bluuebunny/crossref_metadata_2025 huggingface dataset:
Counteractive effects of HGF on PDGF-induced mesangial cell proliferation in a rat model of glomerulonephritis
Authors: Bessho Kazuhiko , Mizuno Shinya , Matsumoto Kunio , Nakamura Toshikazu
Published: March 2015

Activation and proliferation of glomerular mesangial cells play an important role in the development of mesangioproliferative glomerulonephritis. We investigated the role of hepatocyte growth factor (HGF) in regulating activated mesangial cell proliferation. In glomeruli of normal rats, mesangial cells barely expressed the c-Met/HGF receptor. However, when mesangioproliferative glomerulonephritis was induced in rats by the administration of an anti-Thy 1.1 antibody, glomerular HGF expression transiently decreased along with mesangiolysis, and activation of mesangial cells was associated with upregulation of the c-Met receptor. Activated mesangial cells in culture also expressed the c-Met/HGF receptor. Although addition of HGF to cultured mesangial cells did not increase DNA synthesis, HGF did diminish PDGF-induced DNA synthesis. PDGF induced activation of ERK, which continued for at least 48 h. When PDGF and HGF were simultaneously added, HGF inhibited the prolonged activation of ERK, which suggests that early inactivation of PDGF-induced ERK may be involved in the inhibitory effect of HGF on mesangial cell proliferation. Furthermore, administration of HGF to rats with anti-Thy 1.1 nephritis resulted in a selective suppression of activated mesangial cell proliferation, and this suppressive effect was associated with attenuation of phosphorylated glomerular ERK. These results indicate that HGF counteracts PDGF-induced mesangial cell proliferation and functions as a negative regulator of activated mesangial cell proliferation.
Renal segmental microvascular responses to ANG II in AT1Areceptor null mice
Authors: Harrison-Bernard Lisa M. , Cook Anthony K. , Oliverio Michael I. , Coffman Thomas M.
Published: March 2015

The relative contributions of AT1Aand AT1Breceptors to afferent arteriolar autoregulatory capability and afferent and efferent arteriolar responses to ANG II are not known. Experiments were conducted in kidneys from wild-type (WT) and AT1A−/− mice utilizing the in vitro blood-perfused juxtamedullary nephron technique. Direct measurements of afferent (AAD) and efferent arteriolar diameters (EAD) were assessed at a renal arterial pressure of 100 mmHg. AAD averaged 14.8 ± 0.8 μm for WT and 14.9 ± 0.8 μm for AT1A−/− mice. AAD significantly decreased by 7 ± 1, 16 ± 1, and 26 ± 2% for WT mice and by 11 ± 1, 20 ± 2, and 30 ± 3% for AT1A−/− mice (120, 140, 160 mmHg). AAD autoregulatory capability was not affected by the absence of AT1Areceptors. AAD responses to 10 nM ANG II were significantly blunted for AT1A−/− mice compared with WT (−22 ± 2 vs. −37 ± 5%). ANG II (0.1–10 nM) failed to elicit any change in EAD for AT1A−/− mice. AAD and EAD reductions in ANG II were blocked by 1 μM candesartan. We conclude that afferent arteriole vasoconstrictor responses to ANG II are mediated by AT1Aand AT1Breceptors, whereas efferent arteriolar vasoconstrictor responses to ANG II are mediated by only AT1Areceptors in the mouse kidney.
Amino acids induce indicators of response to injury in glomerular mesangial cells
Authors: Meek Rick L. , Cooney Sheryl K. , Flynn Stephanie D. , Chouinard Robert F. , Poczatek Maria H. , Murphy-Ullrich Joanne E. , Tuttle Katherine R.
Published: March 2015

High-protein diets exacerbate glomerular hyperfiltration and the progression of diabetic nephropathy. The purpose of this study was to determine whether amino acids also produce nonhemodynamic injury in the glomerulus. When rat mesangial cells were cultured with an amino acid mixture designed to replicate the composition in plasma after protein feeding, production of mRNA (Northern blot analysis) and/or protein (ELISA or Western blot analysis) for transforming growth factor-β1(TGF-β1), fibronectin, thrombospondin-1 (TSP-1), and collagen IV were enhanced in a manner comparable to a culture with high glucose (30.5 mM). The bioactive portion of total TGF-β (NRK assay) increased in response to amino acids. The TSP-1 antagonist LSKL peptide reduced bioactive TGF-β and fibronectin, indicating the dependence of TGF-β1activation on TSP-1. DNA synthesis ([3H]thymidine incorporation), an index of cellular proliferation, increased in response to amino acids and was further enhanced by culture with increased levels of both amino acids and glucose. TGF-β1and matrix proteins increased when mesangial cells were cultured with excess l-arginine (2.08 mM) alone. Although l-arginine is the precursor of nitric oxide (NO), such responses to amino acids do not appear to be mediated through increased NO production. NO metabolites decreased in the media, and these responses to mixed amino acids or l-arginine were not prevented by NO synthase inhibition. In conclusion, amino acids induce indicators of response to injury in mesangial cells, even when hemodynamic stress is absent. In conditions associated with increased circulating amino acids, such as diabetes and/or a high-protein diet, direct cellular effects could contribute to glomerular injury.
Estradiol upregulates mesangial cell MMP-2 activity via the transcription factor AP-2
Authors: Guccione Michael , Silbiger Sharon , Lei Jun , Neugarten Joel
Published: March 2015

