bluuebunny/crossref_metadata_2025 huggingface dataset:
Sedentary behavior during postnatal life is determined by the prenatal environment and exacerbated by postnatal hypercaloric nutrition
Authors: Vickers M. H. , Breier B. H. , McCarthy D. , Gluckman P. D.
Published: March 2015

The discovery of a link between in utero experience and later metabolic and cardiovascular disease is one of the most important advances in epidemiology research of recent years. There is now increasing evidence that alterations in the fetal environment have long-term consequences on metabolic and endocrine pathophysiology in adult life. This process has been termed “fetal programming,” and we have shown that undernutrition of the mother during gestation leads to obesity, hypertension, hyperphagia, hyperinsulinemia, and hyperleptinemia in offspring. Using this model of maternal undernutrition throughout pregnancy, we investigated whether prenatal influences may lead to alterations in postnatal locomotor behavior, independent of postnatal nutrition. Virgin Wistar rats were time mated and randomly assigned to receive food either ad libitum (ad libitum group) or at 30% of ad libitum intake (undernourished group). Offspring from UN mothers were significantly smaller at birth than AD offspring. At weaning, offspring were assigned to one of two diets [control or hypercaloric (30% fat)]. At ages of 35 days, 145 days, and 420 days, voluntary locomotor activity was assessed. At all ages studied, offspring from undernourished mothers were significantly less active than offspring born of normal birth weight for all parameters measured, independent of postnatal nutrition. Sedentary behavior in programmed offspring was exacerbated by postnatal hypercaloric nutrition. This work is the first to clearly separate prenatal from postnatal effects and shows that lifestyle choices themselves may have a prenatal origin. We have shown that predispositions to obesity, altered eating behavior, and sedentary activity are linked and occur independently of postnatal hypercaloric nutrition. Moreover, the prenatal influence may be permanent as offspring of undernourished mothers were still significantly less active compared with normal offspring at an advanced adult age, even in the presence of a healthy diet throughout postnatal life.
Inactivation of amino acid receptors in medullary reticular formation modulates and suppresses ingestion and rejection responses in the awake rat
Authors: Chen Zhixiong , Travers Joseph B.
Published: March 2015

The lateral medullary reticular formation (RF) is the source of many preoromotor neurons and is essential for generation of ingestive consummatory responses. Although the neurochemistry mediating these responses is poorly understood, studies of fictive mastication suggest that both excitatory and inhibitory amino acid receptors play important roles in the generation of these ororhythmic behaviors. We tested the hypothesis that amino acid receptors modulate the expression of ingestion and rejection responses elicited by natural stimuli in awake rats. Licking responses were elicited by either intraoral (IO) gustatory stimuli or sucrose presented in a bottle. Oral rejection responses (gaping) were elicited by IO delivery of quinine hydrochloride. Bilateral microinjection of the N-methyl-D-aspartate (NMDA) receptor antagonist d-[(3)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (D-CPP) suppressed licking and gape responses recorded electromyographically from a subset of orolingual muscles. Likewise, infusion of the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) significantly reduced licking and gape responses but was accompanied by spontaneous gasping responses. Rats still actively probed the bottle, indicating an intact appetitive response. Neither D-CPP nor CNQX differentially affected ingestion or rejection, suggesting that the switch from one behavior to the other does not simply rely on one glutamate receptor subtype. Nevertheless, a glutamate receptor-mediated switch from consummatory behavior to gasps after CNQX infusions suggests a multifunctional substrate for coordinating the jaw and tongue in different behaviors. Bilateral infusions of the GABAA receptor antagonist bicuculline or the glycine receptor antagonist strychnine enhanced the amplitude of IO stimulation-induced oral responses. These data suggest that the neural substrate underlying ingestive consummatory responses is under tonic inhibition. Release of this inhibition may be one mechanism by which aversive oral stimuli produce large-amplitude mouth openings associated with the rejection response.
Reloading of atrophied rat soleus muscle induces tenascin-C expression around damaged muscle fibers
Authors: Flück Martin , Chiquet Matthias , Schmutz Silvia , Mayet-Sornay Marie-Hélène , Desplanches Dominique
Published: March 2015

The hypothesis was tested that mechanical loading, induced by hindlimb suspension and subsequent reloading, affects expression of the basement membrane components tenascin-C and fibronectin in the belly portion of rat soleus muscle. One day of reloading, but not the previous 14 days of hindlimb suspension, led to ectopic accumulation of tenascin-C and an increase of fibronectin in the endomysium of a proportion (8 and 15%) of muscle fibers. Large increases of tenascin-C (40-fold) and fibronectin (7-fold) mRNA within 1 day of reloading indicates the involvement of pretranslational mechanisms in tenascin-C and fibronectin accumulation. The endomysial accumulation of tenascin-C was maintained up to 14 days of reloading and was strongly associated with centrally nucleated fibers. The observations demonstrate that an unaccustomed increase of rat soleus muscle loading causes modification of the basement membrane of damaged muscle fibers through ectopic endomysial expression of tenascin-C.
Inhibition of hibernation by exercise is not affected by intergeniculate leaflets lesion in hamsters
Authors: Menet Jérôme S. , Vuillez Patrick , Saboureau Michel , Pévet Paul
Published: March 2015

