Margaret L.

    2017-01-01

    Cholesterol regulates numerous cellular processes. Depleting its synthesis in skeletal myofibers induces vacuolization and contraction impairment. However, little is known about how cholesterol reduction affects cardiomyocyte behavior. Here, we deplete cholesterol by incubating neonatal cardiomyocytes with methyl-beta-cyclodextrin. Traction force microscopy shows that lowering cholesterol increases the rate of cell contraction and generates defects in cell relaxation. Cholesterol depletion also increases membrane tension, Ca2+ spikes frequency and intracellular Ca2+ concentration. These changes can be correlated with modifications in caveolin-3 and L-Type Ca2+ channel distributions across the sarcolemma. Channel regulation is also compromised since cAMP-dependent PKA activity is enhanced, increasing the probability of L-Type Ca2+ channel opening events. Immunofluorescence reveals that cholesterol depletion abrogates sarcomeric organization, changing spacing and alignment of α-actinin bands due to increase in proteolytic activity of calpain. We propose a mechanism in which cholesterol depletion triggers a signaling cascade, culminating with contraction impairment and myofibril disruption in cardiomyocytes. PMID:28256617

  8. Roles of thyroid hormones in follicular development in the ovary of neonatal and immature rats.

    PubMed

    Fedail, Jaafar Sulieman; Zheng, Kaizhi; Wei, Quanwei; Kong, Lingfa; Shi, Fangxiong

    2014-08-01

    Thyroid hormones (TH) play a critical role in ovarian follicular development, maturation and the maintenance of various endocrine functions. However, whether TH can affect ovarian follicular development in neonatal and immature rats remains unclear. Therefore, the aim of the present study was to elucidate the effect of TH on ovarian follicular development in neonatal and immature rats. Thirty female post-lactation mothers of Sprague-Dawley rat pups were randomly divided into three groups: control, hyperthyroid (hyper), and hypothyroid (hypo). On postnatal days (PND) 10 and 21, body weights, serum hormones, ovarian histologic changes, and immunohistochemistry of thyroid hormone receptor alpha 1 (TRα1) and nitric oxide synthase types (NOS), and NOS activities, were determined. The data showed that body weights significantly decreased in both hyper and hypo groups compared with the control group (P < 0.05). In addition, the hyper group had increased serum concentrations of T3, T4, and E2; whereas the hypo group manifested reduced serum concentrations of T3, T4, and E2 on PND 10 and 21. The hyper and hypo groups showed significantly reduced total number of primordial, primary and secondary follicles on PND 10 and 21 compared with the control group (P < 0.05). Similarly, antral follicle numbers in the hyper and hypo groups were significantly decreased on PND 21 compared with the control group (P < 0.05). Immunostaining indicated that TRα1 and NOS were expressed in ovarian surface epithelium and oocytes of growing and antral follicles, with strong staining of the granulosa and theca cells of follicles. NOS activities were significantly augmented in the hyper, but diminished in the hypo groups on PND 10 and 21. In summary, our findings suggest that TH play important roles in ovarian functions and in the regulation of NOS activity. Our results also indicate that a relationship exists between the TH and NO signaling pathways during the process of ovarian follicular

  9. Gender and estrous cycle influences on behavioral and neurochemical alterations in adult rats neonatally administered ketamine.

    PubMed

    Célia Moreira Borella, Vládia; Seeman, Mary V; Carneiro Cordeiro, Rafaela; Vieira dos Santos, Júnia; Romário Matos de Souza, Marcos; Nunes de Sousa Fernandes, Ethel; Santos Monte, Aline; Maria Mendes Vasconcelos, Silvânia; Quinn, John P; de Lucena, David F; Carvalho, André F; Macêdo, Danielle

    2016-05-01

    Neonatal N-methyl-D-aspartate (NMDA) receptor blockade in rodents triggers schizophrenia (SCZ)-like alterations during adult life. SCZ is influenced by gender in age of onset, premorbid functioning, and course. Estrogen, the hormone potentially driving the gender differences in SCZ, is known to present neuroprotective effects such as regulate oxidative pathways and the expression of brain-derived neurotrophic factor (BDNF). Thus, the aim of this study was to verify if differences in gender and/or estrous cycle phase during adulthood would influence the development of behavioral and neurochemical alterations in animals neonatally administered ketamine. The results showed that ketamine-treated male (KT-male) and female-in-diestrus (KTF-diestrus, the low estrogen phase) presented significant deficits in prepulse inhibition of the startle reflex and spatial working memory, two behavioral SCZ endophenotypes. On the contrary, female ketamine-treated rats during proestrus (KTF-proestrus, the high estradiol phase) had no behavioral alterations. This correlated with an oxidative imbalance in the hippocampus (HC) of both male and KTF-diestrus female rats, that is, decreased levels of GSH and increased levels of lipid peroxidation and nitrite. Similarly, BDNF was decreased in the KTF-diestrus rats while no alterations were observed in KTF-proestrus and male animals. The changes in the HC were in contrast to those in the prefrontal cortex in which only increased levels of nitrite in all groups studied were observed. Thus, there is a gender difference in the adult rat HC in response to ketamine neonatal administration, which is based on the estrous cycle. This is discussed in relation to neuropsychiatric conditions and in particular SCZ. © 2015 Wiley Periodicals, Inc.

  10. Gestational and neonatal-onset hypothyroidism alters androgen receptor status in rat prostate glands at adulthood.

    PubMed

    Aruldhas, Michael Maria; Ramalingam, Neelamohan; Jaganathan, Anbalagan; John Sashi, Arokya Mary; Stanley, Jone Arulrajadurai; Nagappan, Arumugam Suriyam; Vasavan, Jyothilakshmi; Kannan, Annapoorna; Seshadri, Venkatesh Nagamangalam

    2010-05-15

    Infertility associated with congenital and early childhood hypothyroidism is an important reproductive health problem in men. Nevertheless, the exact mechanism underlying hypothyroidism-induced changes in the prostate gland, an androgen-dependent organ that contributes a significant portion of the seminal plasma remains obscure. The present study tested the hypothesis "transient gestational- or neonatal-onset hypothyroidism may have duration dependent and lobe specific effect on androgen receptor (AR) status in the prostate glands of adult rats." Hypothyroidism was induced in pregnant and lactating rats by feeding 0.05% methimazole (MMI) through drinking water during fetal and neonatal milestones of testicular and prostatic development. Pregnant dams had MMI exposure from 9th day post-coitum (dpc) to 14 dpc (group II) or 21 dpc (group III). Lactating mothers had MMI exposure from day 1 post-partum (dpp) to 14 dpp (group IV) or up to 29 dpp (group V). AR status in the dorsolateral and ventral prostate lobes (DLP and VP) of the pups was assessed by RT-PCR, western blot and radio receptor assay. AR mRNA expression consistently decreased in the DLP of all groups, whereas it increased in VP of group III and V rats. AR protein consistently decreased in both DLP and VP of all experimental rats. AR nuclear ligand-binding activity diminished in groups II and IV, whereas it increased in groups III and V. The results obtained support the proposed hypothesis and indicate that an optimum thyroid activity during pre- and neonatal period determines AR status in the prostate glands at adulthood.

  11. Intramyocardial sustained delivery of basic fibroblast growth factor improves angiogenesis and ventricular function in a rat infarct model.

    PubMed

    Iwakura, Atsushi; Fujita, Masatoshi; Kataoka, Kazuaki; Tambara, Keiichi; Sakakibara, Yutaka; Komeda, Masashi; Tabata, Yasuhiko

    2003-05-01

    Recently we have demonstrated that the release of basic fibroblast growth factor (bFGF) from a biodegradable gelatin hydrogel carrier depends on the degradation of hydrogel in vivo. The purpose of our study was to assess whether bFGF-incorporating gelatin hydrogels induce myocardial angiogenesis and improve left ventricular function in the infarcted myocardium of rats. Studies were conducted in 22 Lewis rats after a 4-week ligation of the proximal left anterior descending coronary artery. The rats were randomized into the following two groups: the control group (n = 11) had an intramyocardial injection of saline alone, and the FGF group (n = 11) had gelatin hydrogel microspheres containing 100 microg of bFGF injected into the border zone of the infarct area after the repeat left thoracotomy. For visualization of the regional myocardial blood flow in the rat heart, (201)Tl images were taken just before and 4 weeks after the treatment using a 4-head single photon emission computed tomography scanner with pinhole collimators. Left ventricular function was also assessed with echocardiography and a micromanometer-tipped catheter. Finally, the extent of myocardial angiogenesis was evaluated quantitatively in the postmortem analysis. The (201)Tl defect score in the control group remained unchanged before and after the treatment, whereas it decreased significantly in the FGF group. Both regional and global left ventricular function was significantly better in the FGF group compared with the control group. The vascular density in the border zone of the infarct in the FGF group was significantly higher than that in the control group. In conclusion, intramyocardial injection of bFGF-impregnated gelatin hydrogels induces functionally significant angiogenesis and improves left ventricular systolic and diastolic function in the infarcted myocardium of rats.

  12. Morphometry of right ventricular hypertrophy induced by myocardial infarction in the rat.

    PubMed Central

    Anversa, P.; Beghi, C.; McDonald, S. L.; Levicky, V.; Kikkawa, Y.; Olivetti, G.

    1984-01-01

    The growth response of the right ventricle was studied in rats following ligation of the left coronary artery, which produced infarcts comprising approximately 40% of the left ventricle. A month after surgery the weight of the right ventricle was increased 30%, and this hypertrophic change was characterized by a 17% wall thickening, consistent with the 13% greater diameter of myocytes. Myocardial hypertrophy was accompanied by an inadequate growth of the microvasculature that supports tissue oxygenation. This was seen by relative decreases in capillary luminal volume density (-27%) and capillary luminal surface density (-21%) and by an increase in the average maximum distance from the capillary wall to the mitochondria of myocytes (19%). In contrast, measurements of the mean myocyte volume per nucleus showed a proportional enlargement of these cells (32%), from 16,300 cu mu in control animals to 21,500 cu mu in experimental rats. Quantitative analysis of the right coronary artery revealed a 33% increase in its luminal area, commensurate with the magnitude of ventricular hypertrophy. PMID:6236695

  13. Effects of mercury on myosin ATPase in the ventricular myocardium of the rat.

    PubMed

    Moreira, C M; Oliveira, E M; Bonan, C D; Sarkis, J J F; Vassallo, D V

    2003-07-01

    Mercury reduces twitch and tetanic force development in isolated rat papillary muscles, and a putative toxic effect on the contractile machinery has been suggested. Based on that, the actions of HgCl2 on the myosin ATPase activity of the left ventricular myocardium were investigated. Samples for assay of myosin ATPase activity were obtained from rats' left ventricles. Increasing concentrations of HgCl2 reduced dose-dependently the activity of the myosin ATPase. This reduction was observed even at very small concentrations, 50 nM HgCl2. This effect was dependent on the presence of SH groups in the myosin molecule since DTT and glutathione protected the myosin ATPase against toxic effects of mercury; full activity being restored by using 500 nM DTT or 500 nM glutathione. Results also suggested that the metal acts as an uncompetitive inhibitor with a Ki of 200 nM HgCl2. Our results suggest that mercury reduces the activity of the myosin ATPase by an uncompetitive mechanism at a very low dose that does not depress force. DTT and glutathione are effective for protection against the actions of mercury suggesting that SH groups might be the sites of action of the metal on the myosin molecule.

  14. Long-term intake of sesamin improves left ventricular remodelling in spontaneously hypertensive rats.

    PubMed

    Li, Wen-xing; Kong, Xiang; Zhang, Jun-xiu; Yang, Jie-ren

    2013-02-26

    This study was designed to evaluate the in vivo cardioprotective effects of food-derived sesamin in spontaneously hypertensive rats (SHR). The study was performed with 17-week-old male normotensive Wistar-Kyoto rats (WKY) and SHR which are untreated or treated with orally administered sesamin for 16 weeks before they were sacrificed. Long-term treatment with sesamin obviously improved left ventricular (LV) hypertrophy and fibrosis in SHR, as indicated by the decrease of LV weight/body weight, myocardial cell size, cardiac fibrosis and collagen type I expression as well as the amelioration of the LV ultrastructure. These effects were associated with reduced systolic blood pressure, enhanced cardiac total antioxidant capability and decreased malondialdehyde content, nitrotyrosine level and transforming growth factor β1 (TGF-β1) expression. All these results suggest that chronic treatment with sesamin improves LV remodeling in SHR through alleviation of oxidative and nitrative stress, reduction of blood pressure and downregulation of TGF-β1 expression.

  15. Tyrosine kinase inhibitor BIBF1000 does not hamper right ventricular pressure adaptation in rats.

    PubMed

    de Raaf, Michiel Alexander; Herrmann, Franziska Elena; Schalij, Ingrid; de Man, Frances S; Vonk-Noordegraaf, Anton; Guignabert, Christophe; Wollin, Lutz; Bogaard, Harm Jan

    2016-09-01

    BIBF1000 is a small molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR) and is a powerful inhibitor of fibrogenesis. BIBF1000 is very similar to BIBF1120 (nintedanib), a drug recently approved for the treatment of idiopathic pulmonary fibrosis (IPF). A safety concern pertaining to VEGFR, FGFR, and PDGFR inhibition is the possible interference with right ventricular (RV) responses to an increased afterload, which could adversely affect clinical outcome in patients with IPF who developed pulmonary hypertension. We tested the effect of BIBF1000 on the adaptation of the RV in rats subjected to mechanical pressure overload. BIBF1000 was administered for 35 days in pulmonary artery-banded (PAB) rats. RV adaptation was assessed by echocardiography, pressure volume loop analysis, histology, and determination of atrial natriuretic peptide (ANP) expression. BIBF1000 treatment resulted in growth attenuation but had no effects on RV function after PAB, given absence of changes in cardiac index, end-systolic elastance, connective tissue disposition, and capillary density. We conclude that, in this experimental model of increased afterload, combined VEGFR, FGFR, and PDGFR inhibition does not hamper RV adaptation to pressure overload. Copyright © 2016 the American Physiological Society.

  16. Neonatal exposure to fenoterol and betamethasone: effects on the behavioral development in the rat.

    PubMed

    Pitzer, Martina; Schmidt, Martin H

    2009-01-01

    We investigated longitudinally the behavioral development in the rat following exposure to beta-agonists and glucocorticoids (GC). Neonatal rats received either 1 mg/kg fenoterol (FEN), 0.3 mg/kg betamethasone (BET), or saline (SAL). Weanling and young adult rats were tested in the open field, the elevated-plus maze, and the water maze. FEN-treated as well as BET-treated animals displayed increased anxiety-like behavior. Furthermore, BET-treated adult animals showed a reduced locomotor activity. An enhanced 24-h memory in the water maze in both treatment groups may be facilitated by emotional arousal due to the increased anxiety levels. The possible neurobiological underpinnings are discussed in detail.

  17. Dependence of normal development of skeletal muscle in neonatal rats on load bearing

    NASA Technical Reports Server (NTRS)

    Ohira, Y.; Tanaka, T.; Yoshinaga, T.; Kawano, F.; Nomura, T.; Nonaka, I.; Allen, D. L.; Roy, R. R.; Edgerton, V. R.

    2000-01-01

    Antigravity function plays an important role in determining the morphological and physiological properties of the neuromuscular system. Inhibition of the normal development of the neuromuscular system is induced by hindlimb unloading during the neonatal period in rats. However, the role of gravitational loading on the development of skeletal muscle in rats is not well understood. It could be hypothesized that during the early postnatal period, i.e. when minimal weight-supporting activity occurs, the activity imposed by gravity would be of little consequence in directing the normal development of the skeletal musculature. We have addressed this issue by limiting the amount of postnatal weight-support activity of the hindlimbs of rats during the lactation period. We have focused on the development of three characteristics of the muscle fibers, i.e. size, myonuclear number and myosin heavy chain expression.

  18. Dependence of normal development of skeletal muscle in neonatal rats on load bearing

    NASA Technical Reports Server (NTRS)

    Ohira, Y.; Tanaka, T.; Yoshinaga, T.; Kawano, F.; Nomura, T.; Nonaka, I.; Allen, D. L.; Roy, R. R.; Edgerton, V. R.

    2000-01-01

    Antigravity function plays an important role in determining the morphological and physiological properties of the neuromuscular system. Inhibition of the normal development of the neuromuscular system is induced by hindlimb unloading during the neonatal period in rats. However, the role of gravitational loading on the development of skeletal muscle in rats is not well understood. It could be hypothesized that during the early postnatal period, i.e. when minimal weight-supporting activity occurs, the activity imposed by gravity would be of little consequence in directing the normal development of the skeletal musculature. We have addressed this issue by limiting the amount of postnatal weight-support activity of the hindlimbs of rats during the lactation period. We have focused on the development of three characteristics of the muscle fibers, i.e. size, myonuclear number and myosin heavy chain expression.

  19. Neonatal isolation enhances acquisition of cocaine self-administration and food responding in female rats.

    PubMed

    Kosten, Therese A; Sanchez, Hayde; Zhang, Xiang Yang; Kehoe, Priscilla

    2004-05-05

    We showed previously that neonatal isolation (ISO) enhances acquisition of cocaine self-administration in adult male rats without altering acquisition of food responding. Female rats show poorer performance in learning tasks and are differentially affected by stress compared to male rats. Thus, we investigated whether ISO alters acquisition of operant responding for cocaine and food in female rats with comparison to male rats. Litters were subjected to ISO or were non-handled (NH). Activity levels were assessed in adult rats. Then, rats were implanted with jugular catheters and allowed to self-administer cocaine under a fixed-ratio 1 (FR1) schedule of reinforcement using an escalating dose presentation procedure. Cocaine intake, discrimination of active versus inactive levers, and ineffective active lever responses were tabulated. Effects of non-contingent cocaine infusions (primes) and increasing FR on responding were then assessed. Other rats were allowed to lever press for food under an FR1 schedule (10 s time-out). ISO enhanced acquisition of operant responding for food and cocaine in female rats. The latter was demonstrated by better lever discrimination, emission of fewer ineffective responses, and superior performance in response to primes. Yet, NH females ingested more cocaine than ISO females during the initial acquisition phase. In male rats, ISO enhanced acquisition of cocaine self-administration but not food responding. Activity levels were unaffected by ISO or gender. These data confirm and extend our previous findings demonstrating the enduring effects of ISO on adult self-administration behavior and emphasize the importance of measuring behavioral patterns versus intake in acquisition studies.

  20. Early environmental enrichment affects neurobehavioral development and prevents brain damage in rats submitted to neonatal hypoxia-ischemia.

    PubMed

    Schuch, Clarissa Pedrini; Diaz, Ramiro; Deckmann, Iohanna; Rojas, Joseane Jiménez; Deniz, Bruna Ferrary; Pereira, Lenir Orlandi

    2016-03-23

    Our previous results demonstrated improved cognition in adolescent rats housed in environmental enrichment (EE) that underwent neonatal hypoxia-ischemia (HI). The aim of this study was to investigate the effects of early EE on neurobehavioral development and brain damage in rats submitted to neonatal HI. Wistar rats were submitted to the HI procedure on the 7th postnatal day (PND) and housed in an enriched environment (8th-20th PND). The maturation of physical characteristics and the neurological reflexes were evaluated and the volume of striatum, corpus callosum and neocortex was measured. Data analysis demonstrated a clear effect of EE on neurobehavioral development; also, daily performance was improved in enriched rats on righting, negative geotaxis and cliff aversion reflex. HI caused a transient motor deficit on gait latency. Brain atrophy was found in HI animals and this damage was partially prevented by the EE. In conclusion, early EE stimulated neurobehavioral development in neonate rats and also protects the neocortex and the corpus callosum from atrophy following HI. These findings reinforce the potential of EE as a strategy for rehabilitation following neonatal HI and provide scientific support to the use of this therapeutic strategy in the treatment of neonatal brain injuries in humans. Copyright © 2016. Published by Elsevier Ireland Ltd.

  1. Neonatal handling (resilience) attenuates water-avoidance stress induced enhancement of chronic mechanical hyperalgesia in the rat

    PubMed Central

    Alvarez, Pedro; Levine, Jon D.; Green, Paul G.

    2015-01-01

    Chronic stress is well known to exacerbate pain. We tested the hypothesis that neonatal handling, which induces resilience to the negative impact of stress by increasing the quality and quantity of maternal care, attenuates the mechanical hyperalgesia produced by water-avoidance stress in the adult rat. Neonatal male rats underwent the handling protocol on postnatal days 2–9, weaned at 21 days and tested for muscle mechanical nociceptive threshold at postnatal days 50–75. Decrease in mechanical nociceptive threshold in skeletal muscle in adult rats, produced by exposure to water-avoidance stress, was significantly attenuated by neonatal handling. Neonatal handling also attenuated the mechanical hyperalgesia produced by intramuscular administration of the pronociceptive inflammatory mediator, prostaglandin E2 in rats exposed as adults to water-avoidance stress. Neonatal handling, which induces a smaller corticosterone response in adult rats exposed to a stressor as well as changes in central nervous system neurotransmitter systems, attenuates mechanical hyperalgesia produced by water-avoidance stress and enhanced prostaglandin hyperalgesia in adult animals. PMID:25637700

  2. Neonatal handling (resilience) attenuates water-avoidance stress induced enhancement of chronic mechanical hyperalgesia in the rat.