The accumulation of extracellular matrix in the glomerular mesangium reflects the net balance between the synthesis and degradation of matrix components. We have shown that estradiol suppresses the synthesis of types I and IV collagen by cultured mesangial cells (Kwan G, Neugarten J, Sherman M, Ding Q, Fotadar U, Lei J, and Silbiger S. Kidney Int 50: 1173–1179, 1996; Neugarten J, Acharya A, Lei J, and Silbiger S. Am J Physiol Renal Physiol 279: F309–F318, 2000; Neugarten J, Medve I, Lei J, and Silbiger SR. Am J Physiol Renal Physiol 277: F1–F8, 1999; Neugarten J and Silbiger S. Am J Kidney Dis 26: 147–151, 1995; Silbiger S, Lei J, and Neugarten J. Kidney Int 55: 1268–1276, 1998; Silbiger S, Lei J, Ziyadeh FN, and Neugarten J. Am J Physiol Renal Physiol 274: F1113–F1118, 1998). In the present study, we evaluated the effects of sex hormones on the activity of matrix metalloproteinase-2 (MMP-2) in murine mesangial cells, the synthesis of which is regulated by the transcription factor activator protein-2 (AP-2). Estradiol stimulated MMP-2 activity by increasing MMP-2 protein levels in a dose-dependent manner. These effects occurred at physiological concentrations of estradiol and were receptor mediated. Estradiol also increased AP-2 protein levels and increased binding of mesangial cell nuclear extracts to an AP-2 consensus binding sequence oligonucleotide. The ability of estradiol to increase AP-2 protein expression, AP-2/DNA binding activity, MMP-2 protein expression, and metalloproteinase activity was reversed by PD-98059, a selective inhibitor of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling cascade. We conclude that estradiol upregulates the MAPK cascade, which in turn stimulates the synthesis of AP-2 protein. The resultant increased AP-2/DNA binding activity leads to increased synthesis of MMP-2 and increased metalloproteinase activity. Stimulation of metalloproteinase activity by estradiol may contribute to the protective effect of female gender on renal disease progression.
Effects of hypothyroidism on maximum specific force in rat diaphragm muscle fibers
Authors: Geiger Paige C. , Cody Mark J. , Han Young Soo , Hunter Larry W. , Zhan Wen-Zhi , Sieck Gary C.
Published: March 2015

We hypothesized that 1) hypothyroidism (Hyp) decreases myosin heavy chain (MHC) content per half-sarcomere in diaphragm muscle (Diam) fibers, 2) Hyp decreases the maximum specific force (Fmax) of Diamfibers because of the reduction in MHC content per half-sarcomere, and 3) Hyp affects MHC content per half-sarcomere and Fmaxto a greater extent in fibers expressing MHC type 2X (MHC2X) and/or MHC type 2B (MHC2B). Studies were performed on single Triton X-permeabilized fibers activated at pCa 4.0. MHC content per half-sarcomere was determined by densitometric analysis of SDS-polyacrylamide gels and comparison with a standard curve of known MHC concentrations. After 3 wk of Hyp, MHC content per half-sarcomere was reduced in fibers expressing MHC2Xand/or MHC2B. On the basis of electron-microscopic analysis, this reduction in MHC content was also reflected by a decrease in myofibrillar volume density and thick filament density. Hyp decreased Fmaxacross all MHC isoforms; however, the greatest decrease occurred in fibers expressing fast MHC isoforms (∼40 vs. ∼20% for fibers expressing slow MHC isoforms). When normalized for MHC content per half-sarcomere, force generated by Hyp fibers expressing MHC2Awas reduced compared with control fibers, whereas force per half-sarcomere MHC content was higher for fibers expressing MHC2Xand/or MHC2Bin the Hyp Diamthan for controls. These results indicate that the effect of Hyp is more pronounced on fibers expressing MHC2Xand/or MHC2Band that the reduction of Fmaxwith Hyp may be at least partially attributed to a decrease in MHC content per half-sarcomere but not to changes in force per cross bridge.
O2affinity of cross-linked hemoglobins modifies O2metabolism in proximal tubules
Authors: Baines A. D. , Ho P.
Published: March 2015

Previous experiments using cross-linked tetrameric hemoglobins (XLHb) to perfuse isolated rat kidneys showed that high-O2-affinity XLHb improved proximal tubule function more effectively than low-O2-affinity XLHb. To determine how function was improved, proximal tubule fragments were incubated with albumin, Hb34[half-saturation point (P50) 34 Torr], or Hb13(P5013 Torr) with Po2values ranging from 22 to 147 Torr. ATP content reflected O2delivery to mitochondria. Both XLHb increased ATP, Hb34with Po2≥ 47 Torr and Hb13with Po2≤ 47 Torr. XLHb increased Na-K-ATPase activity (86Rb uptake) in similar Po2-dependent patterns. O2consumption (Q̇o2) was measured in a closed, well-stirred chamber. Ouabain- and oligomycin-inhibited Q̇o2, reflecting Na-K-ATPase activity and oxidative phosphorylation, respectively, mirrored the Po2-dependent patterns of ATP and86Rb uptake. As Po2fell below the midpoint of XLHb desaturation, Q̇o2, uncoupled from oxidative phosphorylation, transiently increased. The increase was most pronounced with Hb34. Nitro-l-arginine methyl ester had no effect on Q̇o2. Inhibitors of NAD(P)H oxidases and diamine oxidase partially prevented the Q̇o2surge with Hb34. In conclusion, facilitated diffusion accounts for Po2-dependent XLHb effects on ATP content and Na-K-ATPase and for Hb13's effectiveness in hypoxic perfused kidneys. NO scavenging was not a factor. O2-binding characteristics influence XLHb effects on mitochondria and O2-sensitive enzymes such as oxidases.
α,β-Methylene ATP elicits a reflex pressor response arising from muscle in decerebrate cats
Authors: Hanna Ramy L. , Hayes Shawn G. , Kaufman Marc P.
Published: March 2015

