bluuebunny/crossref_metadata_2025 huggingface dataset:
Rho-kinase regulates myosin II activation in MDCK cells during recovery after ATP depletion
Authors: Sutton Timothy A. , Mang Henry E. , Atkinson Simon J.
Published: December 2017

Alterations in the actin cytoskeleton of renal tubular epithelial cells during periods of ischemic injury and recovery have important consequences for normal cell and kidney function. Myosin II has been demonstrated to be an important effector in organizing basal actin structures in some cell types. ATP depletion in vitro has been demonstrated to recapitulate alterations of the actin cytoskeleton in renal tubular epithelial cells observed during renal ischemia in vivo. We utilized this reversible cell culture model of ischemia to examine the correlation of the activation state and cellular distribution of myosin II with disruption of actin stress fibers in Madin-Darby canine kidney (MDCK) cells during ATP depletion and recovery from ATP depletion. We found that myosin II inactivation occurs rapidly and precedes dissociation of myosin II from actin stress fibers during ATP depletion. Myosin II activation temporally correlates with colocalization of myosin II to reorganizing stress fibers during recovery from ATP depletion. Furthermore, myosin activation and actin stress fiber formation were found to be Rho-associated Ser/Thr protein kinase dependent during recovery from ATP depletion.
Bufo marinusbladder H-K-ATPase carries out electroneutral ion transport
Authors: Burnay Muriel , Crambert Gilles , Kharoubi-Hess Solange , Geering Käthi , Horisberger Jean-Daniel
Published: December 2017

Bufo marinus bladder H-K-ATPase belongs to the Na-K-ATPase and H-K-ATPase subfamily of oligomeric P-type ATPases and is closely related to rat and human nongastric H-K-ATPases. It has been demonstrated that this ATPase transports K+into the cell in exchange for protons and sodium ions, but the stoichiometry of this cation exchange is not yet known. We studied the electrogenic properties of B. marinus bladder H-K-ATPase expressed in Xenopus laevis oocytes. In a HEPES-buffered solution, K+activation of the H-K-ATPase induced a slow-onset inward current that reached an amplitude of ∼20 nA after 1–2 min. When measurements were performed in a solution containing 25 mM HCO[Formula: see text] at a Pco2of 40 Torr, the negative current activated by K+was reduced. In noninjected oocytes, intracellular alkalization activated an inward current similar to that due to B. marinus H-K-ATPase. We conclude that the transport activity of the nongastric B. marinus H-K-ATPase is not intrinsically electrogenic but that the inward current observed in oocytes expressing this ion pump is secondary to intracellular alkalization induced by proton transport.
Transcriptional regulation of heme oxygenases by HIF-1α in renal medullary interstitial cells
Authors: Yang Zhi-Zhang , Zou Ai-Ping
Published: December 2017

The present study was designed to test the hypothesis that hypoxia-inducible factor-1α (HIF-1α)-mediated transcriptional activation contributes to increased expression of heme oxygenase (HO) genes in renal medullary interstitial cells (RMICs). By Northern blot analysis, HO-1 mRNA expression was found to significantly increase in response to reduction of Po2in culture medium. However, HO-2 mRNA was not altered by hypoxia. This hypoxia-induced upregulation of HO-1 mRNA was significantly blocked by HIF-1α inhibition with ferrous ammonium sulfate. To further determine the role of HIF-1α in the activation of HO-1, the inducers of HIF-1α were used to address whether induction of HIF-1α stimulates HO-1 mRNA expression. Both desferrioxamine and CoCl2markedly increased HIF-1α mRNA and protein levels and resulted in the upregulation of HO-1 mRNA but not HO-2. Furthermore, inhibition of HIF-1α degradation by CBZ-LLL, an inhibitor of ubiquitin-proteasome, significantly increased HIF-1α protein and HO-1 mRNA but not HO-2 in these cells. Using cis-element oligodeoxynucleotide transfection to specifically decoy HIF-1α and block HIF-1α binding, increased mRNA expression of HO-1 in response to hypoxia and CoCl2was attenuated. In vitro nuclear run-on assays further confirmed that hypoxia and alterations of HIF-1α mRNA or protein levels significantly affected the formation of HO-1 mRNA. Taken together, our results indicate that HO-1, but not HO-2, is transcriptionally activated by hypoxia through HIF-1α-mediated mechanism in RMICs. This hypoxia-induced transcriptional activation may be one of the important mechanisms mediating increased expression of HO-1 in the renal medulla.
Adenosine modulates Mg2+ uptake in distal convoluted tubule cells via A1 and A2purinoceptors
Authors: Kang Hyung Sub , Kerstan Dirk , Dai Long-Jun , Ritchie Gordon , Quamme Gary A.
Published: December 2017