The circadian clock of mammals, located in the suprachiasmatic nuclei (SCN) of the hypothalamus, has been demonstrated to integrate day length change from long (LP) to short photoperiod (SP). This photoperiodic change induces in Syrian hamsters a testicular regression through melatonin action, a phenomenon that is inhibited when hamsters have free access to a wheel. The intergeniculate leaflets (IGL), which modulate the integration of photoperiod by the SCN, are a key structure in the circadian system, conveying nonphotic information such as those induced by novelty-induced wheel running activity. We tested in hamsters transferred from LP to a cold SP the effects of wheel running activity on a photoperiod-dependent behavior, hibernation. Lesions of the IGL were done to test the role of this structure in the inhibition induced by exercise of photoperiod integration by the clock. We show that wheel running activity actually inhibits hibernation not only in sham-operated animals, but also in hamsters with a bilateral IGL lesion (IGLX). In contrast, IGL-X hamsters without a wheel integrate slower to the SP but hibernate earlier compared with sham-operated animals. Moreover, some hibernation characteristics are affected by IGL lesion. Throughout the experiment at 7°C, IGL-X hamsters were in hypothermia during 18% of the experiment vs. 32% for sham-operated hamsters. Taken together, these data show that the IGL play a modulatory role in the integration of photoperiodic cues and modulate hibernation, but they are not implicated in the inhibition of hibernation induced by wheel running activity.
Daily CCK injection enhances reduction of body weight by chronic intracerebroventricular leptin infusion
Authors: Matson Claire A. , Reid Dana F. , Ritter Robert C.
Published: March 2015

In the present study, we tested the hypothesis that a single daily injection of the gut peptide CCK, together with continuous leptin infusion, would produce significantly greater loss of body weight than leptin alone. We found that a single daily intraperitoneal injection of CCK-8 (0.5 μg/kg) significantly enhanced the weight-reducing effects of 0.5 μg/day leptin infused continuously into the lateral ventricle of male Sprague-Dawley rats by osmotic minipump. However, CCK and leptin together did not enhance reduction of daily chow intake. Furthermore, there was no synergistic reduction of 30-min sucrose intake, although a significant main effect of both leptin and CCK was observed on sucrose intake. These results 1) confirm our previous reports of synergy between leptin and CCK on body weight, 2) demonstrate that enhancement of leptin-induced weight loss does not require bolus administration of leptin, and 3) suggest that enhanced body weight loss following leptin and CCK does not require synergistic reduction of food intake by leptin and CCK.
Antihypertensive effects of chronic anti-TGF-β antibody therapy in Dahl S rats
Authors: Dahly Annette J. , Hoagland Kimberly M. , Flasch Averia K. , Jha Sharda , Ledbetter Steven R. , Roman Richard J.
Published: March 2015

This study examined the role of transforming growth factor-β (TGF-β) in the development of hypertension and renal disease in 9-wk-old male Dahl salt-sensitive (Dahl S) rats fed an 8% NaCl diet for 3 wk. The rats received an intraperitoneal injection of a control or an anti-TGF-β antibody (anti-TGF-β Ab) every other day for 2 wk. Mean arterial pressure was significantly lower in Dahl S rats treated with anti-TGF-β Ab (177 ± 3 mmHg, n = 12) than in control rats (190 ± 4 mmHg, n = 17). Anti-TGF-β Ab therapy also reduced proteinuria from 226 ± 20 to 154 ± 16 mg/day. Renal blood flow, cortical blood flow, and creatinine clearance were not significantly different in control and treated rats; however, medullary blood flow was threefold higher in the treated rats than in the controls. Despite the reduction in proteinuria, the degree of glomerulosclerosis and renal hypertrophy was similar in control and anti-TGF-β Ab-treated rats. Renal levels of TGF-β1 and -β2, α-actin, type III collagen, and fibronectin mRNA decreased in rats treated with anti-TGF-β Ab. To examine whether an earlier intervention with anti-TGF-β Ab would confer additional renoprotection, these studies were repeated in a group of 6-wk-old Dahl S rats. Anti-TGF-β Ab therapy significantly reduced blood pressure, proteinuria, and the degree of glomerulosclerosis and renal medullary fibrosis in this group of rats. The results indicate that anti-TGF-β Ab therapy reduces blood pressure, proteinuria, and the renal injury associated with hypertension.
Control of renin synthesis
Authors: Persson Pontus B. , Skalweit Angela , Mrowka Ralf , Thiele Bernd-Joachim
Published: March 2015

Studies published recently have considerably enhanced our understanding of the mechanisms controlling renin production. With regard to the control of renin transcription, two enhancer regions have been identified that markedly augment renin synthesis in cell lines. In the absence of this enhancer activity, the basic promoter of the renin gene increases transcription only two- to threefold. The location of one (Jones CA, Sigmund CD, McGowan RA, Kane-Haas CM, and Gross KW. Mol Endocrinol 4: 375-383, 1990) transcription enhancer in the mouse gene is at about -2.7 kb and in humans at roughly -11 kb. A second important region has been identified in a chorionic cell line to be located ∼5 kb upstream of the transcription start site in humans. Another potentially important regulatory region may lie within ∼3.9 kb upstream of the -11 kb enhancer, as suggested by several conserved sequences among species in this region. In addition to the control of renin transcription, it seems that renin translation and the stability of renin mRNA are also effectively regulated. This occurs via the 3′-untranslated region, to which several proteins can bind. The binding proteins were identified as hnRNP K and E1, dynamin, nucleolin, MINT homologous protein, and Y-Box 1.
Neuropeptide FF exerts pro- and anti-opioid actions in the parabrachial nucleus to modulate food intake
Authors: Nicklous Danielle M. , Simansky Kenny J.
Published: March 2015