    PubMed

    Alvarez, Pedro; Levine, Jon D; Green, Paul G

    2015-03-30

    Chronic stress is well known to exacerbate pain. We tested the hypothesis that neonatal handling, which induces resilience to the negative impact of stress by increasing the quality and quantity of maternal care, attenuates the mechanical hyperalgesia produced by water-avoidance stress in the adult rat. Neonatal male rats underwent the handling protocol on postnatal days 2-9, weaned at 21 days and tested for muscle mechanical nociceptive threshold at postnatal days 50-75. Decrease in mechanical nociceptive threshold in skeletal muscle in adult rats, produced by exposure to water-avoidance stress, was significantly attenuated by neonatal handling. Neonatal handling also attenuated the mechanical hyperalgesia produced by intramuscular administration of the pronociceptive inflammatory mediator, prostaglandin E2 in rats exposed as adults to water-avoidance stress. Neonatal handling, which induces a smaller corticosterone response in adult rats exposed to a stressor as well as changes in central nervous system neurotransmitter systems, attenuates mechanical hyperalgesia produced by water-avoidance stress and enhanced prostaglandin hyperalgesia in adult animals. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  3. Asiatic acid inhibits left ventricular remodeling and improves cardiac function in a rat model of myocardial infarction

    PubMed Central

    HUO, LIANYING; SHI, WENBING; CHONG, LING; WANG, JINLONG; ZHANG, KAI; LI, YUFENG

    2016-01-01

    Left ventricular remodeling results in cardiac dysfunction and accounts for the majority of the morbidity and mortality following myocardial infarction (MI). The aim of the present study was to investigate the effect of asiatic acid (AA) on cardiac function and left ventricular remodeling in a rat model of MI and explore the underlying mechanisms. Rats were subjected to coronary artery ligation to model MI and orally treated with AA. After 4 weeks, cardiac function was assessed by echocardiography. Cardiomyocyte cross-sectional area was recorded, and the expression levels of a number of inflammatory cytokines were detected using ELISA. The degree of interstitial fibrosis was determined by evaluating the mRNA expression levels of collagen II and III. Western blot analysis was performed to detect the expression levels of total and phosphorylated p38 MAPK and ERK1/2, to investigate whether they are involved in the mechanism underlying the effect of AA on the heart. Rats subjected to MI displayed significantly impaired cardiac function compared with those subjected to a sham procedure, while this change was reversed by treatment with AA. Furthermore, AA markedly inhibited cardiac hypertrophy, reduced the mRNA expression levels of inflammatory cytokines and decreased interstitial fibrosis in the infarct border zone of MI model rats compared with those in vehicle-treated MI model rats. Furthermore, the phosphorylation of p38 MAPK and ERK1/2 was blocked by AA in the MI rats but not in the sham rats. In summary, AA treatment preserved cardiac function and inhibited left ventricular remodeling, potentially by blocking the phosphorylation of p38 MAPK and ERK1/2 in the infarct border zone of the ischemic myocardium, indicating that AA may be a novel candidate for development as a therapy for MI. PMID:26889217

  4. Opioid mediation of amniotic fluid effects on chemosensory responsiveness in the neonatal rat

    PubMed Central

    Méndez-Gallardo, Valerie; Robinson, Scott R.

    2010-01-01

    The present study investigated if oral exposure to milk or amniotic fluid (AF) alters responsiveness to sensory stimulation in the neonatal rat, and whether these effects are mediated by the opioid system. Facial wiping evoked by intraoral lemon infusion was used as a measure of sensory responsiveness. Pups were tested in a supine posture, because they showed more paw-face strokes during facial wiping than pups tested prone (Experiment 1). Moreover, pups orally exposed to milk (Experiment 2) or AF (Experiment 3) showed a diminished wiping response to lemon compared to controls exposed to water. Blockade of opioid receptors with the non-selective antagonist naltrexone (Experiment 4) or the kappa antagonist nor-binaltorphimine (Experiment 5) reinstated higher levels of facial wiping after AF exposure. These findings confirm developmental continuity between fetal and neonatal behavioral responses to AF and the ability of AF to induce activity at kappa receptors of the endogenous opioid system. PMID:21117244

  5. Neonatally induced mild diabetes: influence on development, behavior and reproductive function of female Wistar rats

    PubMed Central

    2013-01-01

    Background Neonatal STZ treatment induces a state of mild hyperglycemia in adult rats that disrupts metabolism and maternal/fetal interactions. The aim of this study was investigate the effect of neonatal STZ treatment on the physical development, behavior, and reproductive function of female Wistar rats from infancy to adulthood. Methods At birth, litters were assigned either to a Control (subcutaneous (s.c.) citrate buffer, n = 10) or STZ group, (streptozotocin (STZ) - 100 mg/kg-sc, n = 6). Blood glucose levels were measured on postnatal days (PND) 35, 84 and 120. In Experiment 1 body weight, length and the appearance of developmental milestones such as eye and vaginal opening were monitored. To assess the relative contribution of the initial and long term effects of STZ treatment this group was subdivided based on blood glucose levels recorded on PND 120: STZ hyperglycemic (between 120 and 300 mg/dl) and STZ normoglycemic (under 120 mg/dl). Behavioral activity was assessed in an open field on PND 21 and 75. In Experiment 2 estrous cyclicity, sexual behavior and circulating gonadotropin, ovarian steroid, and insulin levels were compared between control and STZ-hyperglycemic rats. In all measures the litter was the experimental unit. Parametric data were analyzed using one-way or, where appropriate, two-way ANOVA and significant effects were investigated using Tukey’s post hoc test. Fisher’s exact test was employed when data did not satisfy the assumption of normality e.g. presence of urine and fecal boli on the open field between groups. Statistical significance was set at p < 0.05 for all data. Results As expected neonatal STZ treatment caused hyperglycemia and hypoinsulinemia in adulthood. STZ-treated pups also showed a temporary reduction in growth rate that probably reflected the early loss of circulating insulin. Hyperglycemic rats also exhibited a reduction in locomotor and exploratory behavior in the open field. Mild hyperglycemia did

  6. Layer-specific strain analysis by speckle tracking echocardiography reveals differences in left ventricular function between rats and humans.

    PubMed

    Bachner-Hinenzon, Noa; Ertracht, Offir; Leitman, Marina; Vered, Zvi; Shimoni, Sara; Beeri, Ronen; Binah, Ofer; Adam, Dan

    2010-09-01

    The rat heart is commonly used as an experimental model of the human heart in both health and disease states, assuming that heart function of rats and humans is alike. When studying a rat model, echocardiography is usually performed on sedated rats, whereas standard echocardiography on adult humans does not require any sedation. Since echocardiography results of sedated rats are usually inferred to alert humans, in the present study, we tested the hypothesis that differences in left ventricular (LV) function may be present between rats sedated by a low dose of ketamine-xylazine and alert humans. Echocardiography was applied to 110 healthy sedated rats and 120 healthy alert humans. Strain parameters were calculated from the scans using a layer-specific speckle tracking echocardiography program. The results showed that layer longitudinal strain is equal in rats and humans, whereas segmental strain is heterogeneous (P < 0.05) in a different way in rats and humans (P < 0.05). Furthermore, layer circumferential strain is larger in humans (P < 0.001), and the segmental results showed different segmental heterogeneity in rats and humans (P < 0.05). Radial strain was found to be homogeneous at the apex and papillary muscle levels in humans and heterogeneous in rats (P < 0.001). Additionally, whereas LV twist was equal in rats and humans, in rats the rotation was larger at the apex (P < 0.01) and smaller at the base (P < 0.001). The torsion-to-shortening ratio parameter, which indicates the transmural distribution of contractile myofibers, was found to be equal in rats and humans. Thus, when evaluating LV function of sedated rats under ketamine-xylazine, it is recommended to measure the global longitudinal strain, LV twist, and torsion-to-shortening ratio, since no scaling is required when converting these parameters and inferring them to humans.

  7. IL-1 receptor antagonist attenuates neonatal lipopolysaccharide-induced long-lasting learning impairment and hippocampal injury in adult rats.

    PubMed

    Lan, Kuo-Mao; Tien, Lu-Tai; Pang, Yi; Bhatt, Abhay J; Fan, Lir-Wan

    2015-04-02

    We have previously reported that neonatal lipopolysaccharide (LPS) exposure resulted in an increase in interleukin-1β (IL-1β) content, injury to the hippocampus, and cognitive deficits in juvenile male and female rats, as well as female adult rats. The present study aimed to determine whether an anti-inflammatory cytokine, interleukin-1 receptor antagonist (IL-1ra), protects against the neonatal LPS exposure-induced inflammatory responses, hippocampal injury, and long-lasting learning deficits in adult rats. LPS (1 mg/kg) or LPS plus IL-1ra (0.1 mg/kg) was injected intracerebrally to Sprague-Dawley male rat pups at postnatal day 5 (P5). Neurobehavioral tests were carried out on P21, P49, and P70, while neuropathological studies were conducted on P71. Our results showed that neonatal LPS exposure resulted in learning deficits in rats at both developmental and adult ages, as demonstrated by a significantly impaired performance in the passive avoidance task (P21, P49, and P70), reduced hippocampal volume, and reduced number of Nissl+ cells in the CA1 region of the middle dorsal hippocampus of P71 rat brain. Those neuropathological and neurobehavioral alterations by LPS exposure were associated with a sustained inflammatory response in the P71 rat hippocampus, indicated by increased number of activated microglia as well as elevated levels of IL-1β. Neonatal administration of IL-1ra significantly attenuated LPS-induced long-lasting learning deficits, hippocampal injury, and sustained inflammatory responses in P71 rats. Our study demonstrates that neonatal LPS exposure leads to a persistent injury to the hippocampus, resulting in long-lasting learning disabilities related to chronic inflammation in rats, and these effects can be attenuated with an IL-1 receptor antagonist.

  8. IL-1 receptor antagonist attenuates neonatal lipopolysaccharide-induced long-lasting learning impairment and hippocampal injury in adult rats

    PubMed Central

    Pang, Yi; Bhatt, Abhay J.; Fan, Lir-Wan

    2015-01-01

    We have previously reported that neonatal lipopolysaccharide (LPS) exposure resulted in an increase in interleukin-1β (IL-1β) content, injury to the hippocampus, and cognitive deficits in juvenile male and female rats, as well as female adult rats. The present study aimed to determine whether an antiinflammatory cytokine, interleukin-1 receptor antagonist (IL-1ra), protects against the neonatal LPS exposure-induced inflammatory responses, hippocampal injury, and long-lasting learning deficits in adult rats. LPS (1 mg/kg) or LPS plus IL-1ra (0.1 mg/kg) was injected intracerebrally to Sprague-Dawley male rat pups at postnatal day 5 (P5). Neurobehavioral tests were carried out on P21, P49, and P70, while neuropathological studies were conducted on P71. Our results showed that neonatal LPS exposure resulted in learning deficits in rats at both developmental and adult ages, as demonstrated by a significantly impaired performance in the passive avoidance task (P21, P49, and P70), reduced hippocampal volume, and reduced number of Nissl+ cells in the CA1 region of the middle dorsal hippocampus of P71 rat brain. Those neuropathological and neurobehavioral alterations by LPS exposure were associated with a sustained inflammatory response in the P71 rat hippocampus, indicated by increased number of activated microglia as well as elevated levels of IL-1β. Neonatal administration of IL-1ra significantly attenuated LPS-induced long-lasting learning deficits, hippocampal injury, and sustained inflammatory responses in P71 rats. Our study demonstrates that neonatal LPS exposure leads to a persistent injury to the hippocampus, resulting in long-lasting learning disabilities related to chronic inflammation in rats, and these effects can be attenuated with an IL-1 receptor antagonist. PMID:25665855

  9. Effects of the endogenous cannabinoid anandamide on voltage-dependent sodium and calcium channels in rat ventricular myocytes

    PubMed Central

    Al Kury, Lina T; Voitychuk, Oleg I; Yang, Keun-Hang Susan; Thayyullathil, Faisal T; Doroshenko, Petro; Ramez, Ali M; Shuba, Yaroslav M; Galadari, Sehamuddin; Howarth, Frank Christopher; Oz, Murat

    2014-01-01

    BACKGROUND AND PURPOSE The endocannabinoid anandamide (N-arachidonoyl ethanolamide; AEA) exerts negative inotropic and antiarrhythmic effects in ventricular myocytes. EXPERIMENTAL APPROACH Whole-cell patch-clamp technique and radioligand-binding methods were used to analyse the effects of anandamide in rat ventricular myocytes. KEY RESULTS In the presence of 1–10 μM AEA, suppression of both Na+ and L-type Ca2+ channels was observed. Inhibition of Na+ channels was voltage and Pertussis toxin (PTX) – independent. Radioligand-binding studies indicated that specific binding of [3H] batrachotoxin (BTX) to ventricular muscle membranes was also inhibited significantly by 10 μM metAEA, a non-metabolized AEA analogue, with a marked decrease in Bmax values but no change in Kd. Further studies on L-type Ca2+ channels indicated that AEA potently inhibited these channels (IC50 0.1 μM) in a voltage- and PTX-independent manner. AEA inhibited maximal amplitudes without affecting the kinetics of Ba2+ currents. MetAEA also inhibited Na+ and L-type Ca2+ currents. Radioligand studies indicated that specific binding of [3H]isradipine, was inhibited significantly by metAEA. (10 μM), changing Bmax but not Kd. CONCLUSION AND IMPLICATIONS Results indicate that AEA inhibited the function of voltage-dependent Na+ and L-type Ca2+ channels in rat ventricular myocytes, independent of CB1 and CB2 receptor activation. PMID:24758718

  10. Selenium repletion protects neonatal rat lungs from hyperoxia

    SciTech Connect

    Hyeyoung Kim; Wallig, M.A.; Picciano, M.F. Pennsylvania State Univ., University Park )

    1991-03-15

    Previously the authors reported that selenium adequate rat pups were resistant to lung damage due to high O{sub 2} exposure. The present study was designed to assess whether Se-deficient pups repleted during postnatal period could also be protected from lung injury. Female SD rats were bred and fed a Se deficient diet during pregnancy. On day 2 postpartum, dams were divided into two groups and either continued on a Se{sup {minus}} diet or fed a Se supplemented diet. On day 5 postpartum, litters in each group were randomly assigned to either air or high O{sub 2} environments. Matched dams were rotated daily between litters in air and O{sub 2} for 4 days. Double-blinded, histopathologic scoring of lungs from 9 day old pup showed that Se repletion significantly reduced the incidence of septal attenuation and interstitial inflammation. Additionally lung volume of Se repleted pups were significantly enhanced. RNA/DNA ratio and glutathione concentration of lung were increased in response to hyperoxia, but unrelated to Se nutriture. These results show that postnatal Se repletion protects the developing lung from oxygen-induced injury.

  11. Neonatal neuronal apoptosis after betamethasone administration in pregnant Wistar rats.

    PubMed

    França, Marcelo Santucci; Moron, Antonio Fernandes; Araujo Júnior, Edward; Avedissian, Marcelo; Pares, David Baptista Silva; Nardozza, Luciano Marcondes Marchado; Jaqueta, Carolina Barros; Mello, Luiz Eugênio Araujo Moraes

    2016-01-01

    To analyze the apoptosis of cortical and hippocampal neurons in newborn following the intramuscular administration of betamethasone in pregnant Wistar rats. Betamethasone or placebo was administered to 10 pregnant rats. Subsequently, 98 newborns were analyzed in three different groups: therapeutic dose (TD, 20 mg/kg), triple therapeutic dose (3TD, 60 mg/kg), and nine times TD (9TD, 180 mg/kg). Forty-four newborns were injected with placebo (control subjects--CTR). Neuronal apoptosis was measured by immunofluorescence using the TUNEL assay. The one-way analysis of variance, Tukey-Kramer (parametric) test and Kruskal-Wallis (non-parametric) test were used for statistical analysis. The CA1 area of the hippocampus of TD and 3TD groups showed significant differences from that of the CTR group (p < 0.001). Compared to the CTR group, there was increased neuronal apoptosis in the dentate gyrus (DG) of animals in TD and 3TD groups (p < 0.0001). There were no significant differences in CA2 and CA3 regions as well as in amygdala and cortex. Prenatal administration of betamethasone leads to significant changes in neuronal apoptosis in CA1 and DG regions.

  12. Surgical Injury in the Neonatal Rat Alters the Adult Pattern of Descending Modulation from the Rostroventral Medulla

    PubMed Central

    Walker, Suellen M.; Fitzgerald, Maria; Hathway, Gareth J.

    2015-01-01

    Background Neonatal pain and injury can alter long-term sensory thresholds. Descending rostroventral medulla (RVM) pathways can inhibit or facilitate spinal nociceptive processing in adulthood. As these pathways undergo significant postnatal maturation, we evaluated long-term effects of neonatal surgical injury on RVM descending modulation. Methods Plantar hindpaw or forepaw incisions were performed in anesthetized postnatal day (P)3 Sprague-Dawley rats. Controls received anesthesia only. Hindlimb mechanical and thermal withdrawal thresholds were measured to 6 weeks of age (adult). Additional groups received pre- and post-incision sciatic nerve bupivacaine or saline. Hindpaw nociceptive reflex sensitivity was quantified in anesthetized adult rats using biceps femoris electromyography, and the effect of RVM electrical stimulation (5-200 μA) measured as percentage change from baseline. Results In adult rats with prior neonatal incision (n=9), all intensities of RVM stimulation decreased hindlimb reflex sensitivity, in contrast to the typical bimodal pattern of facilitation and inhibition with increasing RVM stimulus intensity in controls (n=5) (uninjured vs. neonatally-incised, P<0.001). Neonatal incision of the contralateral hindpaw or forepaw also resulted in RVM inhibition of hindpaw nociceptive reflexes at all stimulation intensities. Behavioral mechanical threshold (mean±SEM, 28.1±8g vs. 21.3±1.2g, P<0.001) and thermal latency (7.1±0.4 vs. 5.3±0.3s, P<0.05) were increased in both hindpaws following unilateral neonatal incision. Neonatal perioperative sciatic nerve blockade prevented injury-induced alterations in RVM descending control. Conclusions Neonatal surgical injury alters the postnatal development of RVM descending control, resulting in a predominance of descending inhibition and generalized reduction in baseline reflex sensitivity. Prevention by local anesthetic blockade highlights the importance of neonatal perioperative analgesia. PMID:25871742

  13. Metabolism of branched-chain keto acids in neonatal rat liver perfusions.

    PubMed

    Frost, S C; Wells, M A

    1983-10-15

    The ability of the neonatal rat to oxidize the branched-chain amino acids leucine and valine and their corresponding keto acids was evaluated. In vivo, about 20% of orally administered labeled amino or keto acids were oxidized in 6 h, after which time little further oxidation occurred. In perfused neonatal liver the amino acids were oxidized at only 5-10% the rate of the keto acids. The oxidation of the keto acids showed a saturable dependence on concentration. The decarboxylation of ketoisocaproate (KIC) had a maximal rate of 40.1 +/- 1.6 mumol/h/g liver with an apparent Km of 0.27 +/- 0.03 mM, and decarboxylation of ketoisovalerate (KIV) had a maximal rate of 37.9 +/- 1.9 mumol/h/g liver and an apparent Km of 0.28 +/- 0.04 mM. KIC was ketogenic, producing mainly acetoacetate at a maximal rate of 44.5 +/- 1.6 mumol/h/g liver with an apparent Km of 0.27 +/- 0.03 mM. On the other hand, KIV was not gluconeogenic, although the perfused neonatal liver was able to produce glucose from lactate. During liver perfusion, KIV did not produce measurable quantities of either propionic or beta-aminoisobutyric acids, which are possible end products of KIV metabolism. Decanoic acid inhibited the decarboxylation of both keto acids to the same extent with a maximal effect at 0.4 mM fatty acid. At saturating levels, KIC was less ketogenic than decanoate. Inhibition of endogenous fatty acid oxidation by 2-tetradecylglycidic acid had no effect on keto acid oxidation. These data suggest that branched-chain amino acids derived from milk proteins are probably not quantitatively significant sources of either ketone bodies or glucose in the neonatal rat.

  14. Neonatal handling causes impulsive behavior and decreased pharmacological response to methylphenidate in male adult wistar rats.

    PubMed

    Lazzaretti, Camilla; Kincheski, Grasielle Clotildes; Pandolfo, Pablo; Krolow, Rachel; Toniazzo, Ana Paula; Arcego, Danusa Mar; Couto-Pereira, Natividade de Sá; Zeidán-Chuliá, Fares; Galvalisi, Martin; Costa, Gustavo; Scorza, Cecilia; Souza, Tadeu Mello E; Dalmaz, Carla

    2016-03-01

    Neonatal handling has an impact on adult behavior of experimental animals and is associated with rapid and increased palatable food ingestion, impaired behavioral flexibility, and fearless behavior to novel environments. These symptoms are characteristic features of impulsive trait, being controlled by the medial prefrontal cortex (mPFC). Impulsive behavior is a key component of many psychiatric disorders such as attention deficit hyperactivity disorder (ADHD), manic behavior, and schizophrenia. Others have reported a methylphenidate (MPH)-induced enhancement of mPFC functioning and improvements in behavioral core symptoms of ADHD patients. The aims of the present study were: (i) to find in vivo evidence for an association between neonatal handling and the development of impulsive behavior in adult Wistar rats and (ii) to test whether neonatal handling could have an impact on monoamine levels in the mPFC and the pharmacological response to MPH in vivo. Therefore, experimental animals (litters) were classified as: "non-handled" and "handled" (10[Formula: see text]min/day, postnatal days 1-10). After puberty, they were exposed to either a larger and delayed or smaller and immediate reward (tolerance to delay of reward task). Acute MPH (3[Formula: see text]mg/Kg. i.p.) was used to suppress and/or regulate impulsive behavior. Our results show that only neonatally handled male adult Wistar rats exhibit impulsive behavior with no significant differences in monoamine levels in the medial prefrontal cortex, together with a decreased response to MPH. On this basis, we postulate that early life interventions may have long-term effects on inhibitory control mechanisms and affect the later response to pharmacological agents during adulthood.