tk;1Adenosine plays a role in the control of water and electrolyte reabsorption in the distal tubule. As the distal convoluted tubule is important in the regulation of renal Mg2+ balance, we determined the effects of adenosine on cellular Mg2+ uptake in this segment. The effect of adenosine was studied on immortalized mouse distal convoluted tubule (MDCT) cells, a model of the intact distal convoluted tubule. The rate of Mg2+ uptake was measured with fluorescence techniques using mag-fura 2. To assess Mg2+ uptake, MDCT cells were first Mg2+ depleted to 0.22 ± 0.01 mM by being cultured in Mg2+-free media for 16 h and then placed in 1.5 mM MgCl2; next, changes in intracellular Mg2+ concentration ([Mg2+]i) were determined. [Mg2+]i returned to basal levels, 0.53 ± 0.02 mM, with a mean refill rate, d([Mg2+]i)/d t, of 137 ± 16 nM/s. Adenosine stimulates basal Mg2+ uptake by 41 ± 10%. The selective A1 purinoceptor agonist N 6-cyclopentyladenosine (CPA) increased intracellular Ca2+ and decreased parathyroid hormone (PTH)-stimulated cAMP formation and PTH-mediated Mg2+uptake. On the other hand, the selective A2 receptor agonist 2-[ p-(2-carbonyl-ethyl)-phenylethylamino]-5′- N-ethylcarboxamidoadenosine (CGS) stimulated Mg2+ entry in a concentration-dependent fashion. CGS increased cAMP formation and the protein kinase A inhibitor RpcAMPS inhibited CGS-stimulated Mg2+ uptake. Selective inhibition of phospholipase C, protein kinase C, or mitogen-activated protein kinase enzyme cascades with U-73122, Ro-31-8220, and PD-98059, respectively, diminished A2 agonist-mediated Mg2+ entry. Aldosterone potentiated CGS-mediated Mg2+ entry, and elevation of extracellular Ca2+ diminished CGS-responsive cAMP formation and Mg2+ uptake. Accordingly, MDCT cells possess both A1 and A2 purinoceptor subtypes with intracellular signaling typical of these respective receptors. We conclude that adenosine has dual effects on Mg2+ uptake in MDCT cells through separate A1 and A2purinoceptor pathways.
A2Aadenosine receptor: a novel therapeutic target in renal disease
Authors: Okusa Mark D.
Published: December 2017

Present strategies in the treatment of inflammatory renal injury have focused on developing agents that specifically target individual mechanisms thought to contribute toward the pathogenesis of the disease. Such an approach is hindered by redundancies in the inflammatory cascade, rendering intervention suboptimal. The A2Aadenosine receptor (A2A-AR) is a member of the family of guanine nucleotide binding proteins and has become a focus of major interest primarily because of its ability to broadly inactivate the inflammatory cascade. This review summarizes our present knowledge regarding the molecular biology and pharmacology of A2A-ARs as well as the physiological effects of activation of A2A-ARs in the kidney. We also review our recent experience in targeting this receptor subtype in abrogating the inflammatory cascade in ischemia-reperfusion injury.
Understanding pulmonary gas exchange: ventilation-perfusion relationships
Authors: West John B.
Published: December 2017

This essay looks at the historical significance of four APS classic papers that are freely available online:

Fenn WO, Rahn H, and Otis AB. A theoretical study of the composition of the alveolar air at altitude. Am J Physiol 146: 637—653, 1946 ( http://ajplegacy.physiology.org/cgi/reprint/146/5/637 ).

Rahn H. A concept of mean alveolar air and the ventilation-bloodflow relationships during pulmonary gas exchange. Am J Physiol 158: 21—30, 1949 ( http://ajplegacy.physiology.org/cgi/reprint/158/1/21 ).

Riley RL and Cournand A. “Ideal” alveolar air and the analysis of ventilation-perfusion relationships in the lungs. J Appl Physiol 1: 825—847, 1949 ( http://jap.physiology.org/cgi/reprint/1/12/825 ).

Riley RL and Cournand A. Analysis of factors affecting partial pressures of oxygen and carbon dioxide in gas and blood of lungs: theory. J Appl Physiol 4: 77—101, 1951 ( http://jap.physiology.org/cgi/reprint/4/2/77 ).
Nitric oxide synthase inhibition attenuates the skeletal muscle VEGF mRNA response to exercise
Authors: Gavin Timothy P. , Spector David A. , Wagner Harrieth , Breen Ellen C. , Wagner Peter D.
Published: December 2017

Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and transforming growth factor-β1 (TGF-β1) mRNA increase in rat skeletal muscle in response to a single acute exercise bout. Nitric oxide (NO) is released locally by muscle vascular endothelium and muscle fibers during exercise, contributes to the blood flow response to exercise, and regulates mitochondrial respiration. We hypothesized that a reduction in NO production, via NO synthase inhibition, would demonstrate a link between NO and the VEGF, bFGF, and TGF-β1 gene responses to exercise. To investigate this hypothesis, 9-wk-old female Wistar rats were divided into eight treatment groups ( n = 6 each): 1) saline + rest, 2) saline + exercise, 3) 30 mg/kg N ω-nitro-l-arginine methyl ester (l-NAME, a known NOS inhibitor) + rest, 4) 30 mg/kgl-NAME + exercise, 5) 300 mg/kg l-NAME + rest, 6) 300 mg/kg l-NAME + exercise, 7) 300 mg/kg N ω-nitro-d-arginine methyl ester (d-NAME, inactive enantiomer of l-NAME) + rest, and 8) 300 mg/kg d-NAME + exercise. Exercise consisted of 1 h of running at 20 m/min on a 10° incline. VEGF, TGF-β1, and bFGF mRNA from left gastrocnemius were analyzed by quantitative Northern blot. Submaximal exercise for 1 h increased VEGF mRNA 4.2-fold and TGF-β1 mRNA 1.5-fold in untreated rats but did not increase bFGF mRNA. The exercise-induced increase in VEGF mRNA was attenuated ∼50% by 30 and 300 mg/kgl-NAME; the TGF-β1 mRNA increase was unaffected by 300 mg/kg l-NAME. In addition, 300 mg/kgd-NAME had no effect on the exercise-induced increase in VEGF mRNA. Administration of 300 mg/kg l-NAME had no effect on bFGF mRNA. These findings suggest that NO is important in the regulation of the VEGF gene response to exercise through increases in VEGF transcription or by increases in the VEGF mRNA half-life.
Lack of skeletal muscle hypertrophy in very aged male Fischer 344 × Brown Norway rats
Authors: Blough E. R. , Linderman J. K.
Published: December 2017

To examine the effect of extreme old age on muscle plasticity, 6- (adult) and 36-mo-old (old) male Fischer 344 × Brown Norway hybrid rats underwent bilateral surgical ablation of the gastrocnemius muscle to functionally overload (OV) the fast-twitch plantaris muscle for 8 wk. Plantaris muscle wet weight, muscle cross-sectional area (CSA), and average fiber CSA decreased by 44, 42, and 40%, respectively, in old compared with adult rats, and peak isometric tetanic tension decreased by 83%. Compared with muscles in age-matched controls, plantaris muscle mass increased by 53% and type I, IIA, and IIX/IIB CSA increased by 91, 76, and 103%, respectively, in adult-OV rats, but neither wet mass nor fiber CSA increased in old-OV rats. OV decreased type I, IIA, and IIX/IIB mean fiber CSA by 31, 35, and 30%, respectively, in old-OV rats. Collectively, our data indicate that in extreme old age the plantaris muscle undergoes significant loss of mass, fiber CSA, and contractile function, as well as its capacity to undergo hypertrophy in response to a chronic increase in mechanical load.
Measurement of thoracoabdominal asynchrony: importance of sensor sensitivity to cross section deformations
Authors: de Groote Anne , Verbandt Yves , Paiva Manuel , Mathys Pierre
Published: December 2017

Discrepancies in the assessment of thoracoabdominal asynchrony are observed depending on the choice of respiratory movement sensors. We test the hypothesis that these discrepancies are due to a different dependence of the sensors on cross-sectional perimeter and area variations of the chest wall. First, we study the phase shift between perimeter and area (ΦPA) for an elliptical model, which is deformed by sinusoidal changes of its principal axes. We show that perimeter and area vary sinusoidally in the physiological range of deformations, and we discuss how ΦPAdepends on the ellipticity of the cross section, on the ratio of transverse and dorsoventral movement amplitudes, and on their phase difference. Second, we compute the relationship between perimeter, area, and the output of the inductive sensor, and we proceed by comparing inductive plethysmography with strain gauges for several cross section deformations. We demonstrate that both sensors can provide different phase information for identical cross section deformations and, hence, can estimate thoracoabdominal asynchrony differently. Furthermore, the complex dependence of the inductive sensor on perimeter and area warns against this sensor for the evaluation of thoracoabdominal asynchrony.
Animal housing influences the response of bone to spaceflight in juvenile rats
Authors: Morey-Holton Emily R. , Halloran Bernard P. , Garetto Lawrence P. , Doty Stephen B.
Published: December 2017