Neurons that synthesize the morphine modulatory peptide neuropeptide FF (NPFF; Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2) densely innervate the parabrachial nucleus (PBN), an area implicated in regulating food intake. We analyzed opioid-related actions of NPFF in feeding in adult male Sprague-Dawley rats. Unilateral infusion of 2 nmol/0.5 μl of the μ-opioid receptor agonist [d-Ala2,NMe-Phe4,glycinol5]enkephalin (DAMGO) into the lateral PBN increased 4-h food intake from 0.7 ± 0.1 to 3.3 ± 0.3 g. NPFF (1.25-5.0 nmol) prevented this hyperphagic μ-opioidergic action. In rats fed after 4-h deprivation (baseline = 12.3 ± 0.3 g/2 h), 5 nmol of NPFF did not alter and larger doses (10 and 20 nmol) actually increased food intake (+36, 54%). Twenty nanomoles also elevated intake of freely feeding rats (from 0.7 ± 0.1 to 5.1 ± 1.0 g/4 h). The opioid receptor blocker naloxone (10 nmol) antagonized this increase. These data reveal both pro- and anti-opioid actions of NPFF in the PBN to modulate feeding. The mechanisms for the opposite actions of low and high concentrations of this neuropeptide in parabrachial regulation of food intake remain to be determined.
An orexigenic role for μ-opioid receptors in the lateral parabrachial nucleus
Authors: Wilson John D. , Nicklous Danielle M. , Aloyo Vincent J. , Simansky Kenny J.
Published: March 2015

The pontine parabrachial nucleus (PBN) has been implicated in regulating ingestion and contains opioids that promote feeding elsewhere in the brain. We tested the actions of the selective μ-opioid receptor (μ-OR) agonist [d-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAMGO) in the PBN on feeding in male rats with free access to food. Infusing DAMGO (0.5-4.0 nmol/0.5 μl) into the lateral parabrachial region (LPBN) increased food intake. The hyperphagic effect was anatomically specific to infusions within the LPBN, dose and time related, and selective for ingestion of chow compared with (nonnutritive) kaolin. The nonselective opioid antagonist naloxone (0.1-10.0 nmol intra-PBN) antagonized DAMGO-induced feeding, with complete blockade by 1.0 nmol and no effect on baseline. The highly selective μ-opioid antagonist d-Phe-Cys-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP; 1.0 nmol) also prevented this action of DAMGO, but the κ-antagonist nor-binaltorphimine did not. Naloxone and CTAP (10.0 nmol) decreased intake during scheduled feeding. Thus stimulating μ-ORs in the LPBN increases feeding, whereas antagonizing these sites inhibits feeding. Together, our results implicate μ-ORs in the LPBN in the normal regulation of food intake.
Effect of (±)-epibatidine, a nicotinic agonist, on the central pathways controlling voiding function in the rat
Authors: Lee Sun-Ju , Nakamura Yasuo , de Groat William C.
Published: March 2015

Nicotinic receptors in the brain modulate the release of many transmitters that are known to regulate voiding. This prompted us to examine the central nervous system effects of a neuronal nicotinic agonist, (±)-epibatidine, on voiding function in awake and anesthetized rats. Intracerebroventricular injection of (±)-epibatidine (0.1 μg) significantly increased intercontraction interval (ICI) but did not change pressure threshold (PT) or maximal voiding pressure (MVP), whereas 1 μg of (±)-epibatidine increased PT and MVP ( P < 0.05) and decreased ICI. A low intravenous dose of (±)-epibatidine (0.001–0.1 μg) had no effect; however, a large dose of (±)-epibatidine (1 μg) significantly decreased ICI and increased MVP ( P < 0.05) but did not change PT ( P > 0.05). The effects occurred within 5–10 min after injection and persisted for 1–2 h. Intracerebroventricular chlorisondamine (10 μg), a nicotinic receptor antagonist, blocked the effect of intracerebroventricular (±)-epibatidine (0.1 μg). The experiments revealed that activation of nicotinic receptors in the brain increased bladder capacity in awake and anesthetized rats. These results suggest that the nicotinic agonist can activate mechanisms that inhibit voiding reflexes.
Influence of swim training on cardiac activity, tissue capillarization, and mitochondrial density in muscle tissue of zebrafish larvae
Authors: Pelster B. , Sänger A. M. , Siegele M. , Schwerte T.
Published: March 2015