  15. Neonatal handling reduces the number of cells in the medial preoptic area of female rats.

    PubMed

    Camozzato, Tatiane S C; Winkelmann-Duarte, Elisa C; Padilha, Camila B; Miguel, Sandro P R; Bonzanini, Laisa; Anselmo-Franci, Janete A; Fernandes, Marilda C; Lucion, Aldo B

    2009-01-09

    Early-life events may induce alterations in neuronal function in adulthood. A crucial aspect in studying long-lasting effects induced by environmental interventions imposed to the animal several weeks before is finding a stable change that could be causally related to the phenotype observed in adulthood. In order to explain an adult trait, it seems necessary to look back to early life and establish a temporal line between events. The neonatal handling procedure is an experimental tool to analyze the long-lasting impact of early-life events. Aside from the neuroendocrine response to stress, neonatal handling also alters the functionality of the hypothalamus-pituitary-gonad (HPG) axis. Reductions in ovulation and surge of the luteinizing hormone (LH) on the proestrous day were shown in female rats. Considering the importance of the medial preoptic area (MPA) for the control of ovulation, the present study aimed to verify the effects of neonatal handling on the numerical density and cell size in the MPA in 11-day-old and 90-day-old female rats. Cellular proliferation was also assessed using BrdU (5-bromo-2'-deoxyuridine) in 11-day-old pups. Results showed that neonatal handling induces a stable reduction in the number of cells and in the size of the cell soma, which were lower in handled females than in nonhandled ones at both ages. Cellular proliferation in the MPA was also reduced 24 h after the last manipulation. The repeated mother-infant disruption imposed by the handling procedure "lesioned" the MPA. The dysfunction in the ovulation mechanisms induced by the handling procedure could be related to that neuronal loss. The study also illustrates the impact of an environmental intervention on the development of the brain.

  16. Myocyte cellular hypertrophy and hyperplasia contribute to ventricular wall remodeling in anemia-induced cardiac hypertrophy in rats.

    PubMed Central

    Olivetti, G.; Quaini, F.; Lagrasta, C.; Ricci, R.; Tiberti, G.; Capasso, J. M.; Anversa, P.

    1992-01-01

    To determine the effects of chronic anemia on the functional and structural characteristics of the heart, 1-month-old male rats were fed a diet deficient in iron and copper, which led to a hemoglobin concentration of 4.63 g/dl, for 8 weeks. At sacrifice, under fentanyl citrate and droperidol anesthesia, systolic, diastolic, and mean arterial blood pressures were decreased, whereas differential pressure was increased. Left ventricular systolic pressure and the ventricular rate of pressure rise (mmHg/s) were reduced by 9% and 14%, respectively. Moreover, developed peak systolic ventricular pressure and maximal dP/dt diminished 14% and 12%. After perfusion fixation of the coronary vasculature and the myocardium, at a left ventricular intracavitary pressure equal to the in vivo measured end diastolic pressure, a 10% thickening of the left ventricular wall was measured in association with a 13% increase in the equatorial cavitary diameter and a 44% augmentation in ventricular mass. The 52% hypertrophy of the right ventricle was characterized by an 11% thicker wall and a 37% larger ventricular area. The 33% expansion in the aggregate myocyte volume of the left ventricle was found to be due to a 14% myocyte cellular hypertrophy and a 17% myocyte cellular hyperplasia. These cellular parameters were calculated from the estimation of the number of myocyte nuclei per unit volume of myocardium in situ and the evaluation of the distribution of nuclei per cell in enzymatically dissociated myocytes. Myocyte cellular hyperplasia provoked a 9% increase in the absolute number of cells across the left ventricular wall. In contrast, myocyte cellular hypertrophy (42%) was responsible for the increase in myocyte volume of the right ventricle. The proliferative response of left ventricular myocytes was not capable of restoring diastolic cell stress, which was enhanced by the changes in ventricular anatomy with anemia. In conclusion, chronic anemia induced an unbalanced load on the left

  17. Intrauterine endotoxin-induced impairs pulmonary vascular function and right ventricular performance in infant rats and improvement with early vitamin D therapy.

    PubMed

    Mandell, Erica; Powers, Kyle N; Harral, Julie W; Seedorf, Gregory J; Hunter, Kendall S; Abman, Steven H; Dodson, R Blair

    2015-12-15

    High pulmonary vascular resistance (PVR), proximal pulmonary artery (PA) impedance, and right ventricular (RV) afterload due to remodeling contribute to the pathogenesis and severity of pulmonary hypertension (PH). Intra-amniotic exposure to endotoxin (ETX) causes sustained PH and high mortality in rat pups at birth, which are associated with impaired vascular growth and RV hypertrophy in survivors. Treatment of ETX-exposed pups with antenatal vitamin D (vit D) improves survival and lung growth, but the effects of ETX exposure on RV-PA coupling in the neonatal lung are unknown. We hypothesized that intrauterine ETX impairs RV-PA coupling through sustained abnormalities of PA stiffening and RV performance that are attenuated with vit D therapy. Fetal rats were exposed to intra-amniotic injections of ETX, ETX+vit D, or saline at 20 days gestation (term = 22 days). At postnatal day 14, pups had pressure-volume measurements of the RV and isolated proximal PA, respectively. Lung homogenates were assayed for extracellular matrix (ECM) composition by Western blot. We found that ETX lungs contain decreased α-elastin, lysyl oxidase, collagen I, and collagen III proteins (P < 0.05) compared control and ETX+vit D lungs. ETX-exposed animals have increased RV mechanical stroke work (P < 0.05 vs. control and ETX+vit D) and elastic potential energy (P < 0.05 vs. control and ETX+vit D). Mechanical stiffness and ECM remodeling are increased in the PA (P < 0.05 vs. control and ETX+vit D). We conclude that intrauterine exposure of fetal rats to ETX during late gestation causes persistent impairment of RV-PA coupling throughout infancy that can be prevented with early vit D treatment.

  18. Mechanical allodynia and thermal hyperalgesia upon acute opioid withdrawal in the neonatal rat.

    PubMed

    Sweitzer, Sarah M; Allen, Caroline P; Zissen, Maurice H; Kendig, Joan J

    2004-07-01

    Upon withdrawal from opioids many patients experience a heightened sensitivity to stimuli and an exaggerated pain response. We present evidence that neonatal rats exhibit allodynia and hyperalgesia on acute opiate withdrawal. Postnatal 7 and 21 day rats were used to approximately model a full term human infant and a human child, respectively. The opiate antagonist naloxone was used to precipitate withdrawal at 30 or 120 min after a single acute administration of morphine. Alternatively, rats were allowed to undergo spontaneous withdrawal. Behavioral manifestations of withdrawal syndrome were not observed when naloxone was administered at 30 min post-morphine, but were present when withdrawal was precipitated at 120 min. Spontaneous and precipitated withdrawal from a single acute administration of morphine produced mechanical allodynia and thermal hyperalgesia in postnatal day 7 rats and mechanical allodynia in postnatal day 21 rats. A higher dose of morphine was required to produce mechanical allodynia in postnatal day 21 versus 7 rats but this increase was independent of the analgesic efficacy of morphine at these two ages. The present work illustrates the need to examine the phenomenon of hypersensitivity upon opioid withdrawal in the human pediatric population.

  19. Hydroethanolic extract of Smallanthus sonchifolius leaves improves hyperglycemia of streptozotocin induced neonatal diabetic rats.

    PubMed

    Baroni, Silmara; da Rocha, Bruno Ambrosio; Oliveira de Melo, Juliana; Comar, Jurandir Fernando; Caparroz-Assef, Silvana Martins; Bersani-Amado, Ciomar Aparecida

    2016-05-01

    To evaluate the effect of hydroethanolic extract of yacon on the hyperglycemia induced by streptozotocin (STZ) in neonatal rats. Wistar rats aged two days old received an intraperitoneal injection of STZ (160 mg/kg); after seven weeks, glycosuria was determined and animals with glucose levels above 250 mg/dL were included in the study. Groups of diabetic and non-diabetic rats were treated orally with yacon extract at a dose of 400 mg/kg/d for 14 d. Tests were made for phytochemical characterization, glucose tolerance and toxicity. The results showed that treatment with the extract reduced the glucose levels of fed diabetic rats and did not change the glucose levels of fasting diabetic and normal rats. Additionally, also it was observed that treatment with the extract reduced blood glucose levels of diabetic rats during the oral and intravenous glucose tolerance tests. There was no change in body weight, liver enzymes or mortality with yacon extract treatment. The phytochemical screening revealed the presence of caffeic acid, chlorogenic acid, ferulic acid and gallic acid. The data suggest that yacon extract reduces hyperglycemia, possibly by improving insulin sensibility through its phytochemicals constituents (phenolic compounds). Copyright © 2016 Hainan Medical College. Production and hosting by Elsevier B.V. All rights reserved.

  20. Neonatal manipulation of oxytocin alters oxytocin levels in the pituitary of adult rats.

    PubMed

    Young, E; Carter, C S; Cushing, B S; Caldwell, J D

    2005-07-01

    The neuropeptide oxytocin (OT) and its OT antagonists (OTA) in infant rats affect their behavior as adults. In this study we attempted to determine whether treating rats on the day of birth (postnatal day 1) with OT or OTA would affect brain OT levels of these rats as adults. Rat pups were injected with OT (3 microg), OTA (0.3 microg) or saline vehicle ip on postnatal day 1. As 60-day-old adults, treated rats were killed, and the OT content in their medial preoptic areas (MPOAs), medial hypothalami (MH) and pituitaries were assayed. In females, treatment with OTA on postnatal day 1 significantly decreased pituitary OT levels as adults. In males, by contrast, treatment with OTA on postnatal day 1 resulted in increased pituitary OT levels when they become adults compared to male rats treated with OT on postnatal day 1. There were no significant effects of neonatal treatment on OT levels in either the MH or MPOA. Day 1 postnatal treatment with OT or OTA had a long-term sexually dimorphic effect on OT levels in the pituitary.

  1. Digestive enzyme expression and epithelial structure of small intestine in neonatal rats after 16 days spaceflight

    NASA Astrophysics Data System (ADS)

    Miyake, M.; Yamasaki, M.; Hazama, A.; Ijiri, K.; Shimizu, T.

    It is important to assure whether digestive system can develop normally in neonates during spaceflight. Because the small intestine changes its function and structure drastically around weaning known as redifferentiation. Lactase expression declines and sucrase increases in small intestine for digestion of solid food before weaning. In this paper, we compared this enzyme transition and structural development of small intestine in neonatal rats after spaceflight. To find digestive genes differentially expressed in fight rats, DNA membrane macroarray was also used. Eight-day old rats were loaded to Space Shuttle Columbia, and housed in the animal facility for 16 days in space (STS-90, Neurolab mission). Two control groups (AGC; asynchronous ground control and VIV; vivarium) against flight group (FLT) were prepared. There was no difference in structure (crypt depth) and cell differentiation of epithelium between FLT and AGC by immunohistochemical analysis. We found that the amount of sucrase mRNA compared to lactase was decreased in FLT by RT-PCR. It reflected the enzyme transition was inhibited. Increase of 5 genes (APO A-I, APO A-IV, ACE, aFABP and aminopeptidase M) and decrease of carboxypeptidase-D were detected in FLT using macroarray. We think nutrition differences (less nourishment and late weaning) during spaceflight may cause inhibition of enzyme transition at least partly. The weightlessness might contribute to the inhibition through behavioral change.

  2. Feeding neonatal rats with IgG antibodies leads to humoral hyporesponsiveness in the adult.

    PubMed Central

    Peppard, J V

    1992-01-01

    Feeding monoclonal IgG2a or IgG1 anti-horseradish peroxidase (HRP) antibodies to 12-16-day-old neonatal rats caused a profound suppression of the humoral anti-HRP response in these rats as adults. The hyporesponsiveness to HRP was specific and long-lasting (up to 5 months). It was shown to be dose dependent, requiring relatively large doses of IgG (100-600 micrograms) for maximum effect. Secondary IgG (IgG1, IgG2a and IgG2b) responses were most depressed. The effect could be reproduced by i.p. injection of antibody. Hyporesponsiveness was not attributable to circulating antiidiotype antibodies directed against the monoclonal IgG, nor to the continued presence of the monoclonal anti-HRP since rats receiving antibody at or some weeks after the time of weaning and gut 'closure' responded well to subsequent HRP challenge. The effect was thus dependent on IgG administered over the identical period during which the neonatal circulation is rich in maternal IgG supplied via the milk. A direct function for maternal IgG in moulding the immune repertoire of the offspring, as well as providing passive protection, is suggested by these results. PMID:1385314

  3. Neonatal exposure to a glyphosate-based herbicide alters uterine decidualization in rats.

    PubMed

    Ingaramo, Paola I; Varayoud, Jorgelina; Milesi, María M; Guerrero Schimpf, Marlise; Alarcón, Ramiro; Muñoz-de-Toro, Mónica; Luque, Enrique H

    2017-08-02

    We investigated whether defective modulation of uterine signaling may cause decidualization failure in rats neonatally exposed to a glyphosate-based herbicide (GBH). Female pups received vehicle or 2mg/kg of GBH from postnatal day (PND) 1 to PND7. On PND8 and PND21, Wnt5a and β-catenin expression was evaluated in uterine samples. On gestational day (GD) 9, Wnt5a, Wnt7a and β-catenin expression and Dkk1 and sFRP4 mRNA were evaluated on implantation sites. On PND8, GBH-exposed rats showed increased Wnt5a and β-catenin expression in luminal epithelium (LE), whereas on PND21, they showed increased Wnt5a and β-catenin expression in subepithelial stroma but decreased β-catenin expression in glandular epithelium. On GD9, GBH-exposed rats showed decreased Wnt5a and Wnt7a expression in the antimesometrial zone and LE respectively, without changes in β-catenin expression, while Dkk1 and sFRP4 were up- and down-regulated respectively. We concluded that neonatal GBH exposure may lead to embryo losses by disturbing uterine signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Treatment with carnosine reduces hypoxia-ischemia brain damage in a neonatal rat model.

    PubMed

    Zhang, Huizhen; Guo, Shang; Zhang, Linlin; Jia, Liting; Zhang, Zhan; Duan, Hongbao; Zhang, Jingbin; Liu, Jingyan; Zhang, Weidong

    2014-03-15

    Perinatal hypoxia-ischemia brain damage (HIBD) is a major cause of mortality and morbidity in neonates, and there is currently no effective therapy for HIBD. Carnosine plays a neuroprotective role in adult brain damage. We have previously demonstrated that carnosine pretreatment protects against HIBD in a neonatal rat model. Therefore, we hypothesized that treatment with carnosine would also have neuroprotective effects. Hypoxia-ischemia was induced in rats on postnatal days 7-9 (P7-9). Carnosine was administered intraperitoneally at a dose of 250mg/kg at 0h, 24h, and 48h after hypoxia-ischemia was induced. The biochemical markers of oxidative stress and apoptosis were evaluated at 72h after hypoxia-ischemia was induced, Brain learning and memory function performance were observed using the Morris water maze test on postnatal days 28-33 (P28-33). Treatment with carnosine post-HIBD significantly reduced the concentration of 8-iso-prostaglandinF2alpha in brain tissue and decreased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells in the hippocampus CA1 region and cortex as well as the mitochondria caspase-3 protein expression. Furthermore, carnosine also improved the cognitive function of P28-33 rats, whose cognitive function decline was due to HIBD. These results demonstrate that carnosine treatment after HIBD can reduce the brain injury, improving brain function. Carnosine could be an attractive candidate for treating HIBD.

  5. Dexamethasone suppresses the locomotor response of neonatal rats to novel environment.

    PubMed

    Menshanov, Petr N; Bannova, Anita V; Dygalo, Nikolay N

    2014-09-01

    Locomotion of animals in the novel environment is determined by two main factors-the intrinsic motor activity and the specific locomotor response to novelty. Glucocorticoids alter neurobehavioral development of mammals and its locomotor manifestations. However, it remains unclear whether the intrinsic and/or the novelty-induced activity are affected by glucocorticoids during early life. Here, the principal component analysis was used to determine the main factors that underlie alterations in locomotion of rat pups treated with dexamethasone. It was shown that neonatal rats exhibited an enhanced locomotion in the novel environment beginning from postnatal day (PD) 5. We found for the first time that this reaction was significantly suppressed by dexamethasone. The effect was specific to the novelty-induced component of behavior, while the intrinsic locomotor activity was not affected by glucocorticoid treatment. The suppression of the behavioral response to novelty was maximal at PD7 and vanquished at PD10-11. In parallel with the hormonal effect on the behavior, dexamethasone upregulated the main cell death executor-active caspase-3 in the prefrontal cortex of 7-day old rats. Thus, dexamethasone-induced alterations in the novelty-related behavior may be the earliest visible signs of the brain damage that could lead to forthcoming depressive state or schizophrenia, emerging as a result of neonatal stress or glucocorticoid treatment. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. Neonatal isoflavone exposure interferes with the reproductive system of female Wistar rats.

    PubMed

    Müller, Dennis R; Soukup, Sebastian T; Kurrat, Anne; Liu, Xin; Schmicke, Marion; Xie, Ming-Yong; Kulling, Sabine E; Diel, Patrick

    2016-11-16

    There is increasing concern about possible adverse effects of soy based infant formulas (SBIF) due to their high amount of isoflavones (ISO). The aim of the present study was to investigate effects of neonatal exposure to ISO on reproductive system of female Wistar rats. Animals were exposed to an ISO depleted diet or a diet enriched with an ISO extract (IRD; 508mg ISO/kg) during embryogenesis and adolescence. Pups of each group were fed daily by pipette with ISO-suspension (ISO+; 32mg ISO/kg bw) or placebo from postnatal day (PND) 1 until PND23 resulting in plasma concentrations similar to levels reported in infants fed SBIF. The visceral fat mass was reduced by long-term IRD. Vaginal epithelial height was increased at PND23 and vaginal opening was precocious in ISO+ groups. Later in life, more often irregular estrus cycles were observed in rats of ISO+ groups. In addition, FSH levels and uterine epithelial heights were increased at PND80 in ISO+ groups. In summary, the results indicate that neonatal ISO intake, resulting in plasma concentrations achievable through SBIF, has an estrogenic effect on prepubertal rats and influences female reproductive tract later in life. Copyright © 2016. Published by Elsevier Ireland Ltd.

  7. Therapeutic effect of human umbilical cord mesenchymal stem cells on neonatal rat hypoxic-ischemic encephalopathy.

    PubMed

    Zhang, Xinhua; Zhang, Qinfen; Li, Wei; Nie, Dekang; Chen, Weiwei; Xu, Chunxiang; Yi, Xin; Shi, Jinhong; Tian, Meiling; Qin, Jianbing; Jin, Guohua; Tu, Wenjuan

    2014-01-01

    The therapeutic potential of umbilical cord blood mesenchymal stem cells has been studied in several diseases. However, the possibility that human umbilical cord Wharton's jelly-derived mesenchymal stem cells (hUCMSCs) can be used to treat neonatal hypoxic-ischemic encephalopathy (HIE) has not yet been investigated. This study focuses on the potential therapeutic effect of hUCMSC transplantation in a rat model of HIE. Dermal fibroblasts served as cell controls. HIE was induced in neonatal rats aged 7 days. hUCMSCs labeled with Dil were then transplanted into the models 24 hr or 72 hr post-HIE through the peritoneal cavity or the jugular vein. Behavioral testing revealed that hUCMSC transplantation but not the dermal fibroblast improved significantly the locomotor function vs. vehicle controls. Animals receiving cell grafts 24 hr after surgery showed a more significant improvement than at 72 hr. More hUCMSCs homed to the ischemic frontal cortex following intravenous administration than after intraperitoneal injection. Differentiation of engrafted cells into neurons was observed in and around the infarct region. Gliosis in ischemic regions was significantly reduced after hUCMSC transplantation. Administration of ganglioside (GM1) enhanced the behavioral recovery on the base of hUCMSC treatment. These results demonstrate that intravenous transplantation of hUCMSCs at an early stage after HIE can improve the behavior of hypoxic-ischemic rats and decrease gliosis. Ganglioside treatment further enhanced the recovery of neurological function following hUCMSC transplantation.

  8. Effects of neonatal handling on central noradrenergic and nitric oxidergic systems and reproductive parameters in female rats.

    PubMed

    Raineki, Charlis; Szawka, Raphael Escorsim; Gomes, Cármen Marilei; Lucion, Marta Knijnik; Barp, Jaqueline; Belló-Klein, Adriane; Franci, Celso Rodrigues; Anselmo-Franci, Janete Aparecida; Sanvitto, Gilberto Luiz; Lucion, Aldo Bolten

    2008-01-01

    Early-life environmental events that disrupt the mother-pup relationship may induce profound long-lasting changes on several behavioral and neuroendocrine systems. The neonatal handling procedure, which involves repeated brief maternal separations followed by experimental manipulations, reduces sexual behavior and induces anovulatory estrous cycles in female rats. On the afternoon of proestrus, neonatally handled females show a reduced surge of luteinizing hormone (LH) and an increased content of gonadotropin-releasing hormone in the medial preoptic area (MPOA). In order to detect the possible causes for the reduced ovulation and sexual behavior, the present study aimed to analyze the effects of neonatal handling on noradrenaline (NA) and nitric oxide (NO) levels in the MPOA on the afternoon of proestrus. Neonatal handling reduced MHPG (NA metabolite) levels and MHPG/NA ratio in the MPOA, indicating decreased NAergic activity. Additionally, neonatal handling decreased NO levels, as measured by the metabolites (NO(x)), nitrite and nitrate in the same period. We may conclude that the neonatal handling procedure decreased activity of the NAergic and NOergic systems in the MPOA during proestrus, which is involved in the control of LH and FSH secretion, and this may possibly explain the anovulatory estrous cycles and reduced sexual behavior of the neonatally handled female rats. (c) 2007 S. Karger AG, Basel

  9. Neonatal overfeeding disrupts pituitary ghrelin signalling in female rats long-term; Implications for the stress response

    PubMed Central

    Ziko, Ilvana; Spencer, Sarah J.