In part, the exercise pressor reflex is believed to be evoked by chemical stimuli signaling that blood supply to exercising muscles is not adequate to meet its metabolic demands. There is evidence that either ATP or adenosine may function as one of these chemical stimuli. For example, muscle interstitial concentrations of both substances have been found to increase during exercise. This finding led us to test the hypothesis that popliteal arterial injection of α,β-methylene ATP (5, 20, and 50 μg/kg), which stimulates P2X receptors, and 2-chloroadenosine (25 μg/kg), which stimulates P1 receptors, evokes reflex pressor responses in decerebrate, unanesthetized cats. We found that popliteal arterial injection of the two highest doses of α,β-methylene ATP evoked pressor responses, whereas popliteal arterial injection of 2-chloroadenosine did not. In addition, the pressor responses evoked by α,β-methylene ATP were blocked either by section of the sciatic nerve or by prior popliteal arterial injection of pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (10 mg/kg), a selective P2-receptor antagonist. We conclude that the stimulation of P2 receptors, which are accessible through the vascular supply of skeletal muscle, evokes reflex pressor responses. In addition, our findings are consistent with the hypothesis that the stimulation of P2 receptors comprises part of the metabolic error signal evoking the exercise pressor reflex.
Does nitric oxide buffer arterial blood pressure variability in humans?
Authors: Cooke William H. , Zhang Rong , Zuckerman Julie H. , Cui Jian , Wilson Thad E. , Crandall Craig G. , Levine Benjamin D.
Published: March 2015

Animal studies suggest that nitric oxide (NO) plays an important role in buffering short-term arterial pressure variability, but data from humans addressing this hypothesis are scarce. We evaluated the effects of NO synthase (NOS) inhibition on arterial blood pressure (BP) variability in eight healthy subjects in the supine position and during 60° head-up tilt (HUT). Systemic NOS was blocked by intravenous infusion of N G-monomethyl-l-arginine (l-NMMA). Electrocardiogram and beat-by-beat BP in the finger (Finapres) were recorded continuously for 6 min, and brachial cuff BP was recorded before and after l-NMMA in each body position. BP and R-R variability and their transfer functions were quantified by power spectral analysis in the low-frequency (LF; 0.05–0.15 Hz) and high-frequency (HF; 0.15–0.35 Hz) ranges.l-NMMA infusion increased supine BP (systolic, 109 ± 4 vs. 122 ± 3 mmHg, P = 0.03; diastolic, 68 ± 2 vs. 78 ± 3 mmHg, P = 0.002), but it did not affect supine R-R interval or BP variability. Beforel-NMMA, HUT decreased HF R-R variability ( P= 0.03), decreased transfer function gain (LF, 12 ± 2 vs. 5 ± 1 ms/mmHg, P = 0.007; HF, 18 ± 3 vs. 3 ± 1 ms/mmHg, P = 0.002), and increased LF BP variability ( P < 0.0001). After l-NMMA, HUT resulted in similar changes in BP and R-R variability compared with tilt without l-NMMA. Increased supine BP afterl-NMMA with no effect on BP variability during HUT suggests that tonic release of NO is important for systemic vascular tone and thus steady-state arterial pressure, but NO does not buffer dynamic BP oscillations in humans.
Effects of hypergravity on mammary metabolic function: gravity acts as a continuum
Authors: Plaut K. , Maple R. L. , Wade C. E. , Baer L. A. , Ronca A. E.
Published: March 2015

Mammary metabolic activity in pregnant rats is significantly increased in response to spaceflight. To determine whether changes in mammary metabolism are related to gravity load, we exposed pregnant rats to hypergravity and measured mammary metabolic activity. From days 11–20 of gestation (G), animals were centrifuged (20 rpm; 1.5, 1.75, or 2.0× gravity) or were maintained at 1 G. On G20, five rats from each group were removed from the centrifuge and euthanized. The remaining dams ( n = 5/treatment) were housed at 1 G until parturition. After 2 h of nursing by the pups, the postpartum dams were euthanized (G22). Glucose oxidation to CO2and incorporation into lipids was measured. Mammary glands from dams euthanized on G20 revealed a strong negative correlation between metabolic rate and increased G load. Approximately 98% of the variation in glucose oxidation and 94% of the variation in glucose incorporation into lipids can be accounted for by differences in G load. Differences in metabolic activity disappeared in the postpartum dams. When we combined previous data from the microgravity with hypergravity environments and plotted the ratio of mammary metabolic rate vs. G load, there was a significant exponential relationship ( r2= 0.99). These data demonstrate a remarkable continuum of response across the microgravity and hypergravity environments and support the concept that gravitational load influences mammary tissue metabolism.
Reducing lung strain after pneumonectomy impairs oxygen diffusing capacity but not ventilation-perfusion matching
Authors: Hsia Connie C. W. , Johnson Robert L. , Wu Eugene Y. , Estrera Aaron S. , Wagner Harrieth , Wagner Peter D.
Published: March 2015

After pneumonectomy (Pnx), mechanical strain on the remaining lung is an important signal for adaptation. To examine how mechanical lung strain alters gas exchange adaptation after Pnx, we replaced the right lung of adult dogs with a custom-shaped inflatable silicone prosthesis. The prosthesis was kept 1) inflated (Inf) to reduce mechanical strain of the remaining lung and maintain the mediastinum in the midline, or 2) deflated (Def) to allow lung strain and mediastinal shift. Gas exchange was studied 4-7 mo later at rest and during treadmill exercise by the multiple inert gas elimination technique while animals breathed 21 and 14% O2in balanced order. In the Inf group compared with Def group during hypoxic exercise, arterial O2saturation was lower and alveolar-arterial O2tension difference higher, whereas O2diffusing capacity was lower at any given cardiac output. Dispersion of the perfusion distribution was similar between groups at rest and during exercise. Dispersion of the ventilation distribution was lower in the Inf group at rest, associated with a much higher respiratory rate, but rose to similar levels in both groups during hypoxic exercise. Mean pulmonary arterial pressure at a given cardiac output was higher in the Inf group, whereas peak cardiac output was similar between groups. Thus creating lung strain by post-Pnx mediastinal shift primarily enhances diffusive gas exchange with only minor effects on ventilation-perfusion matching, consistent with the generation of additional alveolar-capillary surfaces but not conducting airways and blood vessels.
Dynamic interaction between the tongue and soft palate during obstructive apnea in anesthetized patients with sleep-disordered breathing
Authors: Isono Shiroh , Tanaka Atsuko , Nishino Takashi
Published: March 2015