Larval zebrafish ( Danio rerio) of two different age classes (“swim-up” larvae, 9 days old; “free-swimming” larvae, 21 days old) were exposed to either an endurance/continuous training or interval training. Control animals were kept in stagnant water. A comparison of cardiac activity of trained (either endurance or interval) and untrained animals at the end of the training regime revealed no differences in heart rate, end-diastolic and end-systolic ventricular volume, and cardiac output. Training also had no influence on the concentration of erythrocytes in the blood. Thus, at the level of total oxygen transport in the blood, training did not provoke any improvement during the first 32 days of development. Significant changes, however, were observed at the tissue level. In free-swimming larvae [i.e., between 21 and 32 days postfertilization (dpf)] endurance training increased the capillarization of both axial muscle caudal to the anus and the tail fin. In addition, mitochondrial density of red and intermediate muscle fibers increased significantly. In contrast to capillarization, even swim-up larvae, trained between 9 and 15 dpf, were affected. The observed increase in mitochondrial content indicates a high demand for oxygen and energy-rich metabolites for oxidative phosphorylation. In older larvae, this is met by the increase in capillarization that improves the blood supply and with it the required oxygen and metabolite supply of muscle tissue. Both of these adaptational changes result in a reduction of diffusion distances (between capillary and muscle fiber as well as mitochondria) and may contribute to a higher resistance toward oxygen deficiency. Furthermore, this study indicates that plasticity of muscle tissue is already established in early stages of development at both the tissue and cellular levels.
IGF-I binding in primary culture of muscle cells of rainbow trout: changes during in vitro development
Authors: Castillo Juan , Le Bail Pierre-Yves , Paboeuf Gilles , Navarro Isabel , Weil Claudine , Fauconneau Benoit , Gutiérrez Joaquim
Published: March 2015

To characterize and study the variations of IGF-I binding during the development of trout muscle cells, in vitro experiments were conducted using myocyte cultures, and IGF-I binding assays were performed in three stages of cell development: mononuclear cells ( day 1), small myotubes ( day 4), and large myotubes ( day 10). Binding experiments were done by incubating cells with IGF-I for 12 h at 4°C. Specific IGF-I binding increased with the concentration of labeled IGF-I and reached a plateau at 32 pM. The displacement of cold human and trout IGF-I showed a very similar curve (EC50= 1.19 ± 0.05 and 0.95 ± 0.05 nM, respectively). IGF binding proteins did not interfere significantly because displacement of labeled IGF-I by either cold trout recombinant IGF-I or Des (1–3) IGF-I resulted in similar curves. Insulin did not displace labeled IGF-I even at very high concentrations (>1 μM), which indicates the specificity of IGF-I binding. The amount of receptor (R0) increased from 253 ± 51 fmol/mg DNA on day 1 to 766 ± 107 fmol/mg DNA on day 10. However, the affinity ( Kd) of IGF-I receptors did not change significantly during this development (from 1.29 ± 0.19 to 0.79 ± 0.13 nM). On the basis of our results, we conclude that rainbow trout muscle cells in culture express specific IGF-I receptors, which increase their number with development from mononuclear cells to large myotubes.
Physiological significance of α2-adrenergic receptor subtype diversity: one receptor is not enough
Authors: Philipp Melanie , Brede Marc , Hein Lutz
Published: March 2015

α2-Adrenergic receptors mediate part of the diverse biological effects of the endogenous catecholamines epinephrine and norepinephrine. Three distinct subtypes of α2-adrenergic receptors, α2A, α2B, α2C, have been identified from multiple species. Because of the lack of sufficiently subtype-selective ligands, the specific biological functions of these receptor subtypes were largely unknown until recently. Gene-targeted mice carrying deletions in the genes encoding for individual α2-receptor subtypes have added important new insight into the physiological significance of adrenergic receptor diversity. Two different strategies have emerged to regulate adrenergic signal transduction. Some biological functions are controlled by two counteracting α2-receptor subtypes, e.g., α2A-receptors decrease sympathetic outflow and blood pressure, whereas the α2B-subtype increases blood pressure. Other biological functions are regulated by synergistic α2-receptor subtypes. The inhibitory presynaptic feedback loop that tightly regulates neurotransmitter release from adrenergic nerves also requires two receptor subtypes, α2A and α2C. Similarly, nociception is controlled at several levels by one of the three α2-receptor subtypes. Further investigation of the specific function of α2-subtypes will greatly enhance our understanding of the relevance of closely related receptor proteins and point out novel therapeutic strategies for subtype-selective drug development.
Modulation of guinea pig intrinsic cardiac neurons by prostaglandins
Authors: Jelson Gregory S. , DeMasi Gina M. , Sager Kristen L. , Hardwick Jean C.
Published: March 2015

Activation of cardiac mast cells has been shown to alter parasympathetic neuronal function via the activation of histamine receptors. The present study examined the ability of prostaglandins to alter the activity of guinea pig intracardiac neurons. Intracellular voltage recordings from whole mounts of the cardiac plexus showed that antigen-mediated mast cell degranulation produces an attenuation of the afterhyperpolarization (AHP), which was prevented by the phospholipase A2 inhibitor 5,8,11,14-eicosatetraynoic acid. Exogenous application of either PGD2 or PGE2 produced a biphasic change in the membrane potential and an inhibition of both AHP amplitude and duration. Examination of prostanoid receptors using bath perfusions (1 μM PGE2 and PGD2), specific agonists (BW245C, sulprostone, and butaprost), and antagonists (AH6809 and SC19220) found evidence for both the PGE2-specific EP2 and EP3 receptors, but not for EP1 or the PGD2-specific prostanoid (DP) receptors. Sulprostone was able to mimic the PGE2 responses in some cells, but not in all PGE2-sensitive cells. Butaprost was able to mimic the PG-induced hyperpolarization in some cells, but did not alter the AHP. Inhibition of specific potassium channels with either TEA, charybdotoxin, or apamin showed that neither TEA nor charybdotoxin could prevent the PGE2-induced AHP attenuation. Apamin alone inhibited AHP duration, with PGs having no further effect in these cells. These results demonstrate that guinea pig intracardiac neurons can be modulated by PG, most likely through either EP2, EP3, or potentially EP4 receptors, and this response is due, at least in part, to a reduction in small-conductance KCa currents.
Renal and blood pressure phenotype in 18-mo-old bradykinin B2R(-/-)CRD mice
Authors: Harrison-Bernard Lisa M. , Dipp Susana , El-Dahr Samir S.
Published: March 2015