    2017-01-01

    The hypothalamic-pituitary-adrenal (HPA) axis responses to psychological stress are exacerbated in adult female but not male rats made obese due to overfeeding in early life. Ghrelin, traditionally known for its role in energy homeostasis, has been recently recognised for its role in coordinating the HPA responses to stress, particularly by acting directly at the anterior pituitary where the growth hormone secretagogue receptor (GHSR), the receptor for acyl ghrelin, is abundantly expressed. We therefore hypothesised that neonatal overfeeding in female rats would compromise pituitary responsiveness to ghrelin, contributing to a hyperactive central stress responsiveness. Unlike in males where hypothalamic ghrelin signalling is compromised by neonatal overfeeding, there was no effect of early life diet on circulating ghrelin or hypothalamic ghrelin signalling in females, indicating hypothalamic feeding and metabolic ghrelin circuitry remains intact. However, neonatal overfeeding did lead to long-term alterations in the pituitary ghrelin system. The neonatally overfed females had increased neonatal and reduced adult expression of GHSR and ghrelin-O-acyl transferase (GOAT) in the pituitary as well as reduced pituitary responsiveness to exogenous acyl ghrelin-induced adrenocorticotropic hormone (ACTH) release in vitro. These data suggest that neonatal overfeeding dysregulates pituitary ghrelin signalling long-term in females, potentially accounting for the hyper-responsive HPA axis in these animals. These findings have implications for how females may respond to stress throughout life, suggesting the way ghrelin modifies the stress response at the level of the pituitary may be less efficient in the neonatally overfed. PMID:28282447

  10. MicroRNA-15b Modulates Cellular ATP Levels and Degenerates Mitochondria via Arl2 in Neonatal Rat Cardiac Myocytes*

    PubMed Central

    Nishi, Hitoo; Ono, Koh; Iwanaga, Yoshitaka; Horie, Takahiro; Nagao, Kazuya; Takemura, Genzou; Kinoshita, Minako; Kuwabara, Yasuhide; Mori, Rieko Takanabe; Hasegawa, Koji; Kita, Toru; Kimura, Takeshi

    2010-01-01

    MicroRNAs (miRNAs or miRs) are small, non-coding RNAs that modulate mRNA stability and post-transcriptional translation. A growing body of evidence indicates that specific miRNAs can affect the cellular function of cardiomyocytes. In the present study, miRNAs that are highly expressed in the heart were overexpressed in neonatal rat ventricular myocytes, and cellular ATP levels were assessed. As a result, miR-15b, -16, -195, and -424, which have the same seed sequence, the most critical determinant of miRNA targeting, decreased cellular ATP levels. These results suggest that these miRNAs could specifically down-regulate the same target genes and consequently decrease cellular ATP levels. Through a bioinformatics approach, ADP-ribosylation factor-like 2 (Arl2) was identified as a potential target of miR-15b. It has already been shown that Arl2 localizes to adenine nucleotide transporter 1, the exchanger of ADP/ATP in mitochondria. Overexpression of miR-15b, -16, -195, and -424 suppressed the activity of a luciferase reporter construct fused with the 3′-untranslated region of Arl2. In addition, miR-15b overexpression decreased Arl2 mRNA and protein expression levels. The effects of Arl2 siRNA on cellular ATP levels were the same as those of miR-15b, and the expression of Arl2 could restore ATP levels reduced by miR-15b. A loss-of-function study of miR-15b resulted in increased Arl2 protein and cellular ATP levels. Electron microscopic analysis revealed that mitochondria became degenerated in cardiomyocytes that had been transduced with miR-15b and Arl2 siRNA. The present results suggest that miR-15b may decrease mitochondrial integrity by targeting Arl2 in the heart. PMID:20007690

  11. Long Term Hippocampal and Cortical Changes Induced by Maternal Deprivation and Neonatal Leptin Treatment in Male and Female Rats

    PubMed Central

    Mela, Virginia; Díaz, Francisca; Borcel, Erika; Argente, Jesús; Chowen, Julie A.; Viveros, Maria-Paz

    2015-01-01

    Maternal deprivation (MD) during neonatal life has diverse long-term behavioral effects and alters the development of the hippocampus and frontal cortex, with several of these effects being sexually dimorphic. MD animals show a marked reduction in their circulating leptin levels, not only during the MD period, but also several days later (PND 13). A neonatal leptin surge occurs in rodents (beginning around PND 5 and peaking between PND 9 and 10) that has an important neurotrophic role. We hypothesized that the deficient neonatal leptin signaling of MD rats could be involved in the altered development of their hippocampus and frontal cortex. Accordingly, a neonatal leptin treatment in MD rats would at least in part counteract their neurobehavioural alterations. MD was carried out in Wistar rats for 24 h on PND 9. Male and female MD and control rats were treated from PND 9 to 13 with rat leptin (3 mg/kg/day sc) or vehicle. In adulthood, the animals were submitted to the open field, novel object memory test and the elevated plus maze test of anxiety. Neuronal and glial population markers, components of the glutamatergic and cannabinoid systems and diverse synaptic plasticity markers were evaluated by PCR and/or western blotting. Main results include: 1) In some of the parameters analyzed, neonatal leptin treatment reversed the effects of MD (eg., mRNA expression of hippocampal IGF1 and protein expression of GFAP and vimentin) partially confirming our hypothesis; 2) The neonatal leptin treatment, per se, exerted a number of behavioral (increased anxiety) and neural effects (eg., expression of the following proteins: NG2, NeuN, PSD95, NCAM, synaptophysin). Most of these effects were sex dependent. An adequate neonatal leptin level (avoiding excess and deficiency) appears to be necessary for its correct neuro-programing effect. PMID:26382238

  12. Long Term Hippocampal and Cortical Changes Induced by Maternal Deprivation and Neonatal Leptin Treatment in Male and Female Rats.

    PubMed

    Mela, Virginia; Díaz, Francisca; Borcel, Erika; Argente, Jesús; Chowen, Julie A; Viveros, Maria-Paz

    2015-01-01

    Maternal deprivation (MD) during neonatal life has diverse long-term behavioral effects and alters the development of the hippocampus and frontal cortex, with several of these effects being sexually dimorphic. MD animals show a marked reduction in their circulating leptin levels, not only during the MD period, but also several days later (PND 13). A neonatal leptin surge occurs in rodents (beginning around PND 5 and peaking between PND 9 and 10) that has an important neurotrophic role. We hypothesized that the deficient neonatal leptin signaling of MD rats could be involved in the altered development of their hippocampus and frontal cortex. Accordingly, a neonatal leptin treatment in MD rats would at least in part counteract their neurobehavioural alterations. MD was carried out in Wistar rats for 24 h on PND 9. Male and female MD and control rats were treated from PND 9 to 13 with rat leptin (3 mg/kg/day sc) or vehicle. In adulthood, the animals were submitted to the open field, novel object memory test and the elevated plus maze test of anxiety. Neuronal and glial population markers, components of the glutamatergic and cannabinoid systems and diverse synaptic plasticity markers were evaluated by PCR and/or western blotting. Main results include: 1) In some of the parameters analyzed, neonatal leptin treatment reversed the effects of MD (eg., mRNA expression of hippocampal IGF1 and protein expression of GFAP and vimentin) partially confirming our hypothesis; 2) The neonatal leptin treatment, per se, exerted a number of behavioral (increased anxiety) and neural effects (eg., expression of the following proteins: NG2, NeuN, PSD95, NCAM, synaptophysin). Most of these effects were sex dependent. An adequate neonatal leptin level (avoiding excess and deficiency) appears to be necessary for its correct neuro-programing effect.

  13. RECURRENT NEONATAL SEIZURES RESULT IN LONG-TERM INCREASE OF NEURONAL NETWORK EXCITABILITY IN THE RAT NEOCORTEX

    PubMed Central

    Isaeva, Elena; Isaev, Dmytro; Savrasova, Alina; Khazipov, Rustem; Holmes, Gregory L.

    2011-01-01

    Neonatal seizures are associated with a high likelihood of adverse neurological outcomes, including mental retardation, behavioral disorders, and epilepsy. Early seizures typically involve the neocortex, and post-neonatal epilepsy is often of neocortical origin. However, our understanding of the consequences of neonatal seizures for neocortical function is limited. In the present study, we show that neonatal seizures induced by flurothyl result in markedly enhanced susceptibility of the neocortex to seizure-like activity. This change occurs in young rats studied weeks after the last induced seizure and in adult rats studied months after the initial seizures. Neonatal seizures resulted in reductions in the amplitude of spontaneous inhibitory postsynaptic currents and the frequency of miniature inhibitory postsynaptic currents, and significant increases in the amplitude and frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and in the frequency of miniature excitatory postsynaptic currents (mEPSCs) in pyramidal cells of layer 2/3 of the somatosensory cortex. The selective N-methyl-d-aspartate (NMDA) receptor antagonist d-2-amino-5-phosphon-ovalerate eliminated the differences in amplitude and frequency of sEPSCs and mEPSCs in the control and flurothyl groups, suggesting that NMDA receptors contribute significantly to the enhanced excitability seen in slices from rats that experienced recurrent neonatal seizures. Taken together, our results suggest that recurrent seizures in infancy result in a persistent enhancement of neocortical excitability. PMID:20384780

  14. Immunoreactive somatostatin and. beta. -endorphin content in the brain of mature rats after neonatal exposure to propylthiouracil

    SciTech Connect

    Kato, N.; Sundmark, V.C.; Van Middlesworth, L.; Havlicek, V.; Friesen, H.G.

    1982-06-01

    The contents of immunoreactive somatostatin (IR-SRIF) and ..beta..-endorphin (IR-..beta..-EP) in 12 brain regions were examined in rats exposed neonatally to propylthiouracil (PTU) through the mother's milk. Since the dose of PTU used in the study is lower than the usual dose employed to induce hypothyroidism, a milder form of neonatal hypothyroidism resulted. This conclusion is supported by the only mild subnormal growth of rats to adulthood and serum T/sub 4/ and T/sub 3/ concentrations in the normal range. Adult rats treated with PTU neonatally had significantly higher IR-SRIF contents in several brain regions compared to controls, whereas IR-..beta..-EP levels were not significantly different (significant increase only in the thalamus) in most regions. The results indicate that even mild hypothyroidism during early postnatal development causes permanent impairment of brain function, which manifests itself in part by an altered brain content of IR-SRIF.

  15. Immunoreactive somatostatin and. beta. -endorphin content in the brain of mature rats after neonatal exposure to propylthiouacil. [Propylthiouracil

    SciTech Connect

    Kato, N.; Sundmark, V.C.; Van Middlesworth, L.; Havlicek, V.; Friesen, H.G.

    1982-01-01

    The contents of immunoreactive somatostatin (IR-SRIF) and ..beta..-endorphin (IR-..beta..-EP) in 12 brain regions were examined in rats exposed neonatally to propylthiouracil (PTU) through the mother's milk. Since the dose of PTU used in this study is lower than the usual dose employed to induce hypothyroidism, a milder form of neonatal hypothyroidism resulted. This conclusion is supported by the only mild subnormal growth of rats to adulthood and serum T/sub 4/ and T/sub 3/ concentrations in the normal range. Adult rats treated with PTU neonatally had significantly higher IR-SRIF contents in several brain regions compared to controls, whereas IR-..beta..-EP levels were not significantly different in most regions. The results indicate that even mild hypothyroidism during early postnatal development causes permanent impairment of brain function, which manifests itself in part by an altered brain content of IR-SRIF.

  16. Glucocorticoids Protect Neonatal Rat Brain in Model of Hypoxic-Ischemic Encephalopathy (HIE)

    PubMed Central

    Harding, Benjamin; Conception, Katherine; Li, Yong; Zhang, Lubo

    2016-01-01

    Hypoxic-ischemic encephalopathy (HIE) resulting from asphyxia in the peripartum period is the most common cause of neonatal brain damage and can result in significant neurologic sequelae, including cerebral palsy. Currently therapeutic hypothermia is the only accepted treatment in addition to supportive care for infants with HIE, however, many additional neuroprotective therapies have been investigated. Of these, glucocorticoids have previously been shown to have neuroprotective effects. HIE is also frequently compounded by infectious inflammatory processes (sepsis) and as such, the infants may be more amenable to treatment with an anti-inflammatory agent. Thus, the present study investigated dexamethasone and hydrocortisone treatment given after hypoxic-ischemic (HI) insult in neonatal rats via intracerebroventricular (ICV) injection and intranasal administration. In addition, we examined the effects of hydrocortisone treatment in HIE after lipopolysaccharide (LPS) sensitization in a model of HIE and sepsis. We found that dexamethasone significantly reduced rat brain infarction size when given after HI treatment via ICV injection; however it did not demonstrate any neuroprotective effects when given intranasally. Hydrocortisone after HI insult also significantly reduced brain infarction size when given via ICV injection; and the intranasal administration showed to be protective of brain injury in male rats at a dose of 300 µg. LPS sensitization did significantly increase the brain infarction size compared to controls, and hydrocortisone treatment after LPS sensitization showed a significant decrease in brain infarction size when given via ICV injection, as well as intranasal administration in both genders at a dose of 300 µg. To conclude, these results show that glucocorticoids have significant neuroprotective effects when given after HI injury and that these effects may be even more pronounced when given in circumstances of additional inflammatory injury, such

  17. Erythropoietin reduces neuronal cell death and hyperalgesia induced by peripheral inflammatory pain in neonatal rats.

    PubMed

    Mohamad, Osama; Chen, Dongdong; Zhang, Lingling; Hofmann, Cane; Wei, Ling; Yu, Shan Ping

    2011-07-21

    Painful stimuli during neonatal stage may affect brain development and contribute to abnormal behaviors in adulthood. Very few specific therapies are available for this developmental disorder. A better understanding of the mechanisms and consequences of painful stimuli during the neonatal period is essential for the development of effective therapies. In this study, we examined brain reactions in a neonatal rat model of peripheral inflammatory pain. We focused on the inflammatory insult-induced brain responses and delayed changes in behavior and pain sensation. Postnatal day 3 pups received formalin injections into the paws once a day for 3 days. The insult induced dysregulation of several inflammatory factors in the brain and caused selective neuronal cell death in the cortex, hippocampus and hypothalamus. On postnatal day 21, rats that received the inflammatory nociceptive insult exhibited increased local cerebral blood flow in the somatosensory cortex, hyperalgesia, and decreased exploratory behaviors. Based on these observations, we tested recombinant human erythropoietin (rhEPO) as a potential treatment to prevent the inflammatory pain-induced changes. rhEPO treatment (5,000 U/kg/day, i.p.), coupled to formalin injections, ameliorated neuronal cell death and normalized the inflammatory response. Rats that received formalin plus rhEPO exhibited normal levels of cerebral blood flow, pain sensitivity and exploratory behavior. Treatment with rhEPO also restored normal brain and body weights that were reduced in the formalin group. These data suggest that severe inflammatory pain has adverse effects on brain development and rhEPO may be a possible therapy for the prevention and treatment of this developmental disorder.

  18. ROLES OF ALDOSTERONE AND OXYTOCIN IN ABNORMALITIES CAUSED BY SEVOFLURANE ANESTHESIA IN NEONATAL RATS

    PubMed Central

    Cao, Wengang; Pavlinec, Christopher; Gravenstein, Nikolaus; Seubert, Christoph N.; Martynyuk, Anatoly E.

    2012-01-01

    Background We sought whether subjects with pathophysiological conditions that are characterized by elevated levels of aldosterone have increased susceptibility to the side effects of neonatal anesthesia with sevoflurane. Methods Postnatal day 4–20 (P4–P20) rats were exposed to 6% and 2.1% sevoflurane for 3 min and 60–360 min, respectively. Exogenous aldosterone was administered to imitate pathophysiological conditions with elevated levels of aldosterone. Results Six hours of anesthesia with sevoflurane on P4–P5 resulted in more than 30-fold increase in serum levels of aldosterone (7.02 ± 1.61 ng/dl vs. 263.75 ± 22.31 ng/dl, mean ± SE, n = 5–6) and reduced prepulse inhibition of the acoustic startle response (F(2,37)= 5.66, P<0.001). Administration of exogenous aldosterone during anesthesia with sevoflurane further enhanced seizure-like electroencephalogram patterns in neonatal rats (48.25±15.91 s vs. 222.00 ± 53.87 s, mean± SE, n = 4), but did not affect electroencephalographic activity in older rats. Exogenous aldosterone increased activation of caspase-3 (F(3,28)=11.02, P<0.001) and disruption of prepulse inhibition of startle (F(3,46)=6.36; P= 0.001) caused by sevoflurane. Intracerebral administration of oxytocin receptor agonists resulted in depressed seizure-like electroencephalogram patterns (F(2,17)=6.37, P=0.009), reduced activation of caspase-3 ((t(11) = 2.83, P = 0.016) and disruption of PPI of startle (t(7) = −2.9; P = 0.023) caused by sevoflurane. Conclusions These results suggest that adverse developmental effects of neonatal anesthesia with sevoflurane may involve both central and peripheral actions of the anesthetic. Subjects with elevated levels of aldosterone may be more vulnerable, while intracerebral oxytocin receptor agonists may be neuroprotective. PMID:22854980

  19. Phosphatidylcholine kinetics in neonatal rat lungs and the effects of rhuKGF and betamethasone.

    PubMed

    Bernhard, Wolfgang; Gesche, Jens; Raith, Marco; Poets, Christian F

    2016-05-15

    Surfactant, synthesized by type II pneumocytes (PN-II), mainly comprises phosphatidylcholine (PC) and is essential to prevent neonatal respiratory distress. Furthermore, PC is essential to lung tissue growth and maintenance as a membrane component. Recent findings suggest that the lung contributes to systemic lipid homeostasis via PC export through ABC-A1 transporter expression. Hence it is important to consider pharmacological interventions in neonatal lung PC metabolism with respect to such export. Five-day-old rats were treated with carrier (control), intraperitoneal betamethasone, subcutaneous recombinant human keratinocyte growth factor (rhuKGF), or their combination for 48 h. Animals were intraperitoneally injected with 50 mg/kg [D9-methyl]choline chloride 1.5, 3.0, and 6.0 h before death at day 7, and lung lavage fluid (LLF) and tissue were harvested. Endogenous PC, D9-labeled PC species, and their water-soluble precursors (D9-)choline and (D9-)phosphocholine were determined by tandem mass spectrometry. Treatment increased secreted and tissue PC pools but did not change equilibrium composition of PC species in LLF. However, all treatments increased specific surfactant components in tissue. In control rats, peak D9-PC in lavaged lung was reached after 3 h and was decreased at 6 h. Only 13% of this net loss in lavaged lung was found in LLF. Such decrease was not present in lungs treated with betamethasone and/or with rhuKGF. D9-PC loss at 3-6 h and PC synthesis calculated from D9 enrichment of phosphocholine indicated that daily synthesis rate is higher than total pool size. We conclude that lung tissue contributes to systemic PC homeostasis in neonatal rats, which is altered by glucocorticoid and rhuKGF treatment.

  20. Aluminum overload increases oxidative stress in four functional brain areas of neonatal rats

    PubMed Central

    2012-01-01

    Background Higher aluminum (Al) content in infant formula and its effects on neonatal brain development are a cause for concern. This study aimed to evaluate the distribution and concentration of Al in neonatal rat brain following Al treatment, and oxidative stress in brain tissues induced by Al overload. Methods Postnatal day 3 (PND 3) rat pups (n =46) received intraperitoneal injection of aluminum chloride (AlCl3), at dosages of 0, 7, and 35 mg/kg body wt (control, low Al (LA), and high Al (HA), respectively), over 14 d. Results Aluminum concentrations were significantly higher in the hippocampus (751.0 ± 225.8 ng/g v.s. 294.9 ± 180.8 ng/g; p < 0.05), diencephalon (79.6 ± 20.7 ng/g v.s. 20.4 ± 9.6 ng/g; p < 0.05), and cerebellum (144.8 ± 36.2 ng/g v.s. 83.1 ± 15.2 ng/g; p < 0.05) in the HA group compared to the control. The hippocampus, diencephalon, cerebellum, and brain stem of HA animals displayed significantly higher levels of lipid peroxidative products (TBARS) than the same regions in the controls. However, the average superoxide dismutase (SOD) activities in the cerebral cortex, hippocampus, cerebellum, and brain stem were lower in the HA group compared to the control. The HA animals demonstrated increased catalase activity in the diencephalon, and increased glutathione peroxidase (GPx) activity in the cerebral cortex, hippocampus, cerebellum, and brain stem, compared to controls. Conclusion Aluminum overload increases oxidative stress (H2O2) in the hippocampus, diencephalon, cerebellum, and brain stem in neonatal rats. PMID:22613782

  1. Environmental and tactile stimulation modulates the neonatal handling effect on adult rat spatial memory.

    PubMed

    Daskalakis, Nikolaos P; Kaperoni, Maria; Koros, Christos; de Kloet, E Ronald; Kitraki, Efthimia

    2009-12-01

    Handling of rat pups promotes their adult cognitive performance. However, new data suggest that individual components of the handling procedure, like exposure to novelty or tactile stimulation, have distinct lasting effects on behaviour. In this study we examined the interaction of early novelty exposure with a varying amount of tactile stimulation on spatial recognition memory and corticosterone secretion of adult male and female rats. A split litter design was used and the experimental animals were also compared to animal facility reared controls. The experiment was conducted in two phases. In the first phase, we examined the effect of novel or home environment during the 15-min of neonatal handling, following 10 back-strokes. Tactile stimulation of 10 back-strokes combined with novelty exposure, enhanced novel arm discrimination in a Y-maze task in adult rats of both sexes compared to their siblings that stayed at home, as well as to the animal facility reared controls. In the second phase, additional back-stroking (total of 20 back-strokes) reduced the Y-maze performance of males neonatally exposed to novelty, while the same treatment enhanced the performance of their siblings that stayed at home. Basal corticosterone levels, determined 1 week post-Y-maze, were significantly increased only in the novelty exposed/10 back-stroked females compared to same sex non-handled controls. In contrast, 10 back-strokes combined with the home cage environment increased corticosterone in males. Increase to 20 back-strokes reversed the impact of neonatal environment on corticosterone levels. These data suggest that the nature and intensity of the individual components of a mild early life manipulation, like handling, are critical in modifying aspects of adult memory performance and basal adrenocortical function.

  2. Effect of patent ductus arteriosus and patent foramen ovale on left ventricular stroke volume measurement by electrical velocimetry in comparison to transthoracic echocardiography in neonates.