The rat has been used extensively as an animal model to study the effects of spaceflight on bone metabolism. The results of these studies have been inconsistent. On some missions, bone formation at the periosteal bone surface of weight-bearing bones is impaired and on others it is not, suggesting that experimental conditions may be an important determinant of bone responsiveness to spaceflight. To determine whether animal housing can affect the response of bone to spaceflight, we studied young growing (juvenile) rats group housed in the animal enclosure module and singly housed in the research animal holding facility under otherwise identical flight conditions (Spacelab Life Science 1). Spaceflight reduced periosteal bone formation by 30% ( P < 0.001) and bone mass by 7% in single-housed animals but had little or no effect on formation (−6%) or mass (−3%) in group-housed animals. Group housing reduced the response of bone to spaceflight by as much as 80%. The data suggest that housing can dramatically affect the skeletal response of juvenile rats to spaceflight. These observations explain many of the discrepancies in previous flight studies and emphasize the need to study more closely the effects of housing (physical-social interaction) on the response of bone to the weightlessness of spaceflight.
Low-pass filtering, a new method of fractal analysis: application to PET images of pulmonary blood flow
Authors: Venegas Jose G. , Galletti Gaetano G.
Published: December 2017

The pattern of a spatial structure that repeats itself independently of the scale of magnification or resolution is often characterized by a fractal dimension ( D). Two-dimensional low-pass filtering, which may serve as a method to assess D, was applied to functional images of pulmonary perfusion measured by positron emission tomography. The corner frequency of a low-pass filter is inversely proportional to the resolution scale. The method was applied to three types of images: random noise images, synthetic fractal images, and positron emission tomographic images of pulmonary perfusion. Images were processed with two-dimensional low-pass filters of decreasing corner frequencies, and a spatial heterogeneity index, the coefficient of variation, was calculated for each low-pass-filtered image. The natural logarithm of the coefficient of variation scaled linearly with the natural logarithm of the resolution scale for the PET images studied (average R 2 = 0.99). D ranged from 1.25 to 1.36 for the residual distribution of pulmonary perfusion after vertical gradients were removed by linear regression. D of the same data without removal of vertical gradients ranged from 1.11 to 1.14, but the fractal plots had systematic deviations from linearity and a lower linear correlation coefficient ( R 2 = 0.96). The method includes all data in the lung field and is insensitive to the effects of misregistration. We conclude that low-pass filtering offers new insights into the interpretation of D of two-dimensional functional images as a measure of the frequency content of spatial heterogeneity.
Impact of hetastarch on the intestinal microvascular barrier during ECLS
Authors: Cox Charles S. , Brennan Michael , Allen Steven J.
Published: December 2017

The effects of hetastarch on microvascular fluid flux were determined in anesthetized dogs undergoing extracorporeal life support (ECLS) with a roller pump and membrane oxygenator. ECLS with a lactated Ringer priming solution resulted in a decrease in microvascular protein reflection coefficient and an increase in transvascular protein clearance. Use of a 6% hetastarch priming solution attenuated the decrease in microvascular protein reflection coefficient and blunted the increase in transvascular protein clearance. Ileal tissue water increased in the group treated with the lactated Ringer priming solution compared with the group treated with 6% hetastarch. The effective plasma-to-interstitial colloid osmotic pressure gradient was greater in the group treated with hetastarch than in the group treated with lactated Ringer solution. Hetastarch decreases the edema associated with ECLS. The reduction in edema is due to the maintenance of the plasma-to-interstitial colloid osmotic pressure gradient and the reduction in the microvascular permeability to protein.
Enhancing our understanding of the molecular responses to hypoxia in mammals usingDrosophila melanogaster
Authors: Haddad Gabriel G.
Published: December 2017

Drosophila melanogaster has been used as a genetic model, especially in the past decade, to examine normative biological processes and disease conditions very effectively. These span a wide range of major issues such as aging, cancer, embryogenesis, neural development, apoptosis, and alcohol intoxication. Here, we detail how the Drosophila melanogaster can be used as a genetic model to study the molecular and genetic underpinnings of the response to hypoxia. In our study of the basis of anoxia tolerance, one of the potent approaches that we use is a mutagenesis screen to identify loss-of-function mutants that are anoxia sensitive. The major advantage of this approach is that it is not biased for any particular gene or gene product. Although our screen is in progress, we already have evidence that this approach is useful.
Muscle adenine nucleotide metabolism during and in recovery from maximal exercise in humans
Authors: Zhao S. , Snow R. J. , Stathis C. G. , Febbraio M. A. , Carey M. F.
Published: December 2017