Aberrant gene-environment interactions are implicated in the pathogenesis of congenital renal dysgenesis (CRD), a leading cause of renal failure in infants and children. We have recently developed an animal model of CRD that is caused by gestational salt stress (5% NaCl diet; HS) of bradykinin B2R null mice [B2R(-/-)CRD; El-Dahr SS, Harrison-Bernard LM, Dipp S, Yosipiv IV, and Meleg-Smith S. Physiol Genomics 3: 121-131, 2000.]. Developing B2R(-/-)CRD mice exhibit tubular and glomerular cysts, stromal expansion, and loss of corticomedullary differentiation. In addition, B2R(-/-)CRD mice exhibit transient hypertension from 2 to 4 mo of age. The present study was designed to determine the long-term consequences of CRD on renal morphology and salt sensitivity of blood pressure in B2R(-/-)CRD mice. One-year- and 18-mo-old B2R(-/-)CRD mice exhibited stunted renal growth, glomerular cystic abnormalities, and collecting duct ectasia. Moreover, tumors of mesenchymal cell origin emerged in the dysplastic kidneys of 90% of 1-yr-old and 100% of 18-mo-old B2R(-/-)CRD mice but not in age-matched B2R(-/-) or wild-type mice. When challenged with an HS diet, 18-mo-old B2R(-/-)CRD exhibited a significant rise in systolic and diastolic blood pressures and more pronounced natriuresis and diuresis compared with salt-loaded 18-mo-old wild-type mice. Kidney aquaporin-2 expression was decreased by 50%, whereas renin, ANG type 1 receptor, and Na+-K+-ATPase levels were not different in B2R(-/-)CRD mice compared with controls. In conclusion, this study demonstrates that B2R(-/-)CRD mice exhibit permanent phenotypic and functional abnormalities in renal growth and differentiation. This novel model of human disease links gene-environment interactions with renal development and blood pressure homeostasis.
Influence of menstrual cycle on baroreflex control of heart rate: comparison with male volunteers
Authors: Tanaka Makoto , Sato Masayoshi , Umehara Shino , Nishikawa Toshiaki
Published: March 2015

This study was designed to determine baroreflex control of heart rate (HR) to hypotensive and hypertensive stimuli during the early follicular (EF), preovulation (PreOV), and midluteal (ML) phases of the menstrual cycle and to test the hypothesis that cardiovagal reflex responses to hypertensive stimuli would be altered depending on the plasma estradiol levels in healthy women. In addition, these results were compared with those of male volunteers. Fifteen healthy women with regular menstrual cycles and thirteen male volunteers were recruited. Cardiovagal baroreflex sensitivity was defined as the slope of the linear portion relating R-R interval and systolic blood pressure triggered by bolus injections of nitroprusside and phenylephrine, from the overshoot phase of the Valsalva maneuver, and during spontaneous fluctuations. Three measurements were averaged in each test as a representative at each phase, and the order of phases was counterbalanced. Baroreflex sensitivities by the phenylephrine pressor test and Valsalva maneuver during the PreOV phase were significantly greater than those during the EF and ML phases but were similar to those of men. Depressor test sensitivities by nitroprusside and down-sequence spontaneous cardiac baroreflex sensitivity during the EF phase were significantly greater than those of the ML phase and of men. Significant correlations were observed between plasma estradiol concentrations and baroreflex sensitivities assessed by phenylephrine and the Valsalva maneuver. Our results indicate that baroreflex control of HR is altered during the regular menstrual cycle, and estradiol appears to exert cardiovagal modulation in healthy women.
Gene expression analysis in burn wounds of rats
Authors: Spies Marcus , Dasu Mohan R. K. , Svrakic Nenad , Nesic Olivera , Barrow Robert E. , Perez-Polo J. Regino , Herndon David N.
Published: March 2015

The events occurring early in the burn wound trigger a sequence of local and systemic responses that influence cell and tissue survival and, consequently, wound healing and recovery. Using high-density oligonucleotide arrays we identified gene expression patterns in skin samples taken from a region of injury in the burn rat model. The associated genomic events include the differential expression of genes involved in cell survival and death, cell growth regulation, cell metabolism, inflammation, and immune response. The functional gene cluster detected and their time appearance matched the time sequence known to occur in burn wound healing.
Does neonatal cerebrospinal fluid absorption occur via arachnoid projections or extracranial lymphatics?
Authors: Papaiconomou C. , Bozanovic-Sosic R. , Zakharov A. , Johnston M.
Published: March 2015