Little is known about the mechanisms of persistence of obstructive apnea. Structurally, the dorsum of the tongue locates anterior to the soft palate. On the basis of the observation of posterior displacement of the tongue during obstructive apnea, we hypothesized that the dorsum of the tongue pushes the anterior wall of the soft palate posteriorly during inspiratory efforts, maintaining closure at the retropalatal airway. To test this hypothesis, we measured the pressure between dorsum of the tongue and anterior wall of the soft palate (PT&P) during experimentally induced obstructive apneas in anesthetized patients with sleep-disordered breathing. PT&P changes during the obstruction significantly depended on collapsibility of the retroglossal airway. Progressive increase in the PT&P during obstructive apnea was observed only in patients with highly collapsible retroglossal airways. Significant increase in the PT&P during inspiratory effort in accordance with positive deflection pattern of PT&P tracing was evident in the patients with highly collapsible retroglossal airways. The results indicate significant dynamic interaction between the tongue and soft palate during both obstructive apnea and each inspiratory effort, possibly maintaining closure at the retropalatal airway.
Dynamics of intramuscular31P-MRS Pipeak splitting and the slow components of PCr and O2uptake during exercise
Authors: Rossiter H. B. , Ward S. A. , Howe F. A. , Kowalchuk J. M. , Griffiths J. R. , Whipp B. J.
Published: March 2015

The dynamics of pulmonary O2uptake (V˙o2) during the on-transient of high-intensity exercise depart from monoexponentiality as a result of a “slow component” whose mechanisms remain conjectural. Progressive recruitment of glycolytic muscle fibers, with slow O2utilization kinetics and low efficiency, has, however, been suggested as a mechanism. The demonstration of high- and low-pH components of the exercising skeletal muscle31P magnetic resonance (MR) spectrum [inorganic phosphate (Pi) peak] at high work rates (thought to be reflective of differences between oxidative and glycolytic muscle fibers) is also consistent with this conjecture. We therefore investigated the dynamics ofV˙o2(using a turbine and mass spectrometry) and intramuscular ATP, phosphocreatine (PCr), and Piconcentrations and pH, estimated from the31P MR spectrum. Eleven healthy men performed prone square-wave high-intensity knee extensor exercise in the bore of a whole body MR spectrometer. A V˙o2slow component of magnitude 15.9 ± 6.9% of the phase II amplitude was accompanied by a similar response (11.9 ± 7.1%) in PCr concentration. Only five subjects demonstrated a discernable splitting of the Pipeak, however, which began from between 35 and 235 s after exercise onset and continued until cessation. As such, the dynamics of the pH distribution in intramuscular compartments did not consistently reflect the temporal features of theV˙o2slow component, suggesting that Pisplitting does not uniquely reflect the activity of oxidative or glycolytic muscle fibers per se.
Exercise training alters length dependence of contractile properties in rat myocardium
Authors: Diffee Gary M. , Nagle Daniel F.
Published: March 2015

Myocardial function is enhanced by endurance exercise training, but the cellular mechanisms underlying this improved function remain unclear. Exercise training increases the sensitivity of rat cardiac myocytes to activation by Ca2+, and this Ca2+ sensitivity has been shown to be highly dependent on sarcomere length. We tested the hypothesis that exercise training increases this length dependence in cardiac myocytes. Female Sprague-Dawley rats were divided into sedentary control (C) and exercise-trained (T) groups. The T rats underwent 11 wk of progressive treadmill exercise. Heart weight increased by 14% in T compared with C rats, and plantaris muscle citrate synthase activity showed a 39% increase with training. Steady-state tension was determined in permeabilized myocytes by using solutions of various Ca2+concentration (pCa), and tension-pCa curves were generated at two different sarcomere lengths for each myocyte (1.9 and 2.3 μm). We found an increased sarcomere length dependence of both maximal tension and pCa50 (the Ca2+ concentration giving 50% of maximal tension) in T compared with C myocytes. The ΔpCa50 between the long and short sarcomere length was 0.084 ± 0.023 (mean ± SD) in myocytes from C hearts compared with 0.132 ± 0.014 in myocytes from T hearts ( n = 50 myocytes per group). The Δmaximal tension was 5.11 ± 1.42 kN/m2 in C myocytes and 9.01 ± 1.28 in T myocytes. We conclude that exercise training increases the length dependence of maximal and submaximal tension in cardiac myocytes, and this change may underlie, at least in part, training-induced enhancement of myocardial function.
Bioimpedance analysis: a useful technique for assessing appendicular lean soft tissue mass and distribution
Authors: Salinari Serenella , Bertuzzi Alessandro , Mingrone Geltrude , Capristo Esmeralda , Scarfone Antonino , Greco Aldo V. , Heymsfield Steven B.
Published: March 2015

The present study was aimed at evaluating the feasibility and reliability of lower limb skeletal muscle (SM) mass estimates obtained by bioimpedance analysis (BIA). BIA estimates were compared with the estimates obtained by dual-energy X-ray absorptiometry (DXA). Ten normal weight and 10 obese women had BIA and DXA evaluations. Lower limb SM mass was then derived from DXA appendicular lean soft tissue estimates. Lower limb SM mass and SM distribution were also estimated from BIA modeling that fits measured resistance values along the leg. SM mass (mean ± SD) was 5.8 ± 1.0 kg by BIA vs. 5.8 ± 1.1 kg by DXA in normal weight subjects and 7.2 ± 1.4 kg by BIA vs. 7.2 ± 1.2 kg by DXA in obese subjects. Mean ± SD of the absolute value of the relative error was 7.0 ± 3.4 and 5.9 ± 3.4% in the two groups, respectively. Similar results were obtained by using five resistance values for the analysis. In conclusion, the proposed BIA model provides an adequate means of evaluating appendicular SM mass.
Short-term plasticity of descending synaptic input to phrenic motoneurons in rats
Authors: Hayashi F. , Hinrichsen C. F. L. , McCrimmon D. R.
Published: March 2015