The relationship between changes in the muscle total adenine nucleotide pool (TAN = ATP + ADP + AMP) and IMP during and after 30 s of sprint cycling was examined. Skeletal muscle samples were obtained from the vastus lateralis muscle of seven untrained men (23.9 ± 2.3 yr, 74.4 ± 3.6 kg, and 55.0 ± 2.9 ml ⋅ kg−1⋅ min−1peak oxygen consumption) before and immediately after exercise and after 5 and 10 min of passive recovery. The exercise-induced increase in muscle IMP was linearly related to the decrease in muscle TAN ( r = −0.97, P < 0.01), and the slope of this relationship (−0.83) was not different from 1.0 ( P > 0.05), indicating a 1:1 stoichiometric relationship. This interpretation must be treated cautiously, because all subjects displayed a greater decrease in TAN compared with the increase in IMP content, and the TAN + IMP + inosine + hypoxanthine content was lower ( P < 0.05) immediately after exercise compared with during rest. During the first 5 min of recovery, the increase in TAN was not correlated with the decrease in IMP ( r = −0.18, P> 0.05). In all subjects, the magnitude of TAN increase was higher than the magnitude of IMP decrease over this recovery period. In contrast, the increase in TAN was correlated with the decrease in IMP throughout the second 5 min of recovery ( r = −0.80, P < 0.05), and it was a 1:1 stoichiometric relationship (slope = −1.12). These data indicate that a small proportion of the TAN pool was temporarily lost from the muscle purine stores during sprinting but was rapidly recovered after exercise.
Effects of duration of positive-pressure ventilation on blood-brain barrier function in premature lambs
Authors: Stonestreet Barbara S. , McKnight Amanda J. , Sadowska Grazyna , Petersson Katherine H. , Oen Joyce M. , Patlak Clifford S.
Published: December 2017

We have been studying the ontogeny of the blood-brain barrier function in ovine fetuses and lambs. During these studies, we have found that the duration of ventilation also influences blood-brain barrier permeability in premature lambs. Chronically instrumented hysterotomy-delivered surfactant-treated premature lambs were studied at 90% or 137 days of gestation ( n = 9). Blood-brain barrier function was quantified with the blood-to-brain transfer constant Kito α-aminoisobutyric acid. Linear regression analysis was used to compare the Kivalues in the brain regions, as the dependent variable, to the duration of ventilation, as the independent variable. There were direct correlations ( P < 0.05) between the Kivalues and the duration of ventilation [306 min (mean), 162–474 min (range)] in the cerebral cortex, cerebellum, medulla, caudate nucleus, hippocampus, superior colliculus, inferior colliculus, thalamus, pons, cervical spinal cord, and choroid plexus, but not in the pituitary gland. Ventilatory pressures and rates were established before the onset of the permeability studies. Calculated mean airway pressures [14 cmH2O (mean), 7–20 cmH2O (range)] from similarly studied premature lambs did not correlate with the duration of positive-pressure ventilation. We conclude that increases in the duration of positive-pressure ventilation predispose premature lambs to increases in regional blood-brain barrier permeability. These alterations in barrier function occur over relatively short time intervals (minutes to hours). In our study, these changes in permeability are most likely not attributable to changes in mean airway pressure.
Effect of captopril on skeletal muscle angiogenic growth factor responses to exercise
Authors: Gavin Timothy P. , Spector David A. , Wagner Harrieth , Breen Ellen C. , Wagner Peter D.
Published: December 2017

Acute exercise increases vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGF-β1), and basic fibroblast growth factor (bFGF) mRNA levels in skeletal muscle, with the greatest increase in VEGF mRNA. VEGF functions via binding to the VEGF receptors Flk-1 and Flt-1. Captopril, an angiotensin-converting enzyme inhibitor, has been suggested to reduce the microvasculature in resting and exercising skeletal muscle. However, the molecular mechanisms responsible for this reduction have not been investigated. We hypothesized that this might occur via reduced VEGF, TGF-β1, bFGF, Flk-1, and Flt-1 gene expression at rest and after exercise. To investigate this, 10-wk-old female Wistar rats were placed into four groups ( n = 6 each): 1) saline + rest; 2) saline + exercise; 3) 100 mg/kg ip captopril + rest; and 4) 100 mg/kg ip captopril + exercise. Exercise consisted of 1 h of running at 20 m/min on a 10° incline. VEGF, TGF-β1, bFGF, Flk-1, and Flt-1 mRNA were analyzed from the left gastrocnemius by quantitative Northern blot. Exercise increased VEGF mRNA 4.8-fold, TGF-β1 mRNA 1.6-fold, and Flt-1 mRNA 1.7-fold but did not alter bFGF or Flk-1 mRNA measured 1 h after exercise. Captopril did not affect the rest or exercise levels of VEGF, TGF-β1, bFGF, and Flt-1 mRNA. Captopril did reduce Flk-1 mRNA 30–40%, independently of exercise. This is partially consistent with the suggestion that captopril may inhibit capillary growth.
Inhibition of allergic late airway responses by inhaled heparin-derived oligosaccharides
Authors: Ahmed Tahir , Ungo Jaime , Zhou Min , Campo Carlos
Published: December 2017