Arachnoid villi and granulations are thought to represent the primary sites where cerebrospinal fluid (CSF) is absorbed. However, these structures do not appear to exist in the fetus but begin to develop around the time of birth and increase in number with age. With the use of a constant pressure-perfusion system in 2- to 6-day-old lambs, we observed that global CSF transport (0.012 ± 0.003 ml · min−1 · cmH2O−1) and CSF outflow resistance (96.5 ± 17.8 cmH2O · ml−1 · min) were very similar to comparable measures in adult animals despite the relative paucity of arachnoid villi at this stage of development. In the neonate, the recovery patterns of a radioactive protein CSF tracer in various lymph nodes and tissues indicated that CSF transport occurred through multiple lymphatic pathways. An especially important route was transport through the cribriform plate into extracranial lymphatics located in the nasal submucosa. To investigate the importance of the cribriform route in cranial CSF clearance, the cranial CSF compartment was isolated surgically from its spinal counterpart. When the cribriform plate was sealed extracranially under these conditions, CSF transport was impaired significantly. These data demonstrate an essential function for lymphatics in neonatal CSF transport and imply that arachnoid projections may play a limited role earlier in development.
Insulin-like growth factor I prevents corticosteroid-induced diaphragm muscle atrophy in emphysematous hamsters
Authors: Fournier Mario , Huang Zhi-Shen , Li Hongyan , Da Xiaoyu , Cercek Bojan , Lewis Michael I.
Published: March 2015

The aim of this study was to evaluate whether recombinant human insulin-like growth factor I (rhIGF-I) could attenuate or prevent diaphragm (DIA) fiber atrophy with corticosteroid (CS) administration to emphysematous (EMP) hamsters. DIA muscle IGF-I responses to CS administration with and without exogenous rhIGF-I administration were evaluated. Three groups were studied: 1) EMP; 2) EMP + triamcinolone (T; 0.4 mg·kg-1·day-1 im); and 3) EMP + T + IGF-I (600 μg/day by constant infusion). After 4 wk, the DIA was analyzed histochemically and biochemically (IGF-I mRNA levels by RT-PCR and endogenous and exogenous IGF-I peptide levels immunochemically). Body weights of EMP-T progressively decreased, while those of EMP and EMP-T-IGF-I remained stable despite similarly reduced food intake in both T groups. DIA weight was reduced with T but preserved with rhIGF-I infusion. DIA fiber proportions were similar among the groups. The cross-sectional areas of types I, IIa, and IIx fibers were reduced (17 to 31%) with T administration but unchanged with rhIGF-I infusion. DIA IGF-I mRNA levels were similar across all groups. By contrast, the endogenous DIA IGF-I levels were reduced (41%) in the EMP-T-IGF-I animals. Total DIA IGF-I levels (endogenous + exogenous) were still significantly reduced. IGF-I immunoreactivity confirmed this reduction in all DIA fibers. We conclude that DIA fiber atrophy with T was completely prevented by exogenous rhIGF-I administration. This effect was likely mediated by the pharmacological influences of exogenously administered rhIGF-I. We speculate that this results from increased bioavailability of free IGF-I to react with muscle receptors. Reduced endogenous IGF-I levels in the DIA likely reflect a negative-feedback influence. These results may have important clinical implications for treatment options to offset the adverse effects of CS on the respiratory muscles in patients with chronic lung disorders.
Acute intrarenal infusion of ANG II does not stimulate immediate early gene expression in the kidney
Authors: Edgley Amanda J. , Nichols Nancy R. , Anderson Warwick P.
Published: March 2015

ANG II is capable of stimulating expression of immediate early genes such as egr-1 and c- fos in a variety of cultured cells, including cells of renal origin. To investigate whether ANG II can stimulate early growth response gene expression in vivo, we studied the effects of acute renal artery infusion of low-dose ANG II (2.5 ng · kg−1· min−1) or vehicle on the renal expression of c- fos and egr-1 genes in rats. ANG II infusion for 30 or 240 min decreased renal vascular conductance by ∼13 and 8%, respectively, compared with the vehicle group. Expression of the early growth response genes c-fosand egr-1 was analyzed using Northern blot hybridization. No significant upregulation of c- fos or egr-1 mRNA levels was detected in rats that received ANG II for either 30 or 240 min, compared with the vehicle groups. We conclude that ANG II, at doses that cause significant physiological effects, does not increase the renal expression of c- fos or egr-1 genes over periods of up to 4 h in vivo.
Adaptation to high-fat diet accelerates emptying of fat but not carbohydrate test meals in humans
Authors: Castiglione K. E. , Read N. W. , French S. J.
Published: March 2015

Previous work has shown that the gastric emptying rate in animals and humans can adapt due to previous dietary intake. The present study investigated whether adaptation in gastric emptying rate due to consumption of a high-fat diet (HFD) is nutrient specific in humans. Gastric emptying of high-fat and high-carbohydrate test meals was measured (using gamma scintigraphy) before and after consumption of an HFD for 14 days in eight free-living male volunteers. Visual analog ratings of appetite were recorded throughout each test. There was no effect of HFD on any parameters of gastric emptying rate (lag phase, half-emptying time, and linear emptying rate) measured for carbohydrate test meals. HFD led to an acceleration of the linear emptying rate of the high-fat test meal (0.36 vs. 0.47%/min; P < 0.05). All meals reduced appetite ratings, but there were no differences between tests. These results support our previous findings of accelerated gastric emptying of high-fat test meals following an HFD and show that these changes appear to be nutrient specific, confirming recent studies in rats.
Adrenomedullin influences magnocellular and parvocellular neurons of paraventricular nucleus via separate mechanisms
Authors: Follwell Matthew J. , Ferguson Alastair V.
Published: March 2015

We previously reported that adrenomedullin (AM) decreases blood pressure following microinjection into the paraventricular nucleus of the hypothalamus (PVN) of the rat. With the use of whole cell recordings in rat hypothalamic slice preparations, we characterized the effects of AM on electrophysiologically identified PVN neurons and described the membrane events underlying such actions.