Respiratory afferent stimulation can elicit increases in respiratory motor output that outlast the period of stimulation by seconds to minutes [short-term potentiation (STP)]. This study examined the potential contribution of spinal mechanisms to STP in anesthetized, vagotomized, paralyzed rats. After C1 spinal cord transection, stimulus trains (100 Hz, 5–60 s) of the C1-C2 lateral funiculus elicited STP of phrenic nerve activity that peaked several seconds poststimulation. Intracellular recording revealed that individual phrenic motoneurons exhibited one of three different responses to stimulation: 1) depolarization that peaked several seconds poststimulation, 2) depolarization during stimulation and then exponential repolarization after stimulation, and 3) bistable behavior in which motoneurons depolarized to a new, relatively stable level that was maintained after stimulus termination. During the STP, excitatory postsynaptic potentials elicited by single-stimulus pulses were larger and longer. In conclusion, repetitive activation of the descending inputs to phrenic motoneurons causes a short-lasting depolarization of phrenic motoneurons, and augmentation of excitatory postsynaptic potentials, consistent with a contribution to STP.
Empirical model for dynamic force-length behavior of airway smooth muscle
Authors: Anafi Ron C. , Wilson Theodore A.
Published: March 2015

An empirical mathematical model that describes the relation between force and length for dynamic loading of maximally activated airway smooth muscle is described. The model consists of three first-order, ordinary differential equations: one for muscle shortening, one for lengthening, and a third that describes the evolution of an internal variable that depends on muscle history. The model fits data on the dynamic force-length behavior of maximally activated trachealis muscle for a range of amplitudes and rates of shortening and lengthening. The muscle model is incorporated into a model for an intact airway tethered to the surrounding parenchyma. As an example of its use, the model airway is subjected to the loading that occurs during a deep breath. After the breath, the rate of muscle shortening is determined by the interaction between muscle dynamics and the elastic load that is imposed by interdependence forces.
Upregulation of hepatic prolactin receptor gene expression by 17β-estradiol following trauma-hemorrhage
Authors: Yokoyama Yukihiro , Kitchens Williams C. , Toth Balazs , Schwacha Martin G. , Bland Kirby I. , Chaudry Irshad H.
Published: March 2015

Although studies show protective effects of 17β-estradiol (E2) or prolactin (PRL) treatment in male rats after trauma-hemorrhage (TH), the mechanism of the salutary effects of these agents remains unknown. Because E2modulates PRL receptor (PRL-R) expression in the liver, we examined whether E2treatment after T-H has any effects on hepatic PLR-R gene expression. Male Sprague-Dawley rats were subjected to trauma (i.e., 5-cm midline laparotomy) and hemorrhage (35–40 mmHg for 90 min) followed by fluid resuscitation (Ringer lactate) or sham operation and then treated with E2(50 μg/kg body wt sc) or vehicle immediately before resuscitation. Liver samples were collected at 3 h thereafter, and PRL-R mRNA expression was determined by PCR. Liver expression of PRL-R short-form gene was unaffected by T-H, whereas that of the long-form gene was suppressed. Treatment of T-H rats with E2significantly increased PRL-R short-form gene expression and normalized PRL-R long-form gene expression to sham levels. In the isolated hepatocytes, PRL-R short-form gene expression was predominant compared with the long-form gene. In contrast, only the short form was detected in Kupffer cells. In vitro treatment by E2demonstrated an increase in the PRL-R long-form gene in hepatocytes, but E2had no effect on PRL-R short-form gene expression in either the Kupffer cells or hepatocytes. Thus E2treatment after T-H in males appears to directly upregulate PRL-R long-form gene expression in hepatocytes. However, the upregulation of the PRL-R short form might involve the interaction of multiple cell types in the liver.
Thin filament diversity and physiological properties of fast and slow fiber types in astronaut leg muscles
Authors: Riley Danny A. , Bain James L. W. , Thompson Joyce L. , Fitts Robert H. , Widrick Jeffrey J. , Trappe Scott W. , Trappe Todd A. , Costill David L.
Published: March 2015

Slow type I fibers in soleus and fast white (IIa/IIx, IIx), fast red (IIa), and slow red (I) fibers in gastrocnemius were examined electron microscopically and physiologically from pre- and postflight biopsies of four astronauts from the 17-day, Life and Microgravity Sciences Spacelab Shuttle Transport System-78 mission. At 2.5-μm sarcomere length, thick filament density is ∼1,012 filaments/μm2 in all fiber types and unchanged by spaceflight. In preflight aldehyde-fixed biopsies, gastrocnemius fibers possess higher percentages (∼23%) of short thin filaments than soleus (9%). In type I fibers, spaceflight increases short, thin filament content from 9 to 24% in soleus and from 26 to 31% in gastrocnemius. Thick and thin filament spacing is wider at short sarcomere lengths. The Z-band lattice is also expanded, except for soleus type I fibers with presumably stiffer Z bands. Thin filament packing density correlates directly with specific tension for gastrocnemius fibers but not soleus. Thin filament density is inversely related to shortening velocity in all fibers. Thin filament structural variation contributes to the functional diversity of normal and spaceflight-unloaded muscles.
Peripheral opioidergic regulation of the tracheobronchial mucociliary transport system
Authors: Wang Lian , Tiniakov Ruslan L. , Yeates Donovan B.
Published: March 2015