    PubMed

    Blohm, Martin Ernst; Hartwich, Jana; Obrecht, Denise; Kersten, Jan Felix; Singer, Dominique

    2017-06-01

    This prospective single-center observational study compared impedance cardiography [electrical velocimetry (EV)] with transthoracic echocardiography (TTE, based on trans-aortic flow) and analyzed the influence of physiological shunts, such as patent ductus arteriosus (PDA) or patent foramen ovale (PFO), on measurement accuracy. Two hundred and ninety-one triplicate simultaneous paired left ventricular stroke volume (LVSV) measurements by EV (LVSVEV) and TTE (LVSVTTE) in 99 spontaneously breathing neonates (mean weight 3270 g; range 1227-4600 g) were included. For the whole cohort, the mean absolute LVSVEV was 5.5 mL, mean LVSVTTE was 4.9 mL, resulting in an absolute Bland-Altman bias of -0.7 mL (limits of agreement LOA -3.0 to 1.7 mL), relative bias -12.8 %; mean percentage error MPE 44.9 %; true precision TPEV 33.4 % (n = 99 aggregated data points). In neonates without shunts (n = 32): mean LVSVEV 5.0 mL, mean LVSVTTE 4.6 mL, Bland-Altman bias -0.4 mL (LOA -2.8 to 2.0 mL), relative bias -8.2 %; MPE 50.7 %; TPEV 40.9 %. In neonates with shunts (PDA and/or PFO; n = 67): mean LVSVEV 5.8 mL, mean LVSVTTE 5.0 mL, bias -0.8 mL (LOA -3.1 to 1.5 mL), relative bias -14.8 %, MPE 41.9 %, TPEV 29.3 %. Accuracy was affected by PDA and/or PFO, with a significant increase in the relative difference in LVSVEV versus LVSVTTE: Subjects without shunts -2.9 % (n = 91), PFO alone -9.6 % (n = 125), PDA alone -14.0 % (n = 12), and PDA and PFO -18.5 % (n = 63). Physiological shunts (PDA and/or PFO) in neonates affect measurement accuracy and cause overestimation of LVSVEV compared with LVSVTTE.

  3. Berberine attenuates adverse left ventricular remodeling and cardiac dysfunction after acute myocardial infarction in rats: role of autophagy.

    PubMed

    Zhang, Yao-Jun; Yang, Shao-Hua; Li, Ming-Hui; Iqbal, Javaid; Bourantas, Christos V; Mi, Qiong-Yu; Yu, Yi-Hui; Li, Jing-Jing; Zhao, Shu-Li; Tian, Nai-Liang; Chen, Shao-Liang

    2014-12-01

    The present study aimed to test the hypothesis that berberine, a plant-derived anti-oxidant, attenuates adverse left ventricular remodelling and improves cardiac function in a rat model of myocardial infarction (MI). Furthermore, the potential mechanisms that mediated the cardioprotective actions of berberine, in particular the effect on autophagy, were also investigated. Acute MI was induced by ligating the left anterior descending coronary artery of Sprague-Dawley rats. Cardiac function was assessed by transthoracic echocardiography. The protein activity/levels of autophagy related to signalling pathways (e.g. LC-3B, Beclin-1) were measured in myocardial tissue by immunohistochemical staining and western blot. Four weeks after MI, berberine significantly prevented cardiac dysfunction and adverse cardiac remodelling. MI rats treated with low dose berberine (10 mg/kg per day) showed higher left ventricular ejection fraction and fractional shortening than those treated with high-dose berberine (50 mg/kg per day). Both doses reduced interstitial fibrosis and post-MI adverse cardiac remodelling. The cardioprotective action of berberine was associated with increased LC-3B II and Beclin-1 expressions. Furthermore, cardioprotection with berberine was potentially related to p38 MAPK inhibition and phospho-Akt activation. The present in vivo study showed that berberine is effective in promoting autophagy, and subsequently attenuating left ventricular remodelling and cardiac dysfunction after MI. The potential underlying mechanism is augmentation of autophagy through inhibition of p38 MAPK and activation of phospho-Akt signalling pathways.

  4. Characterization of two distinct depolarization-activated K+ currents in isolated adult rat ventricular myocytes

    PubMed Central

    1991-01-01

    Depolarization-activated outward K+ currents in isolated adult rat ventricular myocytes were characterized using the whole-cell variation of the patch-clamp recording technique. During brief depolarizations to potentials positive to -40 mV, Ca(2+)-independent outward K+ currents in these cells rise to a transient peak, followed by a slower decay to an apparent plateau. The analyses completed here reveal that the observed outward current waveforms result from the activation of two kinetically distinct voltage-dependent K+ currents: one that activates and inactivates rapidly, and one that activates and inactivates slowly, on membrane depolarization. These currents are referred to here as Ito (transient outward) and IK (delayed rectifier), respectively, because their properties are similar (although not identical) to these K+ current types in other cells. Although the voltage dependences of Ito and IK activation are similar, Ito activates approximately 10-fold and inactivates approximately 30-fold more rapidly than IK at all test potentials. In the composite current waveforms measured during brief depolarizations, therefore, the peak current predominantly reflects Ito, whereas IK is the primary determinant of the plateau. There are also marked differences in the voltage dependences of steady-state inactivation of these two K+ currents: IK undergoes steady-state inactivation at all potentials positive to -120 mV, and is 50% inactivated at -69 mV; Ito, in contrast, is insensitive to steady-state inactivation at membrane potentials negative to -50 mV. In addition, Ito recovers from steady-state inactivation faster than IK: at -90 mV, for example, approximately 70% recovery from the inactivation produced at -20 mV is observed within 20 ms for Ito; IK recovers approximately 25-fold more slowly. The pharmacological properties of Ito and IK are also distinct: 4-aminopyridine preferentially attenuates Ito, and tetraethylammonium suppresses predominantly IK. The voltage- and

  5. Neurological assessments after treatment with the antimalarial β-arteether in neonatal and adult rats.

    PubMed

    Erickson, R I; Defensor, E B; Fairchild, D G; Mirsalis, J C; Steinmetz, K L

    2011-08-01

    The World Health Organization currently recommends combinatorial treatment including artemisinins as first-line therapy against drug-resistant Plasmodium falciparum malaria. Although highly efficacious, artemisinin and its derivatives, including β-arteether (βAE), are associated with ototoxicity, tremors, and other autonomic and motor impairments in the clinic. Similar neurological symptoms, as well as brainstem lesions, have been observed in adult laboratory species (mice, rats, dogs, and non human primates) following acute treatment with βAE; however, few long-term, nonclinical studies have been conducted. Furthermore, the majority of deaths attributed to malarial infection occur in children under age five, yet no laboratory studies have been initiated in neonatal or juvenile animals. In the current study, neonatal 7-day-old rats were administered intramuscular doses of 1-90 mg/kg βAE in sesame oil for up to eight treatment cycles (one cycle=7 days treatment+7 days without treatment). Neonates were tested for changes in sensorimotor function, and the same animals were tested as adults in the Functional Observational Battery, for motor activity, and in the 8-arm radial maze. Pups receiving a single cycle of 60 or 90 mg/kg died within a week of treatment but had few behavioral changes and no brainstem pathology. In the long-term study, behavioral and motor changes and brainstem lesions were observed in a dose- and time-related manner. Rats given repeated cycles of 1 or 5mg/kg βAE showed subtle motor abnormalities (e.g., slight loss of righting reflex) while repeated cycles of 10mg/kg βAE treatment resulted in obvious motor and behavioral changes. Rats receiving 1mg/kg βAE had no brainstem lesions whereas some rats treated with 5mg/kg βAE and all rats treated with 10 mg/kg βAE had brainstem lesions. Brainstem lesions were observed after as few as five cycles and were characterized by gliosis, satellitosis and progressive necrosis in motor neurons of the

  6. Development of motor coordination and cerebellar structure in male and female rat neonates exposed to hypergravity

    NASA Astrophysics Data System (ADS)

    Nguon, K.; Ladd, B.; Baxter, M. G.; Sajdel-Sulkowska, E. M.

    2006-01-01

    We previously reported that the developing rat cerebellum is affected by exposure to hypergravity. In the present study, we explored the hypothesis that the changes in cerebellar structure in hypergravity-exposed rat neonates may affect their motor coordination. Furthermore, we hypothesized that the changes observed at 1.5G will be magnified at higher gravitational loading. To test this hypothesis, we compared motor behavior, cerebellar structure, and protein expression in rat neonates exposed to 1.5 1.75G on a 24-ft centrifuge daily for 22.5 h starting on gestational day (G) 10, through birth on G22/G23 and through postnatal day (P) 21. Exposure to hypergravity impacted the neurodevelopmental process as indicated by: (1) impaired righting response on P3, more than doubling the righting time at 1.75G, and (2) delayed onset of the startle response by one day, from P9 in controls to P10 in hypergravity-exposed pups. Hypergravity exposure resulted in impaired motor functions as evidenced by performance on a rotarod on P21; the duration of the stay on the rotarod recorded for 1.75G pups of both sexes was one tenth that of the stationary control (SC) pups. These changes in motor behavior were associated with cerebellar changes: (1) cerebellar mass on P6 was decreased by 7.5% in 1.5G-exposed male pups, 27.5% in 1.75G-exposed male pups, 17.5% in 1.5G-exposed female pups, and 22.5% in 1.75G female pups and (2) changes in the expression of glial and neuronal proteins. The results of this study suggest that perinatal exposure to hypergravity affects cerebellar development as evidenced by decreased cerebellar mass and altered cerebellar protein expression; cerebellar changes observed in hypergravity-exposed rat neonates are associated with impaired motor behavior. Furthermore, the response to hypergravity appears to be different in male and female neonates. If one accepts that the hypergravity paradigm is a useful animal model with which to predict those biological processes

  7. Choline Acetyltransferase Activity in Striatum of Neonatal Rats Increased by Nerve Growth Factor

    NASA Astrophysics Data System (ADS)

    Mobley, William C.; Rutkowski, J. Lynn; Tennekoon, Gihan I.; Buchanan, Karen; Johnston, Michael V.

    1985-07-01

    Some neurodegenerative disorders may be caused by abnormal synthesis or utilization of trophic molecules required to support neuronal survival. A test of this hypothesis requires that trophic agents specific for the affected neurons be identified. Cholinergic neurons in the corpus striatum of neonatal rats were found to respond to intracerebroventricular administration of nerve growth factor with prominent, dose-dependent, selective increases in choline acetyltransferase activity. Cholinergic neurons in the basal forebrain also respond to nerve growth factor in this way. These actions of nerve growth factor may indicate its involvement in the normal function of forebrain cholinergic neurons as well as in neurodegenerative disorders involving such cells.

  8. Effect of phensuccinal on pancreatic beta-cells in rats with neonatally induced streptozotocin diabetes mellitus.

    PubMed

    Gorbenko, N I; Poltorak, V V; Gladkikh, A I; Ivanova, O V

    2001-07-01

    The effect of phensuccinal, a low-toxic succinic acid derivative, on the function of pancreatic beta-cells in the evolution of absolute insulin insufficiency was studied in rats with neonatally induced streptozotocin diabetes mellitus. Phensuccinal (25 mg/kg body weight) prevented disorders in the secretory response of beta-cells to glucose load at all stages of the study (2, 5, and 14 days after diabetes induction). This effect was realized via stimulation of the regenerative processes in the insulin-producing system of the pancreas and activation of the antioxidant system in diabetic animals.

  9. Metformin attenuates ventricular hypertrophy by activating the AMP-activated protein kinase-endothelial nitric oxide synthase pathway in rats.

    PubMed

    Zhang, Cheng-Xi; Pan, Si-Nian; Meng, Rong-Sen; Peng, Chao-Quan; Xiong, Zhao-Jun; Chen, Bao-Lin; Chen, Guang-Qin; Yao, Feng-Juan; Chen, Yi-Li; Ma, Yue-Dong; Dong, Yu-Gang

    2011-01-01

    1. Metformin is an activator of AMP-activated protein kinase (AMPK). Recent studies suggest that pharmacological activation of AMPK inhibits cardiac hypertrophy. In the present study, we examined whether long-term treatment with metformin could attenuate ventricular hypertrophy in a rat model. The potential involvement of nitric oxide (NO) in the effects of metformin was also investigated. 2. Ventricular hypertrophy was established in rats by transaortic constriction (TAC). Starting 1 week after the TAC procedure, rats were treated with metformin (300 mg/kg per day, p.o.), N(G)-nitro-L-arginine methyl ester (L-NAME; 50 mg/kg per day, p.o.) or both for 8 weeks prior to the assessment of haemodynamic function and cardiac hypertrophy. 3. Cultured cardiomyocytes were used to examine the effects of metformin on the AMPK-endothelial NO synthase (eNOS) pathway. Cells were exposed to angiotensin (Ang) II (10⁻⁶ mol/L) for 24 h under serum-free conditions in the presence or absence of metformin (10⁻³ mol/L), compound C (10⁻⁶ mol/L), L-NAME (10⁻⁶ mol/L) or their combination. The rate of incorporation of [³H]-leucine was determined, western blotting analyses of AMPK-eNOS, neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) were undertaken and the concentration of NO in culture media was determined. 4. Transaortic constriction resulted in significant haemodynamic dysfunction and ventricular hypertrophy. Myocardial fibrosis was also evident. Treatment with metformin improved haemodynamic function and significantly attenuated ventricular hypertrophy. Most of the effects of metformin were abolished by concomitant L-NAME treatment. L-NAME on its own had no effect on haemodynamic function and ventricular hypertrophy in TAC rats. 5. In cardiomyocytes, metformin inhibited AngII-induced protein synthesis, an effect that was suppressed by the AMPK inhibitor compound C or the eNOS inhibitor L-NAME. The improvement in cardiac structure and

  10. Effects of Rosiglitazone with Insulin Combination Therapy on Oxidative Stress and Lipid Profile in Left Ventricular Muscles of Diabetic Rats

    PubMed Central

    Kavak, Servet; Ayaz, Lokman; Emre, Mustafa

    2012-01-01

    Purpose. In this study, we tested the hypothesis that rosiglitazone (RSG) with insulin is able to quench oxidative stress initiated by high glucose through prevention of NAD(P)H oxidase activation. Methods and Materials. Male albino Wistar rats were randomly divided into an untreated control group (C), a diabetic group (D) that was treated with a single intraperitoneal injection of streptozotocin (45 mgkg−1), and rosiglitazone group that was treated with RSG twice daily by gavage and insulin once daily by subcutaneous injection (group B). HbA1c and blood glucose levels in the circulation and malondialdehyde and 3-nitrotyrosine levels in left ventricular muscle were measured. Result. Treatment of D rats with group B resulted in a time-dependent decrease in blood glucose. We found that the lipid profile and HbA1c levels in group B reached the control group D rat values at the end of the treatment period. There was an increase in 3-nitrotyrosine levels in group D compared to group C. Malondialdehyde and 3-nitrotyrosine levels were found to be decreased in group B compared to group D (P < 0.05). Conclusion. Our data suggests that the treatment of diabetic rats with group B for 8 weeks may decrease the oxidative/nitrosative stress in left ventricular tissue of rats. Thus, in diabetes-related vascular diseases, group B treatment may be cardioprotective. PMID:22829806

  11. Effects of rosiglitazone with insulin combination therapy on oxidative stress and lipid profile in left ventricular muscles of diabetic rats.

    PubMed

    Kavak, Servet; Ayaz, Lokman; Emre, Mustafa

    2012-01-01

    In this study, we tested the hypothesis that rosiglitazone (RSG) with insulin is able to quench oxidative stress initiated by high glucose through prevention of NAD(P)H oxidase activation. Male albino Wistar rats were randomly divided into an untreated control group (C), a diabetic group (D) that was treated with a single intraperitoneal injection of streptozotocin (45 mg kg(-1)), and rosiglitazone group that was treated with RSG twice daily by gavage and insulin once daily by subcutaneous injection (group B). HbA1c and blood glucose levels in the circulation and malondialdehyde and 3-nitrotyrosine levels in left ventricular muscle were measured. Treatment of D rats with group B resulted in a time-dependent decrease in blood glucose. We found that the lipid profile and HbA1c levels in group B reached the control group D rat values at the end of the treatment period. There was an increase in 3-nitrotyrosine levels in group D compared to group C. Malondialdehyde and 3-nitrotyrosine levels were found to be decreased in group B compared to group D (P < 0.05). Our data suggests that the treatment of diabetic rats with group B for 8 weeks may decrease the oxidative/nitrosative stress in left ventricular tissue of rats. Thus, in diabetes-related vascular diseases, group B treatment may be cardioprotective.

  12. Development of hematological and immunological characteristics in neonatal rats.

    PubMed

    Sewald, Katherina; Mueller, Meike; Buschmann, Jochen; Hansen, Tanja; Lewin, Geertje

    2015-08-15

    As major immunological and hematological parameters evolve during the early period of life, laboratory data must be interpreted in relation to developmental changes. Wistar (WU) rats were sacrificed on PND2, 4, 7, 10, 14, 17 and 21. Peripheral blood, bone marrow, thymus samples and spleen cells were collected and a bronchoalveolar lavage (BAL) performed. Parameters of blood counts changed considerably between time points. IgM and IgG levels steadily increased. Spontaneous spleen cell proliferation was low before PND21, although mitogens had stimulatory effects above baseline. In the spleen, T-lymphocyte counts tripled by PND17 (mainly attributed to CD8(+) cytotoxic T-cells and CD4(+) T-helper cells). In peripheral blood an increase in B-lymphocytes to about 60% of the cell number was observed. In BAL fluid, macrophages represented 95-98% of the cells. In thymus architecture, lymphoblast migration was seen and epithelial structures appeared. The data presented will help to distinguish between maturational changes and treatment-related effects.

  13. Prenatal nicotine alters vigilance states and AchR gene expression in the neonatal rat: implications for SIDS.

    PubMed

    Frank, M G; Srere, H; Ledezma, C; O'Hara, B; Heller, H C

    2001-04-01

    Maternal smoking is a major risk factor for sudden infant death syndrome (SIDS). The mechanisms by which cigarette smoke predisposes infants to SIDS are not known. We examined the effects of prenatal nicotine exposure on sleep/wake ontogenesis and central cholinergic receptor gene expression in the neonatal rat. Prenatal nicotine exposure transiently increased sleep continuity and accelerated sleep/wake ontogeny in the neonatal rat. Prenatal nicotine also upregulated nicotinic and muscarinic cholinergic receptor mRNAs in brain regions involved in regulating vigilance states. These findings suggest that the nicotine contained in cigarette smoke may predispose human infants to SIDS by interfering with the normal maturation of sleep and wake.

  14. Assessment of neonatal rat's activity by the automated registration of the animal entries in the squares of a testing arena.

    PubMed

    Menshanov, Petr N; Dygalo, Nikolay N

    2007-08-30

    Automated registration of neonatal rat entries in the squares of a testing chamber is suggested for the animal locomotion assessment. This method allows detection of paddling and pivoting activities that are not accompanied by forward movement of the animal. The proposed technique is also relatively insensitive to nonlocomotor changes in a pup's body position, such as breathing and shaking, and thus offers a selective detection of locomotor-related activity. The application of the method permits the evaluation of spontaneous and stimulated motor activity of neonatal rats using relatively short test duration and a minimal number of animals.

  15. Sarcolemmal hydraulic conductivity of guinea-pig and rat ventricular myocytes.

    PubMed

    Ogura, Toshitsugu; Matsuda, Hiroyuki; Imanishi, Sunao; Shibamoto, Toshishige

    2002-06-01

    Osmotic gradient-induced volume change and sarcolemmal water permeability of cardiac myocytes were evaluated to characterize the mechanism of water flux across the plasma membranes. Cell surface dimensions were measured from isolated guinea-pig and rat ventricular myocytes by digital videomicroscopy, and membrane hydraulic conductivity (L(p)) was obtained by analyzing the time course of cell swelling and shrinkage in response to osmotic gradients. Superfusion with anisosmotic solution (0.5-4 times normal osmolality) caused a rapid (<3 min to steady states) and reversible myocyte swelling or shrinkage. L(p) was approximately 1.9 x 10(-10) l N(-1) s(-1) for guinea-pig myocytes and approximately 1.7 x 10(-10) l N(-1) s(-1) for rat myocytes at 35 degrees C. Arrhenius activation energy (E(a)), a measure of the energy barrier to water flux, was approximately 3.7 (guinea-pig) and approximately 3.6 kcal mol(-1) (rat) between 11 and 35 degrees C; these values are equivalent to E(a) of self-diffusion of water in bulk solution ( approximately 4 kcal mol(-1)). Treatment with 0.1 mM Hg(2+), a sulfhydryl-oxidizing reagent that blocks membrane water channels, reduced L(p) by approximately 80%, and the sulfhydryl-reducing reagent dithiothreitol (10 mM) antagonized the inhibitory action of Hg(2+). Inhibition of the volume-sensitive cation (30 microM Gd3+) and anion (1 mM 4,4'-diisothiocyanostilbene-2,2'-disulfonate) channels and Na+-K+ pump (10 microM ouabain) modified the size of osmotic swelling but had little effect on L(p). Although the observed L(p) is relatively small in magnitude, the low E(a) and the sulfhydryl reagent-induced modification of L(p) are characteristic of channel-mediated water transport. These data suggest that water flux across the sarcolemma of guinea-pig and rat heart cells occurs through parallel pathways, i.e., the majority passing through water channels and the remainder penetrating the lipid bilayers.