Inhaled heparin has been shown to inhibit allergic bronchoconstriction in sheep that develop only acute responses to antigen (acute responders) but was ineffective in sheep that develop both acute and late airway responses (LAR) (dual responders). Because the antiallergic activity of heparin is molecular-weight dependent, we hypothesized that heparin-derived oligosaccharides (<2,500) with potential anti-inflammatory activity may attenuate the LAR in the dual-responder sheep. Specific lung resistance was measured in 24 dual-responder sheep before and serially for 8 h after challenge with Ascaris suum antigen for demonstration of early airway response (EAR) and LAR, without and after treatment with inhaled medium-, low-, and ultralow-molecular-weight (ULMW) heparins and “non-anticoagulant” fractions (NAF) of heparin. Airway responsiveness was estimated before and 24 h postantigen as the cumulative provocating dose of carbachol that increased specific lung resistance by 400%. Only ULMW heparins caused a dose-dependent inhibition of antigen-induced EAR and LAR and postantigen airway hyperresponsiveness (AHR), whereas low- and medium-molecular-weight heparins were ineffective. The effects of ULMW heparin and ULMW NAF-heparin were comparable and inhibited the LAR and AHR even when administered “after” the antigen challenge. The ULMW NAF-heparin failed to inhibit the bronchoconstrictor response to histamine, carbachol, and leukotriene D4, excluding a direct effect on airway smooth muscle. In six sheep, segmental antigen challenge caused a marked increase in bronchoalveolar lavage histamine, which was not prevented by inhaled ULMW NAF-heparin. The results of this study in the dual-responder sheep demonstrate that 1) the antiallergic activity of inhaled “fractionated” heparins is molecular-weight dependent, 2) only ULMW heparins inhibit the antigen-induced EAR and LAR and postantigen AHR, and 3) the antiallergic activity is mediated by nonanticoagulant fractions and resides in the ULMW chains of <2,500.
Impairment of Ca2+release in singleXenopusmuscle fibers fatigued at varied extracellular P O 2
Authors: Stary Creed M. , Hogan Michael C.
Published: December 2017

We tested the hypothesis that the mechanisms involved in the more rapid onset of fatigue when O2availability is reduced in contracting skeletal muscle are similar to those when O2availability is more sufficient. Two series of experiments were performed in isolated, single skeletal muscle fibers from Xenopus laevis. First, relative force and free cytosolic Ca2+concentrations ([Ca2+]c) were measured simultaneously in single fibers ( n = 6) stimulated at increasing frequencies (0.25, 0.33, 0.5, and 1 Hz) at an extracellular[Formula: see text] of either 22 or 159 Torr. Muscle fatigue (force = 50% of initial peak tension) occurred significantly sooner ( P < 0.05) during the low- (237 ± 40 s) vs. high-[Formula: see text]treatments (280 ± 38 s). Relative [Ca2+]cwas significantly decreased from maximal values at the fatigue time point during both the high- (72 ± 4%) and low-[Formula: see text] conditions (78 ± 4%), but no significant difference was observed between the treatments. In the second series of experiments, using the same stimulation regime as the first, fibers ( n = 6) exposed to 5 mM caffeine immediately after fatigue demonstrated an immediate but incomplete relative force recovery during both the low- (89 ± 4%) and high-[Formula: see text] treatments (82 ± 3%), with no significant difference between treatments. Additionally, there was no significant difference in relative [Ca2+]cbetween the high- (100 ± 12% of prefatigue values) and low-[Formula: see text] treatments (108 ± 12%) on application of caffeine. These results suggest that in isolated, single skeletal muscle fibers, the earlier onset of fatigue that occurred during the low-extracellular[Formula: see text] condition was modulated through similar pathways as the fatigue process during the high and involved a decrease in relative peak [Ca2+]c.
Kinetics of oxygen uptake at the onset of exercise near or above peak oxygen uptake
Authors: Hughson R. L. , O'Leary D. D. , Betik A. C. , Hebestreit H.
Published: December 2017