AM hyperpolarized magnocellular (type I) neurons in a dose-dependent manner, a response associated with an increase in the frequency and amplitude of inhibitory postsynaptic potentials. Blockade of action potentials with tetrodotoxin (TTX) abolished AM effects on membrane potential and synaptic activity in magnocellular neurons, suggesting direct actions on inhibitory interneurons. Furthermore, blockade of inhibitory synaptic transmission with the GABAA receptor antagonist bicuculline methiodide also abolished AM effects on membrane potential in magnocellular neurons. In contrast, parvocellular (type II) neurons depolarized following AM receptor activation. AM effects on parvocellular neurons were dose dependent and were maintained in the presence of TTX, indicating direct effects on this population of neurons. Voltage-clamp recordings from parvocellular neurons showed AM enhances a nonselective cationic conductance, suggesting a potential mechanism through which AM influences membrane potential.

These observations show clear population-specific actions of AM on separate identified groups of PVN neurons. Such effects on magnocellular neurons likely contribute to the hypotensive actions of this peptide in PVN. Although the effects on parvocellular neurons may also contribute to such cardiovascular effects of AM, it is more likely that actions on this population of PVN neurons underlie the previously demonstrated activational effects of AM on the hypothalamic-pituitary-adrenal axis.
Ca2+ uptake and cellular integrity in rat EDL muscle exposed to electrostimulation, electroporation, or A23187
Authors: Gissel Hanne , Clausen Torben
Published: March 2015

We tested the hypothesis that increased Ca2+ uptake in rat extensor digitorum longus (EDL) muscle elicits cell membrane damage as assessed from release of the intracellular enzyme lactate dehydrogenase (LDH). This was done by using 1) electrostimulation, 2) electroporation, and 3) the Ca2+ ionophore A23187. Stimulation at 1 Hz for 120–240 min caused an increase in 45Ca uptake that was closely correlated to LDH release. This LDH release increased markedly with temperature. After 120 min of stimulation at 1 Hz, resting 45Ca uptake was increased 5.6-fold compared with unstimulated muscles. This was associated with an eightfold increase in LDH release, and this effect was halved by lowering extracellular Ca2+ concentration ([Ca2+]o). The poststimulatory increase in resting 45Ca uptake persisted for at least 120 min. An acute increase in sarcolemma leakiness induced by electroporation markedly increased 45Ca uptake and LDH leakage. Both effects depended on [Ca2+]o. A23187 increased 45Ca uptake. Concomitantly, LDH leakage increased 18-fold within 30 min, and this effect was abolished by omitting Ca2+ from the buffer. We conclude that increased Ca2+ influx may be an important cause of cell membrane damage that arises during and after exercise or electrical shocks. Because membrane damage allows further influx of Ca2+, this results in positive feedback that may further increase membrane degeneration.
μ-Opioid receptor agonist effects on medullary respiratory neurons in the cat: evidence for involvement in certain types of ventilatory disturbances
Authors: Lalley Peter M.
Published: March 2015

μ-Opioid receptor agonists depress tidal volume, decrease chest wall compliance, and increase upper airway resistance. In this study, potential neuronal sites and mechanisms responsible for the disturbances were investigated, dose-response relationships were established, and it was determined whether general anesthesia plays a role. Effects of μ-opioid agonists on membrane properties and discharges of respiratory bulbospinal, vagal, and propriobulbar neurons and phrenic nerve activity were measured in pentobarbital-anesthetized and unanesthetized decerebrate cats. In all types of respiratory neurons tested, threshold intravenous doses of the μ-opioid agonist fentanyl slowed discharge frequency and prolonged duration without altering peak discharge intensity. Larger doses postsynaptically depressed discharges of inspiratory bulbospinal and inspiratory propriobulbar neurons that might account for depression of tidal volume. Iontophoresis of the μ-opioid agonist DAMGO also depressed the intensity of inspiratory bulbospinal neuron discharges. Fentanyl given intravenously prolonged discharges leading to tonic firing of bulbospinal expiratory neurons in association with reduced hyperpolarizing synaptic drive potentials, perhaps explaining decreased inspiratory phase chest wall compliance. Lowest effective doses of fentanyl had similar effects on vagal postinspiratory (laryngeal adductor) motoneurons, whereas in vagal laryngeal abductor and pharyngeal constrictor motoneurons, depression of depolarizing synaptic drive potentials led to sparse, very-low-frequency discharges. Such effects on three types of vagal motoneurons might explain tonic vocal fold closure and pharyngeal obstruction of airflow. Measurements of membrane potential and input resistance suggest the effects on bulbospinal Aug-E neurons and vagal motoneurons are mediated presynaptically. Opioid effects on the respiratory neurons were similar in anesthetized and decerebrate preparations.
Relationship between alertness, performance, and body temperature in humans
Authors: Wright Kenneth P. , Hull Joseph T. , Czeisler Charles A.
Published: March 2015