  16. Prenatal nicotine exposure alters respiratory long term facilitation in neonatal rats

    PubMed Central

    Fuller, DD; Dougherty, BJ; Sandhu, MS; Doperalski, NJ; Reynolds, CR; Hayward, LF

    2009-01-01

    Intermittent hypoxia can evoke persistent increases in ventilation (ν̇ E) in neonates (i.e. long-term facilitation, LTF) (Julien et al. Am J Physiol Regul Integr Comp Physiol 294: R1356–R1366, 2008). Since prenatal nicotine (PN) exposure alters neonatal respiratory control (Fregosi & Pilarski. Respir. Physiol. Neurobiol. 164: 80–86, 2008), we hypothesized that PN would influence LTF of ventilation (ν̇ E) in neonatal rats. An osmotic minipump delivered nicotine (6 mg/kg/day) or saline to pregnant dams. ν̇ E was assessed in unanesthetized pups via whole body plethysmography at post-natal (P) days 9–11 or 15–17 during baseline (BL, 21% O2), hypoxia (10 × 5 min, 5% O2) and 30 min post-hypoxia. PN pups had reduced BL ν̇ E (p<0.05) but greater increases in ν̇ E during hypoxia (p<0.05). Post-hypoxia ν̇ E (i.e. LTF) showed an age × treatment interaction (p<0.01) with similar values at P9-11 but enhanced LTF in saline (30±8 %BL) vs. PN pups (6±5 %BL; p=0.01) at P15-17. We conclude that the post-natal developmental time course of hypoxia-induced LTF is influenced by PN. PMID:19818419

  17. HIF-1α inhibition ameliorates neonatal brain injury in a rat pup hypoxic-ischemic model

    PubMed Central

    Chen, Wanqiu; Jadhav, Vikram; Tang, Jiping; Zhang, John H.

    2008-01-01

    Hypoxia-inducible factor-1alpha (HIF-1α) has been considered as a regulator of both prosurvival and prodeath pathways in the nervous system. The present study was designed to elucidate the role of HIF-1α in neonatal hypoxic-ischemic (HI) brain injury. Rice-Vannucci model of neonatal hypoxic-ischemic brain injury was used in seven-day-old rats, by subjecting unilateral carotid artery ligation followed by 2h of hypoxia (8% O2 at 37°C). HIF-1α activity was inhibited by 2-methoxyestradiol (2ME2) and enhanced by dimethyloxalylglycine (DMOG). Results showed that 2ME2 exhibited dose-dependent neuroprotection by decreasing infarct volume and reducing brain edema at 48 h post HI. The neuroprotection was lost when 2ME2 was administered 3 h post HI. HIF-1α upregulation by DMOG increased the permeability of the BBB and brain edema compared with HI group. 2ME2 attenuated the increase in HIF-1α and VEGF 24 h after HI. 2ME2 also had a long-term effect of protecting against the loss of brain tissue. The study showed that the early inhibition of HIF-1α acutely after injury provided neuroprotection after neonatal hypoxia-ischemia which was associated with preservation of BBB integrity, attenuation of brain edema, and neuronal death. PMID:18602008

  18. Neuroprotective potential of Bacopa monnieri and Bacoside A against dopamine receptor dysfunction in the cerebral cortex of neonatal hypoglycaemic rats.

    PubMed

    Thomas, Roshni Baby; Joy, Shilpa; Ajayan, M S; Paulose, C S

    2013-11-01

    Neonatal hypoglycaemia initiates a series of events leading to neuronal death, even if glucose and glycogen stores return to normal. Disturbances in the cortical dopaminergic function affect memory and cognition. We recommend Bacopa monnieri extract or Bacoside A to treat neonatal hypoglycaemia. We investigated the alterations in dopaminergic functions by studying the Dopamine D1 and D2 receptor subtypes. Receptor-binding studies revealed a significant decrease (p < 0.001) in dopamine D1 receptor number in the hypoglycaemic condition, suggesting cognitive dysfunction. cAMP content was significantly (p < 0.001) downregulated in hypoglycaemic neonatal rats indicating the reduction in cell signalling of the dopamine D1 receptors. It is attributed to the deficits in spatial learning and memory. Hypoglycaemic neonatal rats treated with Bacopa extract alone and Bacoside A ameliorated the dopaminergic and cAMP imbalance as effectively as the glucose therapy. The upregulated Bax expression in the present study indicates the high cell death in hypoglycaemic neonatal rats. Enzyme assay of SOD confirmed cortical cell death due to free radical accumulation. The gene expression of SOD in the cortex was significantly downregulated (p < 0.001). Bacopa treatment showed a significant reversal in the altered gene expression parameters (p < 0.001) of Bax and SOD. Our results suggest that in the rat experimental model of neonatal hypoglycaemia, Bacopa extract improved alterations in D1, D2 receptor expression, cAMP signalling and cell death resulting from oxidative stress. This is an important area of study given the significant motor and cognitive impairment that may arise from neonatal hypoglycaemia if proper treatment is not implemented.

  19. Intra-arterial transplantation of human umbilical cord blood mononuclear cells in neonatal hypoxic-ischemic rats.

    PubMed

    Greggio, Samuel; de Paula, Simone; Azevedo, Pâmella Nunes; Venturin, Gianina Teribele; Dacosta, Jaderson Costa

    2014-02-06

    Based on preclinical findings, cellular therapy has become a promising therapeutic approach for neonatal hypoxia-ischemia (HI). However, before translation into the clinical setting, new and effective routes of cell delivery must be determined. Intra-arterial (IA) delivery is an attractive route of cellular administration but has never been used in neonatal HI rats. In this study, we investigated the feasibility of IA transplantation of human umbilical cord blood (HUCB) mononuclear cells for the treatment of long-term behavior dysfunction and brain lesion after neonatal HI. Seven-day-old rats were subjected to a HI model and the animals received HUCB mononuclear cells into the left common carotid artery 24 h after HI insult. At 9 weeks post-HI, intra-arterially transplanted HUCB mononuclear cells significantly improved learning and long-term spatial memory impairments when evaluated by the Morris water maze paradigm. There was no effect of neonatal HI insult or IA procedure on body weight and on motor coordination and balance when evaluated by the accelerating rotarod test. Cellular transplantation by the IA route did not restore neonatal HI-induced brain damage according to stereological volume assessment. Furthermore, HUCB mononuclear cells were tracked in the injured brain and peripheral organs of HI transplanted-rats by nested polymerase chain reaction analysis at different time points. Our findings contribute to the translational knowledge of cell based-therapy in neonatal HI and demonstrate for the first time that IA transplantation into rat pups is a feasible route for cellular delivery and prevents long-term cognitive deficits induced by experimental neonatal HI. © 2013.

  20. Post-translational modifications of tubulin and microtubule stability in adult rat ventricular myocytes and immortalized HL-1 cardiomyocytes.

    PubMed

    Belmadani, Souad; Poüs, Christian; Fischmeister, Rodolphe; Méry, Pierre-François

    2004-03-01

    Little is known about the subcellular distribution and the dynamics of tubulins in adult cardiac myocytes although both are modified during cardiac hypertrophy and heart failure. Using confocal microscopy, we examined post-translational modifications of tubulin in fully differentiated ventricular myocytes isolated from adult rat hearts, as well as in immortalized and dividing HL-1 cardiomyocytes. Detyrosinated Glu-alpha-tubulin was the most abundant post-translationally modified tubulin found in ventricular myocytes, while acetylated- and delta2-alpha-tubulins were found in lower amounts or absent. In contrast, dividing HL-1 cardiomyocytes exhibited high levels of tyrosinated or acetylated alpha-tubulins. A mild nocodazole treatment (0.1 microM, 1 h) disrupted microtubules in HL-1 myocytes, but not in adult ventricular myocytes. A stronger treatment (10 microM, 2 h) was required to disassemble tubulins in adult myocytes. Glu-alpha-tubulin containing microtubules were more resistant to nocodazole treatment in HL-1 cardiomyocytes than in ventricular myocytes. Endogenous activation of the cAMP pathway with the forskolin analog L858051 (20 microM) or the beta-adrenergic agonist isoprenaline (10 microM) disrupted the most labile microtubules in HL-1 cardiomyocytes. In contrast, isoprenaline (10 microM), cholera toxin (200 ng/ml, a G(S)-protein activator), L858051 (20 microM) or forskolin (10 microM) had no effect on the microtubule network in ventricular myocytes. In addition, intracellular Ca2+ accumulation induced either by thapsigargin (2 microM) or caffeine (10 mM) did not modify microtubule stability in ventricular myocytes. Our data demonstrate the unique stability of the microtubule network in adult cardiac myocytes. We speculate that microtubule stability is required to support cellular integrity during cardiac contraction.

  1. Baroreflex failure increases the risk of pulmonary edema in conscious rats with normal left ventricular function.

    PubMed

    Sakamoto, Kazuo; Hosokawa, Kazuya; Saku, Keita; Sakamoto, Takafumi; Tobushi, Tomoyuki; Oga, Yasuhiro; Kishi, Takuya; Ide, Tomomi; Sunagawa, Kenji

    2016-01-15

    In heart failure with preserved ejection fraction (HFpEF), the complex pathogenesis hinders development of effective therapies. Since HFpEF and arteriosclerosis share common risk factors, it is conceivable that stiffened arterial wall in HFpEF impairs baroreflex function. Previous investigations have indicated that the baroreflex regulates intravascular stressed volume and arterial resistance in addition to cardiac contractility and heart rate. We hypothesized that baroreflex dysfunction impairs regulation of left atrial pressure (LAP) and increases the risk of pulmonary edema in freely moving rats. In 15-wk Sprague-Dawley male rats, we conducted sinoaortic denervation (SAD, n = 6) or sham surgery (Sham, n = 9), and telemetrically monitored ambulatory arterial pressure (AP) and LAP. We compared the mean and SD (lability) of AP and LAP between SAD and Sham under normal-salt diet (NS) or high-salt diet (HS). SAD did not increase mean AP but significantly increased AP lability under both NS (P = 0.001) and HS (P = 0.001). SAD did not change mean LAP but significantly increased LAP lability under both NS (SAD: 2.57 ± 0.43 vs. Sham: 1.73 ± 0.30 mmHg, P = 0.01) and HS (4.13 ± 1.18 vs. 2.45 ± 0.33 mmHg, P = 0.02). SAD markedly increased the frequency of high LAP, and SAD with HS prolonged the duration of LAP > 18 mmHg by nearly 20-fold compared with Sham (SAD + HS: 2,831 ± 2,366 vs. Sham + HS: 148 ± 248 s, P = 0.01). We conclude that baroreflex failure impairs volume tolerance and together with salt loading increases the risk of pulmonary edema even in the absence of left ventricular dysfunction. Baroreflex failure may contribute in part to the pathogenesis of HFpEF.

  2. An increased TREK-1-like potassium current in ventricular myocytes during rat cardiac hypertrophy.

    PubMed

    Wang, Weiping; Zhang, Man; Li, Pingping; Yuan, Hui; Feng, Nan; Peng, Ying; Wang, Ling; Wang, Xiaoliang

    2013-04-01

    To elucidate the expression and identify the functional changes of 2 pore domain potassium channel TREK-1 during cardiac hypertrophy in rats, left ventricular hypertrophy was induced by subcutaneous injection with isoproterenol. Western blot was used to detect the expression of TREK-1 channel protein, and inside-out and whole-cell recordings were used to record TREK-1 currents. The results showed that TREK-1 protein expression in endocardium was slightly higher than that in epicardium in control left ventricles. However, it was obviously upregulated by 89.8% during hypertrophy, 2.3-fold higher than in epicardium. Mechanical stretch, intracellular acidification, and arachidonic acid could activate a TREK-1-like current in cardiomyocytes. The slope conductances of cardiac TREK-1 and CHO/TREK-1 channels were 123 ± 7 and 113 ± 17 pS, respectively. The TREK-1 inhibitor L-3-n-butylphthalide (10 μM) reduced the currents in CHO/TREK-1 cells, normal cardiomyocytes, and hypertrophic cardiomyocytes by 48.5%, 54.3%, and 55.5%, respectively. The percentage of L-3-n-butylphthalide-inhibited outward whole-cell current in hypertrophic cardiomyocytes (23.7%) was larger than that in normal cardiomyocytes (14.2%). The percentage of chloroform-activated outward whole-cell current in hypertrophic cardiomyocytes (58.3%) was also larger than normal control (40.2%). Our results demonstrated that in hypertrophic rats, TREK-1 protein expression in endocardium was specifically increased and the ratio of TREK-1 channel current in cardiac outward currents was also enhanced. TREK-1 might balance potassium ion flow during hypertrophy and might be a potential drug target for heart protection.

  3. [Influence of neonatally administered gonadotropin on the sexual function of adult rats].

    PubMed

    Götz, F; Vedder, I; Dörner, G

    1975-02-01

    Male and female rats were daily injected with 10 IU HCG plus 10 IU FSH from the 1st to 14th day of life in order to investigate the influence of neonatal gonadotrophin administration on the sex-specific differentiation of the brain. When adult, the males showed hypogonadism associated with approximately normal sexual activity. In the females, precocious puberty, indicated by premature vaginal opening and spontaneous estrus, occurred. Furthermore, bisexuality with a tendency towards more male behavioural patterns was observed, but no impairment of ovarian cyclicity. Thus, hypergonadotrophic hypergonadism during the hypothalamic differentiation phase gave rise to bisexual behaviour in adult female rats associated with normal ovarian cycles. The question of a direct or indirect influence of gonadotrophins on the sex-specific brain differentiation is discussed.

  4. Acute antiapoptotic effects of hydrocortisone in the hippocampus of neonatal rats.

    PubMed

    Menshanov, P N; Bannova, A V; Bulygina, V V; Dygalo, N N

    2013-01-01

    Natural glucocorticoid hydrocortisone was suggested as a potent substitution for dexamethasone in the treatment of bronchopulmonary dysplasia in neonates. The aim of this study was to investigate whether hydrocortisone is able to affect the expression of apoptotic genes and the intensity of naturally occurring cell death in the developing rat hippocampus. Hormone treatment decreased procaspase-3 and active caspase-3 levels as well as DNA fragmentation intensity in the hippocampal formation of one-week-old rats in 6 h after injection. These changes were accompanied by an upregulation of antiapoptotic protein Bcl-XL, while expression of proapoptotic protein Bax remained unchanged. The action of hydrocortisone was glucocorticoid receptor-independent, as the selective glucocorticoid receptor agonist dexamethasone did not affect either apoptotic protein levels or DNA fragmentation intensity in the hippocampal region. The data are the first evidences for in vivo antiapoptotic effects of hydrocortisone in the developing hippocampus.

  5. [Cortical alpha-2a adrenoreceptors involved in the inhibitory control of motor activity in neonatal rats].

    PubMed

    Shishkina, G T; Kalinina, T S; Masnavieva, L B; Dygalo, N N

    2003-01-01

    Involvement of alpha 2A-adrenoceptors in control of motor activity in neonatal rats was investigated using intrabrain injections of antisense deoxyoligonucleotide targeting mRNA of these receptors. Antisense-induced decrease in the receptor expression in the brain accompanied by an augmentation of animal's motor activity, which was evaluated as a number of paddling movements with the right forepaw. This antisense effect was stimulatory and was not related to somatic growth and maturation of reflexes in the animals. The antisensetreated pups differed from controls neither in body weight nor the latency of righting reflex. The data suggest that alpha 2A-adrenoceptors are involved in inhibitory control of motor activity of rat pups from the first day of life.

  6. Abnormal endogenous amino acid release in brain slices from vitamin B-6 restricted neonatal rats.

    PubMed

    Guilarte, T R

    1991-01-02

    The basal and potassium-evoked efflux of glutamate, glycine, taurine, and gamma-aminobutyric acid (GABA) was measured in brain slices from vitamin B-6 restricted and sufficient 14-day-old rats. The results indicate a reduced level of basal glutamate, taurine, and GABA efflux in hippocampal slices and taurine and GABA in cortical slices from vitamin B-6 restricted animals. In the presence of depolarizing potassium concentrations, there was a reduced level of GABA efflux in hippocampal and cortical slices, and a marked reduction in the release of glutamate in cortical slices from B-6 restricted rats. The abnormalities in the secretion process of these neuroactive amino acids may be related to the neurological sequelae associated with neonatal vitamin B-6 restriction.

  7. Development of Left Ventricular Longitudinal Speckle Tracking Echocardiography in Very Low Birth Weight Infants with and without Bronchopulmonary Dysplasia during the Neonatal Period

    PubMed Central

    Czernik, Christoph; Rhode, Stefanie; Helfer, Sven; Schmalisch, Gerd; Bührer, Christoph; Schmitz, Lothar

    2014-01-01

    Objectives In preterm infants, postnatal myocardial adaptation may be complicated by bronchopulmonary dysplasia (BPD). We aimed to describe the development of left ventricular function by serial 2D, Doppler, and speckle tracking echocardiography (2D-STE) in infants with and without BPD during the neonatal period and compare these to anthropometric and conventional hemodynamic parameters. Study Design Prospective echocardiography on day of life (DOL) 1, 7, 14, and 28 in 119 preterm infants <1500 g birth weight of whom 36 developed BPD (need for oxygen supplementation at 36 weeks gestational age). Non-BPD and BPD infants differed significantly in median (IQR) gestational age (25.5(24–26.5) weeks vs. 29(27–30) weeks, p<0.001) and birth weight (661(552–871) g vs. 1100(890–1290) g, p<0.001). Results The intra- and inter-observer variability of the 2D-STE parameters measured did not depend on time of measurement, although there were significant differences in the reproducibility of the parameters. Low intra- and inter-observer variability was seen for longitudinal systolic strain and strain rate mid septum with a median CV (coefficient of variation) of <4.6%. Much higher CVs (>10%) were seen for the apical segment. While anthropometric parameters show rapid development during the first 4 weeks of life, the speckle tracking parameters did not differ statistically significantly during the neonatal period. Infants with and without BPD differed significantly (p<0.001) in the development of anthropometric parameters, conventional hemodynamic parameters except for heart rate, and 2D-STE parameters: global longitudinal systolic strain rate (GLSSR) and longitudinal systolic strain for the mid left wall (LSSR). The largest differences were seen at DOL 1 and 7 in GLSSR (p<0.001) and in LSSR (p<0.01). Conclusions Reproducible 2D-STE measurements are possible in preterm infants <1500 g. Cardiac deformation reveals early (DOL 1 and 7) ventricular changes (GLSSR and LSSR) in

  8. Effects of cannabidiol on contractions and calcium signaling in rat ventricular myocytes.

    PubMed

    Ali, Ramez M; Al Kury, Lina T; Yang, Keun-Hang Susan; Qureshi, Anwar; Rajesh, Mohanraj; Galadari, Sehamuddin; Shuba, Yaroslav M; Howarth, Frank Christopher; Oz, Murat

    2015-04-01

    Cannabidiol (CBD), a major nonpsychotropic cannabinoid found in Cannabis plant, has been shown to influence cardiovascular functions under various physiological and pathological conditions. In the present study, the effects of CBD on contractility and electrophysiological properties of rat ventricular myocytes were investigated. Video edge detection was used to measure myocyte shortening. Intracellular Ca(2+) was measured in cells loaded with the Ca(2+) sensitive fluorescent indicator fura-2 AM. Whole-cell patch clamp was used to measure action potential and Ca(2+) currents. Radioligand binding was employed to study pharmacological characteristics of CBD binding. CBD (1μM) caused a significant decrease in the amplitudes of electrically evoked myocyte shortening and Ca(2+) transients. However, the amplitudes of caffeine-evoked Ca(2+) transients and the rate of recovery of electrically evoked Ca(2+) transients following caffeine application were not altered. CBD (1μM) significantly decreased the duration of APs. Further studies on L-type Ca(2+) channels indicated that CBD inhibits these channels with IC50 of 0.1μM in a voltage-independent manner. Radioligand studies indicated that the specific binding of [(3)H]Isradipine, was not altered significantly by CBD. The results suggest that CBD depresses myocyte contractility by suppressing L-type Ca(2+) channels at a site different than dihydropyridine binding site and inhibits excitation-contraction coupling in cardiomyocytes.

  9. Endogenous protein phosphatase 1 runs down gap junctional communication of rat ventricular myocytes.

    PubMed

    Duthe, F; Plaisance, I; Sarrouilhe, D; Hervé, J C

    2001-11-01

    Gap junctional channels are essential for normal cardiac impulse propagation. In ventricular myocytes of newborn rats, channel opening requires the presence of ATP to allow protein kinase activities; otherwise, channels are rapidly deactivated by the action of endogenous protein phosphatases (PPs). The lack of influence of Mg(2+) and of selective PP2B inhibition is not in favor of the involvements of Mg(2+)-dependent PP2C and PP2B, respectively, in the loss of channel activity. Okadaic acid (1 microM) and calyculin A (100 nM), both inhibitors of PP1 and PP2A activities, significantly retarded the loss of channel activity. However, a better preservation was obtained in the presence of selective PP1 inhibitors heparin (100 microg/ml) or protein phosphatase inhibitor 2 (I2; 100 nM). Conversely, the stimulation of endogenous PP1 activity by p-nitrophenyl phosphate, in the presence of ATP, led to a progressive fading of junctional currents unless I2 was simultaneously added. Together, these results suggest that a basal phosphorylation-dephosphorylation turnover regulates gap junctional communication which is rapidly deactivated by PP1 activity when the phosphorylation pathway is hindered.