We tested the hypothesis that kinetics of O2 uptake (V˙o 2) measured in the transition to exercise near or above peakV˙o 2(V˙o 2 peak) would be slower than those for subventilatory threshold exercise. Eight healthy young men exercised at ∼57, ∼96, and ∼125%V˙o 2 peak. Data were fit by a two- or three-component exponential model and with a semilogarithmic transformation that tested the difference between required V˙o 2 and measuredV˙o 2. With the exponential model, phase 2 kinetics appeared to be faster at 125% V˙o 2 peak[time constant (τ2) = 16.3 ± 8.8 (SE) s] than at 57%V˙o 2 peak(τ2 = 29.4 ± 4.0 s) but were not different from that at 96%V˙o 2 peakexercise (τ2 = 22.1 ± 2.1 s).V˙o 2 at the completion of phase 2 was 77 and 80%V˙o 2 peak in tests predicted to require 96 and 125%V˙o 2 peak. WhenV˙o 2 kinetics were calculated with the semilogarithmic model, the estimated τ2 at 96%V˙o 2 peak (49.7 ± 5.1 s) and 125%V˙o 2 peak (40.2 ± 5.1 s) were slower than with the exponential model. These results are consistent with our hypothesis and with a model in which the cardiovascular system is compromised during very heavy exercise.
Simultaneous NMR microdialysis study of brain glucose metabolism in relation to fasting or exercise in the rat
Authors: Béquet F. , Pérès M. , Gomez-Mérino D. , Berthelot M. , Satabin P. , Piérard C. , Guezennec C. Y.
Published: December 2017

To study the impact of exercise or fasting and of subsequent glucose supplementation on glucose metabolism in rats, a spectrophotometric method was used to determine peripheral blood glucose; a technique associating1H-NMR spectroscopy and cortical microdialysis was also used to observe intra- plus extracellular and extracellular brain glucose variations, respectively. Compared with control animals (204 ± 19 μM in dialysate, n = 10), exercise increased brain extracellular glucose levels to 274 ± 22 μM ( n = 8; P < 0.05), whereas fasting induced a drop in glucose levels down to 140 ± 9 μM ( n = 8; P < 0.05). After fasting, glucose supplemented by infusion increased glycemia from 7.4 ± 0.4 to 19.9 ± 0.8 mM ( n = 10; P < 0.001), as well as extracellular and extra- plus intracellular brain glucose to 263 ± 20% ( n = 8; P < 0.001) and 342 ± 28% ( n = 8; P < 0.001), respectively, over basal for that group. After exercise, a similar infusion increased glycemia from 7.3 ± 0.3 to 16.8 ± 1.1 mM ( n = 10; P < 0.001), as well as extracellular and extra- plus intracellular brain glucose to 178 ± 19% ( n = 8; P < 0.001) and 244 ± 20% ( n = 8; P < 0.001), respectively, over basal for that group. These results confirmed the existence of a link between glucose level variations in peripheral and cerebral areas but also showed that exercise increased extracellular brain glucose levels despite peripheral hypoglycemia, suggesting a specific regulation mechanism of cerebral glucose metabolism during exercise.
Cardiovascular and pulmonary response to oral administration of ATP in rabbits
Authors: Kichenin Ketty , Decollogne Stéphanie , Angignard Jean , Seman Michel
Published: December 2017

Extracellular purines such as ATP and adenosine participate in the regulation of cardiovascular and respiratory functions through specific P1 and P2 purine receptors. These properties have mainly been described after intravenous infusion. Experiments reported herein were designed to explore the possible effect of oral ATP administration (3 or 20 mg ⋅ kg−1⋅ day−1) on vascular, cardiac, and pulmonary functions in rabbits. Whereas a unique oral dose of ATP has no effect, chronic supplementation during 14 days reduces peripheral vascular resistance, pulmonary resistance, and respiratory frequency and increases arterial Po2. No effect on central blood pressure and heart rate is observed, but an increase of the left ventricular work index is noticed subsequent to the diminution of vascular resistance. Rather similar cardiovascular modifications are observed in rabbits given 20 mg ⋅ kg−1⋅ day−1adenosine for 14 days but without variation of respiratory parameters. These original effects of repeated oral treatment with ATP may result from an adaptive metabolic response to nucleoside supplementation that might affect the turnover of extracellular purines leading to P1- and/or P2-receptor activation.
Fatigue responses of human triceps surae muscles during repetitive maximal isometric contractions
Authors: Kawakami Yasuo , Amemiya Kenji , Kanehisa Hiroaki , Ikegawa Shigeki , Fukunaga Tetsuo
Published: December 2017

Nine healthy men (22–45 yr) completed 100 repetitive maximal isometric contractions of the ankle plantar flexor muscles in two knee positions of full extension (K0) and flexion at 90° (K90), positions that varied the contribution of the gastrocnemii. Electromyographic activity was recorded from the medial and lateral gastrocnemii and soleus muscles by using surface electrodes. Plantar flexion torque in K0 was greater and decreased more rapidly than in K90. The electromyographic amplitude decreased over time, and there were no significant differences between muscles and knee joint positions. The level of voluntary effort, assessed by a supramaximal electrical stimulation during every 10th contraction, decreased from 96 to 70% ( P < 0.05) with no difference between K0 and K90. It was suggested that a decrease in plantar flexion torque was attributable to both central and peripheral fatigue and that greater fatigability in K0 than in K90 would result from a greater contribution and hence more pronounced fatigue of the gastrocnemius muscle. Further support for this possibility was provided from changes in twitch torque.
CO2/H+ chemoreception in the cat pre-Bötzinger complex in vivo
Authors: Solomon Irene C. , Edelman Norman H. , O'Neal Marvin H.
Published: December 2017