We hypothesized that, in the airway mucosa, opioids are inhibitory neural modulators that cause an increase in net water absorption in the airway mucosa (as in the gut). Changes in bidirectional water fluxes across ovine tracheal mucosa in response to basolateral application of the opioid peptides β-endorphin, dynorphin A-(1–8), and [d-Ala2,d-Leu5]-enkephalin (DADLE) were measured. β-Endorphin and dynorphin A-(1–8) decreased luminal-to-basolateral water fluxes, and dynorphin A-(1–8) and DADLE increased basolateral-to-luminal water flux. These responses were electroneutral. In seven beagle dogs, administration of aerosolized β-endorphin (1 mg) to the tracheobronchial airways decreased the clearance of radiotagged particles from the bronchi in 1 h from 34.7 to 22.0% ( P < 0.001). Naloxone abrogated the β-endorphin-induced changes in vitro and in vivo. Contrary to our hypothesis, the opioid-induced changes in water fluxes would all lead to a predictable increase in airway surface fluid. The β-endorphin-induced increases in airway fluid together with reduced bronchial mucociliary clearance may produce procongestive responses when opioids are administered as antitussives.
Reperfusion injury is reduced in skeletal muscle by inhibition of inducible nitric oxide synthase
Authors: Zhang Li , Looney Colin G. , Qi Wen-Ning , Chen Long-En , Seaber Anthony V. , Stamler Jonathan S. , Urbaniak James R.
Published: March 2015

This study evaluated the effects of the selective inducible nitric oxide synthase (iNOS) inhibitor N-[3-(aminomethyl)benzyl]acetamidine (1400W) on the microcirculation in reperfused skeletal muscle. The cremaster muscles from 32 rats underwent 5 h of ischemia followed by 90 min of reperfusion. Rats received either 3 mg/kg 1400W or PBS subcutaneously before reperfusion. We found that blood flow in reperfused muscles was <45% of baseline in controls but sharply recovered to near baseline levels in 1400W-treated animals. There was a significant ( P < 0.01 to P< 0.001) difference between the two groups at each time point throughout the 90 min of reperfusion. Vessel diameters remained <80% of baseline in controls during reperfusion, but recovered to the baseline level in the 1400W group by 20 min, and reached a maximum of 121 ± 14% (mean ± SD) of baseline in 10- to 20-μm arterioles, 121 ± 6% in 21- to 40-μm arterioles, and 115 ± 8% in 41- to 70-μm arteries ( P < 0.01 to P < 0.001). The muscle weight ratio between ischemia-reperfused (left) and non-ischemia-reperfused (right) cremaster muscles was 193 ± 42% of normal in controls and 124 ± 12% in the 1400W group ( P < 0.001). Histology showed that neutrophil extravasation and edema were markedly reduced in 1400W-treated muscles compared with controls. We conclude that ischemia-reperfusion leads to increased generation of NO from iNOS in skeletal muscle and that the selective iNOS inhibitor 1400W reduces the negative effects of ischemia-reperfusion on vessel diameter and muscle blood flow. Thus 1400W may have therapeutic potential in treatment of ischemia-reperfusion injury.
Carbohydrate loading and supplementation in endurance-trained women runners
Authors: Andrews Jessica L. , Sedlock Darlene A. , Flynn Michael G. , Navalta James W. , Ji Hongguang
Published: March 2015

The purpose of this study was to examine the effect of carbohydrate (CHO) augmentation on endurance performance and substrate utilization in aerobically trained women. Eight endurance-trained women completed a 24.2-km (15 mile) self-paced treadmill performance run under three conditions: CHO supplementation (S), CHO loading and supplementation (L+S), and placebo (P). Dietary CHO was ∼75% of energy intake for L+S and ∼50% for both S and P. A 6% CHO-electrolyte solution (S and L+S) or placebo (P) was ingested preexercise (6 ml/kg) and every 20 min during exercise (3 ml/kg). Blood glucose was significantly higher at 40, 60, and 100 min during L+S, and at 60, 80, and 100 min during S compared with P ( P < 0.05). Blood lactate was significantly higher ( P < 0.05) during L+S than S and P. Blood glycerol was significantly lower ( P < 0.05) at 20, 80, and 100 min during L+S, and at 80 and 100 min during S than P. The proportion of CHO (%) utilized during exercise was significantly higher ( P < 0.05) during L+S (71.3 ± 3.8%) and S (67.3 ± 4.3%) than P (59.2 ± 4.6%). Performance times ( P > 0.05) were 132.5 ± 6.3 min (S), 134.4 ± 6.3 min (L+S), and 136.6 ± 7.9 min (P). In conclusion, it appears that when CHO availability in women is increased through CHO loading and/or CHO supplementation, there is a concomitant increase in CHO utilization. However, this may not necessarily result in significantly improved performance.
A critical analysis of the view that right atrial pressure determines venous return
Authors: Brengelmann George L.
Published: March 2015

A. C. Guyton pioneered major advances in understanding cardiovascular equilibrium. He superimposed venous return curves on cardiac output curves to reveal their intersection at the one level of right atrial pressure (Pra) and flow simultaneously consistent with independent properties of the heart and vasculature. He showed how this point would change with altered properties of the heart (e.g., contractility, sensitivity to preload) and/or of the vasculature (e.g., resistance, total volume). In such graphical representations of negative feedback between two subdivisions of a system, one input/output relationship is necessarily plotted backward, i.e., with the input variable on the y-axis (here, the venous return curve). Unfortunately, this format encourages mistaken ideas about the role of Pra as a “back pressure,” such as the assertion that elevating Pra to the level of mean systemic pressure would stop venous return. These concepts are reexamined through review of the original experiments on venous return, presentation of a hypothetical alternative way for obtaining the same data, and analysis of a simple model.
Effects of pH on the length-dependent twitch potentiation in skeletal muscle
Authors: Rassier Dilson E. , Herzog Walter
Published: March 2015