  10. Modification of distinct ion channels differentially modulates Ca2+ dynamics in primary cultured rat ventricular cardiomyocytes

    PubMed Central

    Li, Xichun; Shen, Liping; Zhao, Fang; Zou, Xiaohan; He, Yuwei; Zhang, Fan; Zhang, Chunlei; Yu, Boyang; Cao, Zhengyu

    2017-01-01

    Primary cultured cardiomyocytes show spontaneous Ca2+ oscillations (SCOs) which not only govern contractile events, but undergo derangements that promote arrhythmogenesis through Ca2+ -dependent mechanism. We systematically examined influence on SCOs of an array of ion channel modifiers by recording intracellular Ca2+ dynamics in rat ventricular cardiomyocytes using Ca2+ specific fluorescence dye, Fluo-8/AM. Voltage-gated sodium channels (VGSCs) activation elongates SCO duration and reduces SCO frequency while inhibition of VGSCs decreases SCO frequency without affecting amplitude and duration. Inhibition of voltage-gated potassium channel increases SCO duration. Direct activation of L-type Ca2+ channels (LTCCs) induces SCO bursts while suppressing LTCCs decreases SCO amplitude and slightly increases SCO frequency. Activation of ryanodine receptors (RyRs) increases SCO duration and decreases both SCO amplitude and frequency while inhibiting RyRs decreases SCO frequency without affecting amplitude and duration. The potencies of these ion channel modifiers on SCO responses are generally consistent with their affinities in respective targets demonstrating that modification of distinct targets produces different SCO profiles. We further demonstrate that clinically-used drugs that produce Long-QT syndrome including cisapride, dofetilide, sotalol, and quinidine all induce SCO bursts while verapamil has no effect. Therefore, occurrence of SCO bursts may have a translational value to predict cardiotoxicants causing Long-QT syndrome. PMID:28102360

  11. Fourth ventricular administration of ghrelin induces relaxation of the proximal stomach in the rat.

    PubMed

    Kobashi, Motoi; Yanagihara, Mamoru; Fujita, Masako; Mitoh, Yoshihiro; Matsuo, Ryuji

    2009-02-01

    The effects of fourth ventricular administration of ghrelin on motility of the proximal stomach were examined in anesthetized rats. Intragastric pressure (IGP) was measured using a balloon situated in the proximal part of the stomach. Administration of ghrelin into the fourth ventricle induced relaxation of the proximal stomach in a dose-dependent manner. Significant reduction of IGP was observed at doses of 3, 10, or 30 pmol. The administration of ghrelin (10 or 30 pmol) with growth hormone secretagogue receptor (GHS-R) antagonist ([D-Lys3] GHRP-6; 1 nmol) into the fourth ventricle did not induce a significant change in IGP. The sole administration of [D-Lys3] GHRP-6 also did not induce a significant change in IGP. Bilateral sectioning of the vagi at the cervical level abolished the relaxation induced by the administration of ghrelin (10 or 30 pmol) into the fourth ventricle, suggesting that relaxation induced by ghrelin is mediated by vagal preganglionic neurons. Microinjections of ghrelin (200 fmol) into the caudal part of the dorsal vagal complex (DVC) induced obvious relaxation of the proximal stomach. Similar injections into the intermediate part of the DVC did not induce significant change. Dose-response analyses revealed that the microinjection of 2 fmol of ghrelin into the caudal DVC significantly reduced IGP. These results revealed that ghrelin induced relaxation in the proximal stomach via GHS-R situated in the caudal DVC.

  12. Dinitrophenol pretreatment of rat ventricular myocytes protects against damage by metabolic inhibition and reperfusion.

    PubMed

    Rodrigo, G C; Lawrence, C L; Standen, N B

    2002-05-01

    We have investigated the protective effects of pretreatment with the mitochondrial uncoupler 2,4-dinitrophenol on the cellular damage induced by metabolic inhibition (with cyanide and iodoacetic acid) and reperfusion in freshly isolated adult rat ventricular myocytes. Damage was assessed from changes in cell length and morphology measured using video microscopy. Intracellular Ca(2+), mitochondrial membrane potential, and NADH were measured using fura-2, tetramethylrhodamine ethyl ester and autofluorescence, respectively. During metabolic inhibition myocytes developed rigor, and on reperfusion 73.6+/-8.1% hypercontracted and 10.8+/-6.7% recovered contractile function in response to electrical stimulation. Intracellular Ca(2+) increased substantially, indicated by a rise in the fura-2 ratio (340/380 nm) on reperfusion from 0.86+/-0.04 to 1.93+/-0.18. Myocytes pretreated with substrate-free Tyrode containing 50 microm dinitrophenol showed reduced reperfusion injury: 29.0+/-7.4% of cells hypercontracted and 65.3+/-7.3% recovered contractile function (P<0.001 vs control). The fura-2 ratio on reperfusion was also lower at 1.01+/-0.08. Fluorescence measurements showed that dinitrophenol caused mitochondrial depolarisation, and decreased NADH. The presence of the substrates glucose and pyruvate reduced these effects, and abolished the protection against damage by metabolic inhibition and reperfusion. However protection was unaffected by block of ATP-sensitive potassium channels. Thus the protective effects of pretreatment with dinitrophenol may result from a reduction in NADH in response to mitochondrial depolarisation.

  13. Biphasic effects of hyposmotic challenge on excitation-contraction coupling in rat ventricular myocytes.

    PubMed

    Brette, F; Calaghan, S C; Lappin, S; White, E; Colyer, J; Le Guennec, J Y

    2000-10-01

    The effects of short (1 min) and long (7-10 min) exposure to hyposmotic solution on excitation-contraction coupling in rat ventricular myocytes were studied. After short exposure, the action potential duration at 90% repolarization (APD(90)), the intracellular Ca(2+) concentration ([Ca(2+)](i)) transient amplitude, and contraction increased, whereas the L-type Ca(2+) current (I(Ca, L)) amplitude decreased. Fractional sarcoplasmic reticulum (SR) Ca(2+) release increased but SR Ca(2+) load did not. After a long exposure, I(Ca,L), APD(90), [Ca(2+)](i) transient amplitude, and contraction decreased. The abbreviation of APD(90) was partially reversed by 50 microM DIDS, which is consistent with the participation of Cl(-) current activated by swelling. After 10-min exposure to hyposmotic solution in cells labeled with di-8-aminonaphthylethenylpyridinium, t-tubule patterning remained intact, suggesting the loss of de-t-tubulation was not responsible for the fall in I(Ca,L). After long exposure, Ca(2+) load of the SR was not increased, and swelling had no effect on the site-specific phosphorylation of phospholamban, but fractional SR Ca(2+) release was depressed. The initial positive inotropic response to hyposmotic challenge may be accounted for by enhanced coupling between Ca(2+) entry and release. The negative inotropic effect of prolonged exposure can be accounted for by shortening of the action potential duration and a fall in the I(Ca,L) amplitude.

  14. Impaired cerebral mitochondrial oxidative phosphorylation function in a rat model of ventricular fibrillation and cardiopulmonary resuscitation.

    PubMed

    Jiang, Jun; Fang, Xiangshao; Fu, Yue; Xu, Wen; Jiang, Longyuan; Huang, Zitong

    2014-01-01

    Postcardiac arrest brain injury significantly contributes to mortality and morbidity in patients suffering from cardiac arrest (CA). Evidence that shows that mitochondrial dysfunction appears to be a key factor in tissue damage after ischemia/reperfusion is accumulating. However, limited data are available regarding the cerebral mitochondrial dysfunction during CA and cardiopulmonary resuscitation (CPR) and its relationship to the alterations of high-energy phosphate. Here, we sought to identify alterations of mitochondrial morphology and oxidative phosphorylation function as well as high-energy phosphates during CA and CPR in a rat model of ventricular fibrillation (VF). We found that impairment of mitochondrial respiration and partial depletion of adenosine triphosphate (ATP) and phosphocreatine (PCr) developed in the cerebral cortex and hippocampus following a prolonged cardiac arrest. Optimal CPR might ameliorate the deranged phosphorus metabolism and preserve mitochondrial function. No obvious ultrastructural abnormalities of mitochondria have been found during CA. We conclude that CA causes cerebral mitochondrial dysfunction along with decay of high-energy phosphates, which would be mitigated with CPR. This study may broaden our understanding of the pathogenic processes underlying global cerebral ischemic injury and provide a potential therapeutic strategy that aimed at preserving cerebral mitochondrial function during CA.

  15. A comparative assessment of fluo Ca2+ indicators in rat ventricular myocytes

    PubMed Central

    Hagen, Brian M.; Boyman, Liron; Kao, Joseph P.Y.; Lederer, W. Jonathan

    2012-01-01

    Summary The fluo family of indicators is frequently used in studying Ca2+ physiology; however, choosing which fluo indicator to use is not obvious. Indicator properties are typically determined in well-defined aqueous solutions. Inside cells, however, the properties can change markedly. We have characterized each of three fluo variants (fluo-2MA, fluo-3 and fluo-4) in two forms—the acetoxymethyl (AM) ester and the K+ salt. We loaded indicators into rat ventricular myocytes and used confocal microscopy to monitor depolarization-induced fluorescence changes and fractional shortening. Myocytes loaded with the indicator AM esters showed significantly different Ca2+ transients and fractional shortening kinetics. Loading the K+ salts via whole-cell patch-pipette eliminated differences between fluo-3 and fluo-4, but not fluo-2. Cells loaded with different indicator AM esters showed different staining patterns—suggesting differential loading into organelles. Ca2+ dissociation constants (Kd,Ca), measured in protein-rich buffers mimicking the cytosol were significantly higher than values determined in simple buffers. This increase in Kd,Ca (decrease in Ca2+ affinity) was greatest for fluo-3 and fluo-4, and least for fluo-2. We conclude that the structurally-similar fluo variants differ with respect to cellular loading, subcellular compartmentalization, and intracellular Ca2+ affinity. Therefore, judicious choice of fluo indicator and loading procedure is advisable when designing experiments. PMID:22721780

  16. A comparative assessment of fluo Ca2+ indicators in rat ventricular myocytes.

    PubMed

    Hagen, Brian M; Boyman, Liron; Kao, Joseph P Y; Lederer, W Jonathan

    2012-08-01

    The fluo family of indicators is frequently used in studying Ca(2+) physiology; however, choosing which fluo indicator to use is not obvious. Indicator properties are typically determined in well-defined aqueous solutions. Inside cells, however, the properties can change markedly. We have characterized each of three fluo variants (fluo-2MA, fluo-3 and fluo-4) in two forms-the acetoxymethyl (AM) ester and the K(+) salt. We loaded indicators into rat ventricular myocytes and used confocal microscopy to monitor depolarization-induced fluorescence changes and fractional shortening. Myocytes loaded with the indicator AM esters showed significantly different Ca(2+) transients and fractional shortening kinetics. Loading the K(+) salts via whole-cell patch-pipette eliminated differences between fluo-3 and fluo-4, but not fluo-2MA. Cells loaded with different indicator AM esters showed different staining patterns-suggesting differential loading into organelles. Ca(2+) dissociation constants (K(d,Ca)), measured in protein-rich buffers mimicking the cytosol were significantly higher than values determined in simple buffers. This increase in K(d,Ca) (decrease in Ca(2+) affinity) was greatest for fluo-3 and fluo-4, and least for fluo-2MA. We conclude that the structurally-similar fluo variants differ with respect to cellular loading, subcellular compartmentalization, and intracellular Ca(2+) affinity. Therefore, judicious choice of fluo indicator and loading procedure is advisable when designing experiments. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. Ultrastructural localization of calsequestrin in adult rat atrial and ventricular muscle cells

    PubMed Central

    1985-01-01

    The distribution of calsequestrin in rat atrial and ventricular myocardial cells was determined by indirect immunocolloidal gold labeling of ultrathin frozen sections. The results presented show that calsequestrin is confined to the sarcoplasmic reticulum where it is localized in the lumen of the peripheral and the interior junctional sarcoplasmic reticulum as well as in the lumen of the corbular sarcoplasmic reticulum, but absent from the lumen of the network sarcoplasmic reticulum. Comparison of these results with our previous studies on the distribution of the Ca2+ + Mg2+-dependent ATPase of the cardiac sarcoplasmic reticulum show directly that the Ca2+ + Mg2+- dependent ATPase and calsequestrin are confined to distinct regions within the continuous sarcoplasmic reticulum membrane. Assuming that calsequestrin provides the major site of Ca2+ sequestration in the lumen of the sarcoplasmic reticulum, the results presented support the idea that both junctional (interior and peripheral) and specialized nonjunctional (corbular) regions of the sarcoplasmic reticulum are involved in Ca2+ storage and possibly release. Furthermore, the structural differences between the junctional and the corbular sarcoplasmic reticulum support the possibility that Ca2+ storage and/or release from the lumen of the junctional and the corbular sarcoplasmic reticulum are regulated by different physiological signals. PMID:4008530

  18. Barnidipine block of L-type Ca(2+) channel currents in rat ventricular cardiomyocytes.

    PubMed

    Wegener, J W; Meyrer, H; Rupp, J; Nawrath, H

    2000-08-01

    The effects of barnidipine and nifedipine on L-type Ca(2+) current (I(Ca(L))) were investigated in ventricular cardiomyocytes from rats. Both barnidipine and nifedipine reduced I(Ca(L)) in a concentration and voltage dependent manner; the EC(50) were 80 and 130 nM at a holding potential of -80 mV, respectively, and 18 and 6 nM at -40 mV, respectively. Both drugs induced a leftward shift of the steady-state inactivation curve of I(Ca(L)). Using a twin pulse protocol, the relationships between the amount of block of I(Ca(L)) by either drug, seen during the second pulse, and the length of the first pulse were described by monoexponential functions reflecting onset of block, dependent on drug concentration. The onset of block by barnidipine was three times faster than that by nifedipine. With both drugs, recovery of I(Ca(L)) was 50 times slower than under control conditions and described by monoexponential functions reflecting offset of block (independent of drug concentration). The offset of block with barnidipine was three times slower than that with nifedipine. The time constants of block and unblock of I(Ca(L)) by both drugs were used to calculate binding and unbinding and to predict their effects at two frequencies. It is suggested that barnidipine exhibits a higher affinity to the inactivated Ca(2+) channel state as compared to nifedipine.

  19. Barnidipine block of L-type Ca2+ channel currents in rat ventricular cardiomyocytes

    PubMed Central

    Wegener, Jörg W; Meyrer, Hans; Rupp, Johanna; Nawrath, Hermann

    2000-01-01

    The effects of barnidipine and nifedipine on L-type Ca2+ current (ICa(L)) were investigated in ventricular cardiomyocytes from rats.Both barnidipine and nifedipine reduced ICa(L) in a concentration and voltage dependent manner; the EC50 were 80 and 130 nM at a holding potential of −80 mV, respectively, and 18 and 6 nM at −40 mV, respectively.Both drugs induced a leftward shift of the steady-state inactivation curve of ICa(L).Using a twin pulse protocol, the relationships between the amount of block of ICa(L) by either drug, seen during the second pulse, and the length of the first pulse were described by monoexponential functions reflecting onset of block, dependent on drug concentration. The onset of block by barnidipine was three times faster than that by nifedipine.With both drugs, recovery of ICa(L) was 50 times slower than under control conditions and described by monoexponential functions reflecting offset of block (independent of drug concentration). The offset of block with barnidipine was three times slower than that with nifedipine.The time constants of block and unblock of ICa(L) by both drugs were used to calculate binding and unbinding and to predict their effects at two frequencies.It is suggested that barnidipine exhibits a higher affinity to the inactivated Ca2+ channel state as compared to nifedipine. PMID:10952695

  20. Effects of injectable anesthetic combinations on left ventricular function and cardiac morphology in Sprague-Dawley rats.

    PubMed

    Sabatini, Carla F; O'Sullivan, M Lynne; Valcour, James E; Sears, William; Johnson, Ron J

    2013-01-01

    Novel anesthetic agents or combinations may provide superior general anesthesia for echocardiography in rodents with the potential for reduced adverse effects. This study sought to characterize the effects of 3 injectable anesthetics on left ventricular (LV) systolic function and cardiac morphology in healthy male and female rats. Rats underwent echocardiographic assessment after general anesthesia via pentobarbital or combinations of ketamine and medetomidine (KME) and ketamine and midazolam (KMI) according to a crossover Latin-square design. Blood samples for serum estradiol measurements were obtained from all females after echocardiography with each anesthetic. Rats given KMI showed superior LV systolic function with the highest values for fractional shortening (FS), ejection fraction (EF) and stroke volume, whereas heart rate was greatest with pentobarbital, followed by KMI and then KME. KME produced the greatest effects on cardiac morphology, most notably during systole, including reduced septal and posterior wall thickness and increased LV chamber dimensions and volumes. In addition, KME had the greatest cardiac-depressing effects on LV systolic function, including reduced FS, EF, and heart rate values. Compared with male rats, female rats had superior LV function with greater EF and FS values, whereas male rats showed higher heart rate. Significant negative correlations were noted between serum estradiol levels and FS and EF values in female rats receiving KME. We conclude that the combination of KMI may be a superior anesthetic for use in male and female rats undergoing echocardiography.

  1. Pancreatic and Pancreatic-Like Microbial Proteases Accelerate Gut Maturation in Neonatal Rats

    PubMed Central

    Prykhodko, Olena; Pierzynowski, Stefan G.; Nikpey, Elham; Arevalo Sureda, Ester; Fedkiv, Olexandr; Weström, Björn R.

    2015-01-01

    Objectives Postnatal gut maturation in neonatal mammals, either at natural weaning or after precocious inducement, is coinciding with enhanced enzymes production by exocrine pancreas. Since the involvement of enzymes in gut functional maturation was overlooked, the present study aimed to investigate the role of enzymes in gut functional maturation using neonatal rats. Methods Suckling rats (Rattus norvegicus) were instagastrically gavaged with porcine pancreatic enzymes (Creon), microbial-derived amylase, protease, lipase and mixture thereof, while controls received α-lactalbumin or water once per day during 14–16 d of age. At 17 d of age the animals were euthanized and visceral organs were dissected, weighed and analyzed for structural and functional properties. For some of the rats, gavage with the macromolecular markers such as bovine serum albumin and bovine IgG was performed 3 hours prior to blood collection to assess the intestinal permeability. Results Gavage with the pancreatic or pancreatic-like enzymes resulted in stimulated gut growth, increased gastric acid secretion and switched intestinal disaccharidases, with decreased lactase and increased maltase and sucrase activities. The fetal-type vacuolated enterocytes were replaced by the adult-type in the distal intestine, and macromolecular transfer to the blood was declined. Enzyme exposure also promoted pancreas growth with increased amylase and trypsin production. These effects were confined to the proteases in a dose-dependent manner. Conclusion Feeding exogenous enzymes, containing proteases, induced precocious gut maturation in suckling rats. This suggests that luminal exposure to proteases by oral loading or, possibly, via enhanced pancreatic secretion involves in the gut maturation of young mammals. PMID:25658606

  2. Repeated exposure to propofol potentiates neuroapoptosis and long-term behavioral deficits in neonatal rats.

    PubMed

    Yu, Deshui; Jiang, Yan; Gao, Jin; Liu, Bin; Chen, Ping

    2013-02-08

    Previous studies have shown that exposure of the immature brain to drugs that block NMDA glutamate receptors or drugs that potentiate GABA(A) receptors can trigger widespread neuroapoptosis. Almost all currently used general anesthetics have either NMDA receptor blocking or GABA(A) receptor enhancing properties. Propofol, a new intravenous anesthetic, is widely used in pediatric anesthesia and intensive care practice whose neurotoxicity on brain development remains unknown. We investigated the effects of neonatal propofol anesthesia on neuroapoptosis and long-term spatial learning/memory functions. Propofol was administered to 7 day-old rats either as a single dose or in 7 doses at concentrations sufficient to maintain a surgical plane of anesthesia. Immunohistochemical studies revealed a significant increase in the levels of caspase-3 in the hippocampal CA1 region after propofol administration. At postnatal day 34, light microscopic observations revealed a significant reduction in neuronal density and apparent morphological changes in the pyramidal cells of rats that had received 7 doses of propofol. These rats showed a longer escape latency/path length, less time spent in the target quadrant and fewer original platform crossings in the Morris Water Maze test. This treatment also produced a remarkable reduction in the levels of excitatory neurotransmitters in the cortex and the hippocampus as measured by high performance liquid chromatography. Repeated exposure to propofol induced exposure-time dependent neuroapoptosis and long-term neurocognitive deficits in neonatal rats. The neurocognitive deficits may be attributed to neuronal loss and a reduction of excitatory neurotransmitter release in the cortex and hippocampus. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  3. Effect of neonatal handling on adult rat spatial learning and memory following acute stress.

    PubMed

    Stamatakis, A; Pondiki, S; Kitraki, E; Diamantopoulou, A; Panagiotaropoulos, T; Raftogianni, A; Stylianopoulou, F

    2008-03-01

    Brief neonatal handling permanently alters hypothalamic-pituitary-adrenal axis function resulting in increased ability to cope with stress. Since stress is known to affect cognitive abilities, in the present study we investigated the effect of brief (15 min) handling on learning and memory in the Morris water maze, following exposure to an acute restraint stress either before training or recall. Exposure of non-handled rats to the acute stress prior to training resulted in quicker learning of the task, than in the absence of the stressor. When acute stress preceded acquisition, male handled rats showed an overall better learning performance, and both sexes of handled animals were less impaired in the subsequent memory trial, compared to the respective non-handled. In addition, the number of neurons immunoreactive for GR was higher in all areas of Ammon's horn of the handled rats during the recall. In contrast, the number of neurons immunoreactive for MR was higher in the CA1 and CA2 areas of the non-handled males. When the acute restraint stress was applied prior to the memory test, neonatal handling was not effective in preventing mnemonic impairment, as all animal groups showed a similar deficit in recall. In this case, no difference between handled and non-handled rats was observed in the number of GR positive neurons in the CA2 and CA3 hippocampal areas during the memory test. These results indicate that early experience interacts with sex and acute stress exposure in adulthood to affect performance in the water maze. Hippocampal corticosterone receptors may play a role in determining the final outcome.