Body temperature has been reported to influence human performance. Performance is reported to be better when body temperature is high/near its circadian peak and worse when body temperature is low/near its circadian minimum. We assessed whether this relationship between performance and body temperature reflects the regulation of both the internal biological timekeeping system and/or the influence of body temperature on performance independent of circadian phase. Fourteen subjects participated in a forced desynchrony protocol allowing assessment of the relationship between body temperature and performance while controlling for circadian phase and hours awake. Most neurobehavioral measures varied as a function of internal biological time and duration of wakefulness. A number of performance measures were better when body temperature was elevated, including working memory, subjective alertness, visual attention, and the slowest 10% of reaction times. These findings demonstrate that an increased body temperature, associated with and independent of internal biological time, is correlated with improved performance and alertness. These results support the hypothesis that body temperature modulates neurobehavioral function in humans.
Photoperiod modulates the effects of norepinephrine on lymphocyte proliferation in Siberian hamsters
Authors: Demas Gregory E. , Bartness Timothy J. , Nelson Randy J. , Drazen Deborah L.
Published: March 2015

Siberian hamsters ( Phodopus sungorus) rely on photoperiod to coordinate seasonally appropriate changes in physiology, including immune function. Immunity is regulated, in part, by the sympathetic nervous system (SNS), although the precise role of the SNS in regulating photoperiodic changes in immunity remains unspecified. The goal of the present study was to examine the contributions of norepinephrine (NE), the predominant neurotransmitter of the SNS, to photoperiodic changes in lymphocyte proliferation. In experiment 1, animals were maintained in long [16:8-h light-dark cycle (16:8 LD)] or short days (8:16 LD) for 10 wk, and splenic NE content was determined. In experiment 2, in vitro splenocyte proliferation in response to mitogenic stimulation (concanavalin A) was assessed in spleen cell suspensions taken from long- or short-day hamsters in which varying concentrations of NE were added to the cultures. In experiment 3, splenocyte proliferation was examined in the presence of NE and selective α- and β-noradrenergic receptor antagonists (phenoxybenzamine and propranolol, respectively) in vitro. Short-day animals had increased splenic NE content compared with long-day animals. Long-day animals had higher proliferation compared with short-day animals independent of NE. NE (1 μM) further suppressed splenocyte proliferation in short but not long days. Last, NE-induced suppression of proliferation in short-day hamsters was blocked by propranolol but not phenoxybenzamine. The present results suggest that NE plays a role in photoperiodic changes in lymphocyte proliferation. Additionally, the data suggest that the effects of NE on proliferation are specific to activation of β-adrenergic receptors located on splenic tissue. Collectively, these results provide further support that photoperiodic changes in immunity are influenced by changes in SNS activity.
Circadian clock resetting by arousal in Syrian hamsters: the role of stress and activity
Authors: Mistlberger R. E. , Antle M. C. , Webb I. C. , Jones M. , Weinberg J. , Pollock M. S.
Published: March 2015

Circadian rhythms in the Syrian hamster can be markedly phase shifted by 3 h of wheel running or arousal stimulation during their usual daily rest period (“subjective day”). Continuous wheel running is predictive but not necessary for phase shifts of this “nonphotic” type; hamsters aroused by gentle handling without running can also show maximal shifts. By contrast, physical restraint, a standard stress procedure and thus presumably arousing, is ineffective. To resolve this apparent paradox, phase-shifting effects of 3-h sessions of restraint or other stress procedures were assessed. In a preliminary study, phase shifts to arousal by gentle handling were significantly potentiated by the cortisol synthesis inhibitor metyrapone, suggesting that stress-related cortisol release may inhibit phase shifts to arousal. Next, it was confirmed that restraint in the subjective day does not induce phase shifts, but behavioral observations revealed that it also does not sustain arousal. Restraint combined with noxious compressed air blasts did sustain arousal and induced a significant cortisol response compared with arousal by gentle handling but did not induce shifts. Restraint combined with continuous horizontal rotation was also ineffective, as was EEG-validated arousal via confinement to a pedestal over water. However, 3 h of resident-intruder interactions (an intense psychosocial stress) or exposure to an open field (a mild stress) did induce large shifts that were positively correlated with indexes of forward locomotion. The results indicate that large phase shifts associated with arousal in the usual sleep period are neither induced nor prevented by stress per se, but are dependent on the expression of at least low levels of locomotor activity. Sustained arousal alone is not sufficient.
A nonlinear compartmental model of Sr metabolism. I. Non-steady-state kinetics and model building
Authors: Staub J. F. , Foos E. , Courtin B. , Jochemsen R. , Perault-Staub A. M.
Published: March 2015

A model of Sr metabolism was developed by using plasma and urinary Sr kinetic data obtained in groups of postmenopausal women who received four different oral doses of Sr and collected during the Sr administration period (25 days) and for 28 days after cessation of treatment. A nonlinear compartmental formalism that is appropriate for study of non-steady-state kinetics and allows dissociation of variables pertaining to Sr metabolism ( system 1) from those indirectly operating on it ( system 2) was used. At each stage of model development, the dose-dependent model response was fitted to the four sets of data considered simultaneously (1 set per dose). A seven-compartment model with internal Sr distribution and intestinal, urinary, and bone metabolic pathways was selected. It includes two kinds of nonlinearities: those accounting for saturable intestinal and bone processes, which behave as intrinsic nonlinearities because they are directly dependent on Sr, and extrinsic nonlinearities (dependent on system 2), which suggest the cooperative involvement of plasma Sr changes in modulating some intestinal and bone mineral metabolic pathways. With the set of identified parameter values, the initial steady-state model predictions are relevant to known physiology, and some peculiarities of model behavior for long-term Sr administration were simulated.