When muscle is elongated, there is a length dependence of twitch potentiation and an increased Ca2+sensitivity of the myofilaments. Changes in the charge potential of myofilaments, induced by a decrease in pH, are known to abolish the length dependence of Ca2+sensitivity. This study was aimed at testing the hypothesis that a decrease in pH, and the concomitant loss of length dependence of Ca2+sensitivity, depresses the length dependence of staircase potentiation. In vitro, isometric twitch contractions of fiber bundles dissected from the mouse extensor digitorum longus, performed before and after 10 s of 10-Hz stimulation (i.e., the staircase potentiation protocol) were analyzed at five different lengths, ranging from optimal length for maximal force production ( Lo; = 12 ± 0.7 mm) to Lo+ 1.2 mm ( Lo+ 10%). These measurements were made at an extracellular pH of 6.6, 7.4, and 7.8 (pH changes induced by altering the CO2concentration of the bath solution). At pH 7.4 and 7.8, the degree of potentiation after 10-Hz stimulation showed a linear decrease with increased fiber bundle length ( r2= 0.95 and r2= 0.99, respectively). At pH 6.6, the length dependence of potentiation was abolished, and the slope of the length-potentiation relationship was not different from zero ( r2= 0.05). The results of this study indicate that length dependence of potentiation in intact skeletal muscle is abolished by lowering the pH. Because decreasing the pH decreases Ca2+sensitivity and changes the charge potential of the filaments, the mechanism of length-dependent potentiation may be closely related to the length dependence of Ca2+sensitivity, and changes in the charge potential of the myofilaments may be important in regulating this relationship.
Enhanced sympathoinhibitory response to volume expansion in conscious hindlimb-unloaded rats
Authors: Mueller Patrick J. , Hasser Eileen M.
Published: March 2015

Prolonged exposure to microgravity or bed rest produces cardiovascular deconditioning, which is characterized by reductions in plasma volume, alterations in autonomic function, and a predisposition toward orthostatic intolerance. Although the precise mechanisms have not been fully elucidated, it is possible that augmented cardiopulmonary reflexes contribute to some of these effects. The purpose of the present study was to test the hypothesis that sympathoinhibitory responses to volume expansion are enhanced in the hindlimb-unloaded (HU) rat, a model of cardiovascular deconditioning. Mean arterial blood pressure, heart rate, and renal sympathetic nerve activity (RSNA) responses to isotonic volume expansion (0.9% saline iv, 15% of plasma volume over 5 min) were examined in conscious HU (14 days) and control animals. Volume expansion produced decreases in RSNA in both groups; however, this effect was significantly greater in HU rats (−46 ± 7 vs. −25 ± 4% in controls). Animals instrumented for central venous pressure (CVP) did not exhibit differences in CVP responses to volume expansion. These data suggest that enhanced cardiopulmonary reflexes may be involved in the maintenance of reduced plasma volume and contribute to attenuated baroreflex-mediated sympathoexcitation after spaceflight or bed rest.
Regulation of flow and wall shear stress in arteriolar networks of the hamster cheek pouch
Authors: Fox Randall J. , Frame Mary D.
Published: March 2015

Our purpose was to define arteriolar network hemodynamics during moderate increases in interstitial adenosine or nitric oxide in the hamster ( n = 34, pentobarbital sodium 70 mg/kg) cheek pouch tissue. The network consists of a feed arteriole (∼12-μm diameter, ∼800-μm length) with three to six branches. Observations of diameter, red blood cell flux, and velocity were obtained at the feed before the branch and within the branch. A comparison of baseline with suffused adenosine or sodium nitroprusside (SNP) 10−9to 10−5M showed the following. First, diameter change was heterogeneous by agonist, did not reflect the expected dilatory response, and was related to location within the network. With adenosine, upstream branch points constricted and those downstream dilated, even at 10−5M. With SNP, upstream branch points dilated, whereas those downstream constricted. Second, with adenosine, changes in diameter, flux, and velocity together resulted in no change in wall shear stress until 10−5M. Wall shear stress was not maintained at a constant level with Nω-nitro-l-arginine (10−5M), suggesting a role for flow-dependent diameter changes with adenosine. With SNP, diameter change correlated with the baseline (before SNP) shear stress conditions.
Effects of prolonged reduction in blood flow on submandibular secretory function in anesthetized sheep
Authors: Thakor A. S. , Brown C. N. , Edwards A. V.
Published: March 2015

Submandibular vascular and secretory responses to parasympathetic chorda-lingual (C-L) stimulation were investigated in anesthetized sheep before, during, and after an intracarotid (ic) infusion of endothelin-1 (ET-1). Stimulation of the peripheral end of the C-L nerve at 4 and 8 Hz produced a frequency-dependent reduction in submandibular vascular resistance (SVR) associated with a frequency-dependent increase in submandibular blood flow, salivary flow, and Na+, K+, and protein output from the gland. During stimulation at 4 Hz, ic ET-1 significantly increased SVR ( P < 0.01), without significantly affecting either the aortic blood pressure or heart rate. Submandibular blood flow (SBF) was reduced by 48 ± 4% and the flow of saliva by 50 ± 1%. The effect on blood and salivary flow persisted for at least 30 min after the infusion of ET-1. The reduction in SBF was associated with a diminution in the output of Na+,K+, and protein in the saliva ( P < 0.01). These effects persisted for 30 min after the infusion of ET-1 had been discontinued and were linearly related to the flow of plasma throughout.
Gender governs the relationship between exercise intensity and growth hormone release in young adults
Authors: Pritzlaff-Roy Cathy J. , Widemen Laurie , Weltman Judy Y. , Abbott Rob , Gutgesell Margaret , Hartman Mark L. , Veldhuis Johannes D. , Weltman Arthur
Published: March 2015