  4. Xenon Combined with Therapeutic Hypothermia Is Not Neuroprotective after Severe Hypoxia-Ischemia in Neonatal Rats

    PubMed Central

    Sabir, Hemmen; Osredkar, Damjan; Maes, Elke; Wood, Thomas; Thoresen, Marianne

    2016-01-01

    Background Therapeutic hypothermia (TH) is standard treatment following perinatal asphyxia in newborn infants. Experimentally, TH is neuroprotective after moderate hypoxia-ischemia (HI) in seven-day-old (P7) rats. However, TH is not neuroprotective after severe HI. After a moderate HI insult in newborn brain injury models, the anesthetic gas xenon (Xe) doubles TH neuroprotection. The aim of this study was to examine whether combining Xe and TH is neuroprotective as applied in a P7 rat model of severe HI. Design/Methods 120 P7 rat pups underwent a severe HI insult; unilateral carotid artery ligation followed by hypoxia (8% O2 for 150min at experimental normothermia (NT-37: Trectal 37°C). Surviving pups were randomised to immediate NT-37 for 5h (n = 36), immediate TH-32: Trectal 32°C for 5h (n = 25) or immediate TH-32 plus 50% inhaled Xe for 5h (n = 24). Pups were sacrificed after one week of survival. Relative area loss of the ligated hemisphere was measured, and neurons in the subventricular zone of this injured hemisphere were counted, to quantify brain damage. Results Following the HI insult, median (interquartile range, IQR) hemispheric brain area loss was similar in all groups: 63.5% (55.5–75.0) for NT-37 group, 65.0% (57.0–65.0) for TH-32 group, and 66.5% (59.0–72.0) for TH-32+Xe50% group (not significant). Correspondingly, there was no difference in neuronal cell count (NeuN marker) in the subventricular zone across the three treatment groups. Conclusions Immediate therapeutic hypothermia with or without additional 50% inhaled Xe, does not provide neuroprotection one week after severe HI brain injury in the P7 neonatal rat. This model aims to mimic the clinical situation in severely asphyxiated neonates and treatment these newborns remains an ongoing challenge. PMID:27253085

  5. Bifidobacterium adolescentis protects against necrotizing enterocolitis and upregulates TOLLIP and SIGIRR in premature neonatal rats.

    PubMed

    Wu, Wenshen; Wang, Yanli; Zou, Jingjing; Long, Fang; Yan, Huiheng; Zeng, Lijuan; Chen, Yunbin

    2017-01-05

    Necrotizing enterocolitis (NEC) is a serious gastrointestinal disorder that is often seen in premature infants. Probiotics decrease the risk of NEC; however, the mechanism by which probiotics work is not clear. The goal of this study was to evaluate the preventive effect of Bifidobacterium adolescentis in an NEC rat model. Sprague-Dawley neonatal rats were obtained by caesarean section after 20-21 d gestation and randomly divided into the following 3 groups: dam fed (DF), formula fed (FF), and formula + B. adolescentis (FB). Those in the FF and FB groups developed NEC after exposure to asphyxia and cold stress. All rats were sacrificed 72 h after birth and intestinal injury and mRNA expression of TLR4, TOLLIP and SIGIRR were assessed. B. adolescentis significantly increased the 72-h survival rate from 56.3% in the FF group to 86.7% in the FB group. B. adolescentis significantly reduced the histological score from a median of 3.0 in the FF group to a median of 1.0 in the FB group,and significantly decreased the rate of NEC-like intestinal injury from 77.8% in the FF group to 23.1% in the FB group. The mRNA expression of TLR4 increased 3.6 fold in the FF group but decreased by 2 fold from B. adolescentis treatment. mRNA expression of TOLLIP and SIGIRR decreased 4.3 and 3.7 fold, respectively, in the FF group. B. adolescentis significantly increased mRNA expression of TOLLIP and SIGIRR by 3.7 fold and 2.6 fold, respectively. This study demonstrated B. adolescentis prevents NEC in preterm neonatal rats and that the mechanism for this action might be associated with the alteration of TLR4, TOLLIP, and SIGIRR expression.

  6. Neonatal hyperleptinaemia programmes adrenal medullary function in adult rats: effects on cardiovascular parameters.

    PubMed

    Trevenzoli, I H; Valle, M M R; Machado, F B; Garcia, R M G; Passos, M C F; Lisboa, P C; Moura, E G

    2007-04-15

    Epidemiological studies have shown a strong correlation between stressful events (nutritional, hormonal or environmental) in early life and development of adult diseases such as obesity, diabetes and cardiovascular failure. It is known that gestation and lactation are crucial periods for healthy growth in mammals and that the sympathoadrenal system is markedly influenced by environmental conditions during these periods. We previously demonstrated that neonatal hyperleptinaemia in rats programmes higher body weight, higher food intake and hypothalamic leptin resistance in adulthood. Using this model of programming, we investigated adrenal medullary function and effects on cardiovascular parameters in male rats in adulthood. Leptin treatment during the first 10 days of lactation (8 microg 100 g(-1) day(-1), s.c.) resulted in lower body weight (6.5%, P < 0.05), hyperleptinaemia (10-fold, P < 0.05) and higher catecholamine content in adrenal glands (18.5%, P < 0.05) on the last day of treatment. In adulthood (150 days), the rats presented higher body weight (5%, P < 0.05), adrenal catecholamine content (3-fold, P < 0.05), tyrosine hydroxylase expression (35%, P < 0.05) and basal and caffeine-stimulated catecholamine release (53% and 100%, respectively, P < 0.05). Systolic blood pressure and heart rate were also higher in adult rats (7% and 6%, respectively, P < 0.05). Our results show that hyperleptinaemia in early life increases adrenal medullary function in adulthood and that this may alter cardiovascular parameters. Thus, we suggest that imprinting factors which increase leptin and catecholamine levels during the neonatal period could be involved in development of adult chronic diseases.

  7. Induction of sarcomas by a single subcutaneous injection of 7,12-dimethylbenz[a]anthracene into neonatal male Sprague-Dawley rats: histopathological and immunohistochemical analyses.

    PubMed

    Taguchi, Shuuhei; Kuriwaki, Kazumi; Souda, Masakazu; Funato, Mamoru; Ninomiya, Kenjiro; Umekita, Yoshihisa; Yoshida, Hiroki

    2006-01-01

    Animal experiments have shown that carcinogenicity of chemicals is higher in fetal or neonatal periods than adult. We investigated sensitivities to a carcinogen in peri-neonatal rats with a model of sarcomas-induction by a subcutaneous injection of chemo-carcinogen that has rarely done in neonatal rats. Neonatal male SD rats were injected with 7,12-DMBA 10, 100, and 500 microg, which resulted in sarcomas-induction in 0, 62, and 94% of rats. Male SD rats were injected with DMBA 500 microg at 0, 3, 7, 14, and 21 days, which resulted in sarcomas-induction in 94, 70, 64, 50, and 44% of rats. Although the induced sarcomas were occasionally in mixed morphological feature as previous reports for sarcomas of rat, each was immunohistochemically in almost monotonous pattern, and classification was feasible. The incidence of rhabdomyosarcomas was higher in rats neonatally injected with a higher dose of DMBA than a lower dose, and in rats injected at peri-neonatal periods than later periods. In histological observations for the site of injection before overt sarcomas develop, clusters of atypical mesenchymal cells emerged as previous studies, but also those were immunohistochemically differentiated into rhabdomyocytes and other mesenchymal cells. We consider these findings may contribute a little to elucidation of process of sarcomas-induction in rats.

  8. Susceptibility to inhaled flame-generated ultrafine soot in neonatal and adult rat lungs.

    PubMed

    Chan, Jackie K W; Fanucchi, Michelle V; Anderson, Donald S; Abid, Aamir D; Wallis, Christopher D; Dickinson, Dale A; Kumfer, Benjamin M; Kennedy, Ian M; Wexler, Anthony S; Van Winkle, Laura S

    2011-12-01

    Over a quarter of the U.S. population is exposed to harmful levels of airborne particulate matter (PM) pollution, which has been linked to development and exacerbation of respiratory diseases leading to morbidity and mortality, especially in susceptible populations. Young children are especially susceptible to PM and can experience altered anatomic, physiologic, and biological responses. Current studies of ambient PM are confounded by the complex mixture of soot, metals, allergens, and organics present in the complex mixture as well as seasonal and temporal variance. We have developed a laboratory-based PM devoid of metals and allergens that can be replicated to study health effects of specific PM components in animal models. We exposed 7-day-old postnatal and adult rats to a single 6-h exposure of fuel-rich ultrafine premixed flame particles (PFPs) or filtered air. These particles are high in polycyclic aromatic hydrocarbons content. Pulmonary cytotoxicity, gene, and protein expression were evaluated at 2 and 24 h postexposure. Neonates were more susceptible to PFP, exhibiting increased lactate dehydrogenase activity in bronchoalveolar lavage fluid and ethidium homodimer-1 cellular staining in the lung in situ as an index of cytotoxicity. Basal gene expression between neonates and adults differed for a significant number of antioxidant, oxidative stress, and proliferation genes and was further altered by PFP exposure. PFP diminishes proliferation marker PCNA gene and protein expression in neonates but not adults. We conclude that neonates have an impaired ability to respond to environmental exposures that increases lung cytotoxicity and results in enhanced susceptibility to PFP, which may lead to abnormal airway growth.

  9. Susceptibility to Inhaled Flame-Generated Ultrafine Soot in Neonatal and Adult Rat Lungs

    PubMed Central

    Chan, Jackie K. W.; Fanucchi, Michelle V.; Anderson, Donald S.; Abid, Aamir D.; Wallis, Christopher D.; Dickinson, Dale A.; Kumfer, Benjamin M.; Kennedy, Ian M.; Wexler, Anthony S.; Van Winkle, Laura S.

    2011-01-01

    Over a quarter of the U.S. population is exposed to harmful levels of airborne particulate matter (PM) pollution, which has been linked to development and exacerbation of respiratory diseases leading to morbidity and mortality, especially in susceptible populations. Young children are especially susceptible to PM and can experience altered anatomic, physiologic, and biological responses. Current studies of ambient PM are confounded by the complex mixture of soot, metals, allergens, and organics present in the complex mixture as well as seasonal and temporal variance. We have developed a laboratory-based PM devoid of metals and allergens that can be replicated to study health effects of specific PM components in animal models. We exposed 7-day-old postnatal and adult rats to a single 6-h exposure of fuel-rich ultrafine premixed flame particles (PFPs) or filtered air. These particles are high in polycyclic aromatic hydrocarbons content. Pulmonary cytotoxicity, gene, and protein expression were evaluated at 2 and 24 h postexposure. Neonates were more susceptible to PFP, exhibiting increased lactate dehydrogenase activity in bronchoalveolar lavage fluid and ethidium homodimer-1 cellular staining in the lung in situ as an index of cytotoxicity. Basal gene expression between neonates and adults differed for a significant number of antioxidant, oxidative stress, and proliferation genes and was further altered by PFP exposure. PFP diminishes proliferation marker PCNA gene and protein expression in neonates but not adults. We conclude that neonates have an impaired ability to respond to environmental exposures that increases lung cytotoxicity and results in enhanced susceptibility to PFP, which may lead to abnormal airway growth. PMID:21914721

  10. Effect of chromium picolinate on histopathological alterations in STZ and neonatal STZ diabetic rats.

    PubMed

    Shinde, Urmila A; Goyal, R K

    2003-01-01

    Earlier studies from our laboratory have indicated insulin sensitizing action of chromium picolinate as the mechanism of its anti-diabetic activity in experimental models of type I and type II diabetes. In the present investigation, we have evaluated the effects of chronic administration of chromium picolinate on the functional and histological alterations of streptozotocin (STZ)-induced diabetes in rats. Type I diabetes was induced by intravenous injection of STZ (40 mg/kg) in adult rats, whereas, type II diabetes was induced by intraperitoneal injection of STZ (90 mg/kg) in 2-day old rat pups which in adulthood develop abnormalities resembling type II diabetes. Chromium picolinate was administered at 8 microg/ml in drinking water for 6 weeks and was found to improve glucose tolerance and increase insulin sensitivity of STZ-diabetic rats. This treatment decrease elevated serum creatinine and urea levels as well as elevated serum levels of hepatic enzymes of both groups of diabetic rats. Histopathological studies of kidney and liver show decrease in the intensity and incidence of vacuolations, cellular infiltration and hypertrophy of STZ and nSTZ (neonatal STZ) diabetic rats. Chronic treatment with chromium picolinate however, did not alter the normal function or morphology of control rats. Chronic chromium picolinate at the therapeutic doses that improved glucose tolerance, was observed to have no hepatotoxic or nephrotoxic potential. It was rather found to improve renal and hepatic function and to reduce abnormalities associated with STZ-diabetes. Chromium picolinate could play an important role in the long term management of diabetes mellitus.

  11. Ventilatory and chemoreceptor responses to hypercapnia in neonatal rats chronically exposed to moderate hyperoxia.

    PubMed

    Bavis, Ryan W; Li, Ke-Yong; DeAngelis, Kathryn J; March, Ryan J; Wallace, Josefine A; Logan, Sarah; Putnam, Robert W

    2017-03-01

    Rats reared in hyperoxia hypoventilate in normoxia and exhibit progressive blunting of the hypoxic ventilatory response, changes which are at least partially attributed to abnormal carotid body development. Since the carotid body also responds to changes in arterial CO2/pH, we tested the hypothesis that developmental hyperoxia would attenuate the hypercapnic ventilatory response (HCVR) of neonatal rats by blunting peripheral and/or central chemoreceptor responses to hypercapnic challenges. Rats were reared in 21% O2 (Control) or 60% O2 (Hyperoxia) until studied at 4, 6-7, or 13-14days of age. Hyperoxia rats had significantly reduced single-unit carotid chemoafferent responses to 15% CO2 at all ages; CO2 sensitivity recovered within 7days after return to room air. Hypercapnic responses of CO2-sensitive neurons of the caudal nucleus tractus solitarius (cNTS) were unaffected by chronic hyperoxia, but there was evidence for a small decrease in neuronal excitability. There was also evidence for augmented excitatory synaptic input to cNTS neurons within brainstem slices. Steady-state ventilatory responses to 4% and 8% CO2 were unaffected by developmental hyperoxia in all three age groups, but ventilation increased more slowly during the normocapnia-to-hypercapnia transition in 4-day-old Hyperoxia rats. We conclude that developmental hyperoxia impairs carotid body chemosensitivity to hypercapnia, and this may compromise protective ventilatory reflexes during dynamic respiratory challenges in newborn rats. Impaired carotid body function has less of an impact on the HCVR in older rats, potentially reflecting compensatory plasticity within the CNS. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Effects of caffeine or RX821002 in rats with a neonatal ventral hippocampal lesion

    PubMed Central

    Sandner, Guy; Angst, Marie-Josée; Guiberteau, Thierry; Guignard, Blandine; Nehlig, Astrid

    2014-01-01

    Rats with a neonatal ventral hippocampal lesion (NVHL) are used to model schizophrenia. They show enhanced locomotion and difficulties in learning after puberty. Such behavioral modifications are strengthened by dopaminergic psychostimulant drugs, which is also relevant for schizophrenia because illustrating its dopaminergic facet. But it remains questionable that only dopaminergic drugs elicit such effects. The behavioral effects could simply represent a non specific arousal, in which case NVHL rats should also be hyper-responsive to other vigilance enhancing drugs. We administered an adenosine (caffeine) or an adrenaline receptor antagonist, (RX821002) at doses documented to modify alertness of rats, respectively 5 mg/kg and 1 mg/kg. Rats were selected prior to the experiments using magnetic resonance imaging (MRI). Each group contained typical and similar NVHL lesions. They were compared to sham lesioned rats. We evaluated locomotion in a new environment and the capacity to remember a visual or acoustic cue that announced the occurrence of food. Both caffeine and RX82100 enhanced locomotion in the novel environment, particularly in NVHL rats. But, RX82100 had a biphasic effect on locomotion, consisting of an initial reduction preceding the enhancement. It was independent of the lesion. Caffeine did not modify the learning performance of NVHL rats. But, RX821002 was found to facilitate learning. Patients tend to intake much more caffeine than healthy people, which has been interpreted as a means to counter some cognitive deficits. This idea was not validated with the present results. But adrenergic drugs could be helpful for attenuating some of their cognitive deficits. PMID:24478661

  13. Effects of Neonatal Methamphetamine and Stress on Brain Monoamines and Corticosterone in Preweanling Rats.

    PubMed

    Jablonski, Sarah A; Graham, Devon L; Vorhees, Charles V; Williams, Michael T

    2017-02-01

    Neonatal exposure to methamphetamine (MA) and developmental chronic stress significantly alter neurodevelopmental profiles that show a variety of long-term physiological and behavioral effects. In the current experiment, Sprague-Dawley rats were exposed to one of two housing conditions along with MA. Rats were given 0 (saline), 5, or 7.5 mg/kg MA, four times per day from postnatal day (P)11 to 15 or P11 to 20. Half of the litters were reared in cages with standard bedding and half with no bedding. Separate litters were assessed at P15 or P20 for organ weights (adrenals, spleen, thymus); corticosterone; and monoamine assessments (dopamine, serotonin, norepinephrine) and their metabolites within the neostriatum, hippocampus, and prefrontal cortex. Findings show neonatal MA altered monoamines, corticosterone, and organ characteristics alone, and as a function of developmental age and stress compared with controls. These alterations may in part be responsible for MA and early life stress-induced long-term learning and memory deficits.

  14. A Mathematical Model of Neonatal Rat Atrial Monolayers with Constitutively Active Acetylcholine-Mediated K+ Current

    PubMed Central

    Majumder, Rupamanjari; Jangsangthong, Wanchana; Feola, Iolanda; Ypey, Dirk L.; Pijnappels, Daniël A.; Panfilov, Alexander V.

    2016-01-01

    Atrial fibrillation (AF) is the most frequent form of arrhythmia occurring in the industrialized world. Because of its complex nature, each identified form of AF requires specialized treatment. Thus, an in-depth understanding of the bases of these arrhythmias is essential for therapeutic development. A variety of experimental studies aimed at understanding the mechanisms of AF are performed using primary cultures of neonatal rat atrial cardiomyocytes (NRAMs). Previously, we have shown that the distinct advantage of NRAM cultures is that they allow standardized, systematic, robust re-entry induction in the presence of a constitutively-active acetylcholine-mediated K+ current (IKACh-c). Experimental studies dedicated to mechanistic explorations of AF, using these cultures, often use computer models for detailed electrophysiological investigations. However, currently, no mathematical model for NRAMs is available. Therefore, in the present study we propose the first model for the action potential (AP) of a NRAM with constitutively-active acetylcholine-mediated K+ current (IKACh-c). The descriptions of the ionic currents were based on patch-clamp data obtained from neonatal rats. Our monolayer model closely mimics the action potential duration (APD) restitution and conduction velocity (CV) restitution curves presented in our previous in vitro studies. In addition, the model reproduces the experimentally observed dynamics of spiral wave rotation, in the absence and in the presence of drug interventions, and in the presence of localized myofibroblast heterogeneities. PMID:27332890

  15. Neonatal rotenone lesions cause onset of hyperactivity during juvenile and adulthood in the rat.

    PubMed

    Ishido, Masami; Suzuki, Junko; Masuo, Yoshinori

    2017-01-15

    Attention deficit hyperactivity disorder (ADHD) is characterized by behavioral and cognitive symptoms. Longitudinal studies demonstrated that the symptoms remains clinically significant for the majority of ADHD children into adulthood. Furthermore, a population-based birth cohort provided the initial evidence of adult ADHD that lacks a history of childhood ADHD. We previously demonstrated that neonatal exposure to bisphenol A, an environmental chemical caused hyperactivity in the juvenile. Here, we extend to examine other chemical such as rotenone, a dopaminergic toxins. Oral administration of rotenone (3mg/kg) into 5-day-old male Wistar rats significantly caused hyperactivity at adulthood (8∼11 weeks old; p<0.05). It was about 1.3∼1.4-fold more active in the nocturnal phase after administration of rotenone than control rats. Higher dose (16mg/kg) or repeated lower dose of rotenone (1mg/kg/day for 4days) caused hyperactivity in the juvenile. Furthermore, DNA array analyses showed that neonatal exposure to rotenone altered the levels of gene expression of several molecules related to apoptosis/cell cycle, ATPase, skeletal molecule, and glioma. Bivariate normal distribution analysis indicates no correlation in gene expression between a hyperactivity disorder model and a Parkinson's disease model by rotenone. Thus, we demonstrate a rotenone models of ADHD whose onset varies during juvenile and adulthood. Copyright © 2016. Published by Elsevier Ireland Ltd.

  16. Effect of maternal exercise on biochemical parameters in rats submitted to neonatal hypoxia-ischemia.

    PubMed

    Marcelino, Thiago Beltram; de Lemos Rodrigues, Patrícia Idalina; Miguel, Patrícia Maidana; Netto, Carlos Alexandre; Pereira Silva, Lenir Orlandi; Matté, Cristiane

    2015-10-05

    Pregnancy is a critical period for brain metabolic programming, being affected by individual environment, such as nutrition, stress, and physical exercise. In this context, we previously reported a cerebral antioxidant upregulation and mitochondrial biogenesis in the offspring delivered from exercised mothers, which could provide neuroprotection against neonatal insults. Hypoxia-ischemia (HI) encephalopathy is one of the most studied models of neonatal brain injury; disrupting motor, cognitive, and learning abilities. Physiopathology includes oxidative stress, allied to mitochondria energy production failure, glutamatergic excitotoxicity, and cell death. In this study we evaluated the effect of maternal swimming during pregnancy on offspring׳s brain oxidative status evaluated fourteen days after HI stablishment. Swimming exercise was performed by female adult rats one week before and during pregnancy, in controlled environment. Their offspring was submitted to HI on postnatal day 7, and the brain samples for biochemical assays were obtained in the weaning. Contrary to our expectations, maternal exercise did not prevent the oxidative alterations observed in brain from HI-rats. In a general way, we found a positive modulation in the activities of antioxidant enzymes, measured two weeks after HI, in hippocampus, striatum, and cerebellum of pups delivered from exercised mothers. Reactive species levels were modulated differently in each structure evaluated. Considering the scenery presented, we concluded that HI elicited a neurometabolic adaptation in both brain hemispheres, particularly in hippocampus, parietal cortex, and cerebellum; while striatum appears to be most damaged. The protocol of aerobic maternal exercise was not enough to fully prevent HI-induced brain damages.

  17. Prostanoid receptors involved in regulation of the beating rate of neonatal rat cardiomyocytes.

    PubMed

    Mechiche, Hakima; Grassin-Delyle, Stanislas; Robinet, Arnaud; Nazeyrollas, Pierre; Devillier, Philippe

    2012-01-01

    Althoug