We previously reported that in young adult males growth hormone (GH) release is related to exercise intensity in a linear dose-response manner (Pritzlaff et al. J Appl Physiol 87: 498–504, 1999). To investigate the effects of gender and exercise intensity on GH release, eight women (24.3 ± 1.3 yr, 171 ± 3.2 cm height, 63.6 ± 8.7 kg weight) were each tested on six randomly ordered occasions [1 control condition (C), 5 exercise conditions (Ex)]. Serum GH concentrations were measured in samples obtained at 10-min intervals between 0700 and 0900 (baseline) and 0900 and 1300 (Ex + recovery or C). Integrated GH concentrations (IGHC) were calculated by trapezoidal reconstruction. During Ex, subjects exercised for 30 min (0900–0930) at one of the following intensities [normalized to the lactate threshold (LT)]: 25 and 75% of the difference between LT and rest, at LT, and at 25 and 75% of the difference between LT and peak O2 uptake. No differences were observed among conditions for baseline IGHC. To determine whether total (Ex + recovery) IGHC changed with increasing exercise intensity, slopes associated with individual linear regression models were subjected to a Wilcoxon signed-rank test. To test for gender differences, data in women were compared with the previously published data in men. A Wilcoxon ranked-sums two-tailed test was used to analyze the slopes and intercepts from the regression models. Total IGHC increased linearly with increasing exercise intensity. The slope and intercept values for the relationship between total IGHC and exercise intensity were greater in women than in men. Deconvolution analysis (0700–1300 h) revealed that, regardless of gender, increasing exercise intensity resulted in a linear increase in the mass of GH secreted per pulse and summed GH production rate, with no changes in GH secretory pulse frequency or apparent half-life of elimination. Exercise reduced the half-duration of GH secretory burst in men but not in women. Gender comparisons revealed that women had greater basal (nonpulsatile) GH secretion across all conditions, more frequent GH secretory pulses, a greater GH secretory pulse amplitude, a greater production rate, and a trend for a greater mass of GH secreted per pulse than men. We conclude that, in young adults, the GH secretory response to exercise is related to exercise intensity in a linear dose-response pattern. For each incremental increase in exercise intensity, the fractional stimulation of GH secretion is greater in women than in men.
Intracellular sodium in mammalian muscle fibers after eccentric contractions
Authors: Yeung Ella W. , Ballard Heather J. , Bourreau J.-P. , Allen David G.
Published: March 2015

The effect of eccentric contractions on intracellular Na+ concentration ([Na+]i) and its distribution were examined in isolated rat and mouse muscle fiber bundles. [Na+]i was measured with either Na+-binding benzofuran isophthalate or sodium green. Ten isometric contractions had no significant effect on force (measured after 5 min of recovery) and caused no significant change in the resting [Na+]i (7.2 ± 0.5 mM). In contrast 10 eccentric contractions (40% stretch at 4 muscle lengths/s) reduced developed force at 100 Hz to 45 ± 3% of control and increased [Na+]i to 16.3 ± 1.6 mM ( n = 6; P < 0.001). The rise of [Na+]i occurred over 1–2 min and showed only minimal recovery after 30 min. Confocal images of the distribution of [Na+]i showed a spatially uniform distribution both at rest and after eccentric contractions. Gd3+ (20 μM) had no effect on resting [Na+]i or control tetanic force but prevented the rise of [Na+]i and reduced the force deficit after eccentric damage. These data suggest that Na+entry after eccentric contractions may occur principally through stretch-sensitive channels.
Increased concentrations of Piand lactic acid reduce creatine-stimulated respiration in muscle fibers
Authors: Walsh B. , Tiivel T. , Tonkonogi M. , Sahlin K.
Published: March 2015

We tested the hypothesis that the respiratory function of skeletal muscle mitochondria is impaired by lactic acidosis and elevated concentrations of Pi. The rate of respiration of chemically skinned fiber bundles from rat soleus muscle was measured at [Pi] (brackets denote concentration) and pH values similar to those at rest (3 mM Pi, pH 7.0) and high-intensity exercise (20 mM Pi, pH 6.6). Respiration was measured in the absence of ADP and after sequential additions of 0.1 mM ADP, 20 mM creatine (Cr; V˙Cr), and 4 mM ADP. Respiration at 0.1 mM ADP increased after addition of Cr. However,V˙Crwas 23% lower ( P < 0.05) during high-intensity conditions than during resting conditions.V˙Crwas also reduced when Pior H+was increased separately ( P < 0.05). Respiration in the absence of ADP and after additions of 0.1 mM ADP and 4 mM ADP was not affected by changes in [Pi] or [H+]. The response was similar, irrespective of when acidosis was induced (i.e., quiescent or actively respiring mitochondria). In conclusion, Cr-stimulated respiration is impaired by increases in [H+] and [Pi] corresponding to those in exercising muscle. Although the reduced Cr-stimulated respiration could be compensated for by increased [ADP], this might have implications for intracellular homeostasis.
Chemotropic Molecules: Guides for Axonal Pathfinding and Cell Migration During CNS Development
Authors: de Castro Fernando
Published: March 2015

Different molecules (netrins, semaphorins, slits) with chemotropic functions and their receptors (neogenin, DCC, neuropilins, plexins, robos) have been identified that guide axons during development of the nervous system to establish the complex pattern of connections among a large number of neurons. These molecules have been recently identified to play a role in cell migration of the central nervous system during development.
Purinergic Signaling Along the Renal Tubule: The Current State of Play
Authors: Unwin Robert J. , Bailey Matthew A. , Burnstock Geoffrey
Published: March 2015

ATP-sensitive P2 receptors have been described in all mammalian nephron segments. A reductionist approach has demonstrated purinergic control of renal transporters in cell lines and heterologous expression systems. This brief update focuses on what is known of these receptors in native nephron segments (excluding the glomerulus) and outlines recent advances and possible future directions.