We examined the effects of focal tissue acidosis in the pre-Bötzinger complex (pre-BötC; the proposed locus of respiratory rhythm generation) on phrenic nerve discharge in chloralose-anesthetized, vagotomized, paralyzed, mechanically ventilated cats. Focal tissue acidosis was produced by unilateral microinjection of 10–20 nl of the carbonic anhydrase inhibitors acetazolamide (AZ; 50 μM) or methazolamide (MZ; 50 μM). Microinjection of AZ and MZ into 14 sites in the pre-BötC reversibly increased the peak amplitude of integrated phrenic nerve discharge and, in some sites, produced augmented bursts (i.e., eupneic breath ending with a high-amplitude, short-duration burst). Microinjection of AZ and MZ into this region also reversibly increased the frequency of eupneic phrenic bursts in seven sites and produced premature bursts (i.e., doublets) in five sites. Phrenic nerve discharge increased within 5–15 min of microinjection of either agent; however, the time to the peak increase and the time to recovery were less with AZ than with MZ, consistent with the different pharmacological properties of AZ and MZ. In contrast to other CO2/H+ brain stem respiratory chemosensitive sites demonstrated in vivo, which have only shown increases in amplitude of integrated phrenic nerve activity, focal tissue acidosis in the pre-BötC increases frequency of phrenic bursts and produces premature (i.e., doublet) bursts. These data indicate that the pre-BötC has the potential to play a role in the modulation of respiratory rhythm and pattern elicited by increased CO2/H+ and lend additional support to the concept that the proposed locus for respiratory rhythm generation has intrinsic chemosensitivity.
Chronic exercise training does not alter pulmonary vasorelaxation in normal pigs
Authors: Johnson Lynelle R. , Laughlin M. Harold
Published: December 2017

Exercise training increases acetylcholine-induced pulmonary vasorelaxation in pigs with coronary occlusion. The present study tested the hypothesis that chronic exercise training enhances endothelium-mediated vasorelaxation in pulmonary arteries from normal pigs. Yucatan miniswine exercised for 16 wk on a treadmill (Ex); control pigs (Sed) remained in pens. Pulmonary artery rings (2- to 3-mm OD) were studied using standard isometric techniques. Contractile responses to 80 mM KCl and norepinephrine (NE) were determined. Vessels were constricted with levels of NE that resulted in half-maximal contraction to examine endothelium-dependent relaxation to ACh and endothelium-independent relaxation to sodium nitroprusside in the presence and absence of nitric oxide synthase inhibition, cyclooxygenase inhibition, and endothelial denudation. Arteries from Ex pigs developed increased contraction to 80 mM KCl, but the response to NE did not differ between groups. Endothelium-dependent and endothelium-independent responses did not differ between Sed and Ex in the presence or absence of pharmacological inhibitors or denudation. We conclude that chronic exercise training does not alter endothelium-dependent or endothelium-independent vasorelaxation responses of pulmonary arteries from normal pigs.
Respiratory-related bronchial rhythmic constrictions in the dog with extracorporeal circulation
Authors: Kondo Tetsuri , Kobayashi Ichiro , Hayama Naoki , Tazaki Gen , Ohta Yasuyo
Published: December 2017

Respiratory-related bronchial rhythmic contraction was quantitatively analyzed in eight paralyzed dogs. The caliber of the fifth-generation bronchus was continuously measured as the pressure (Pbr) of a balloon-tipped catheter under the condition of complete immobilization due to extracorporeal oxygenation. Pbr changed rhythmically in synchrony with phrenic nerve activity (PNA) bursts. Rhythmic bronchial constriction started at 1.4 ± 0.49 (SD) s after onset of PNA, reached a maximum level at 2.8 ± 1.6 s after termination of PNA, and then decreased exponentially with a time constant of 6.9 ± 2.5 s. When the respiratory rate of dogs increased at hypercapnia, the various bronchial contractions fused to behave like a tonic contraction. The rhythmic component of this contraction was separated and quantitatively analyzed. Each rhythmic Pbr amplitude linearly increased with increases in PNA amplitude, whereas the end-expiratory Pbr level was not significantly changed. Bilateral efferent nerve transection did not decrease the end-expiratory Pbr level. In response to electric stimulation of efferent nerve fibers, the bronchus did not maintain tonic contraction. We concluded that vagally mediated commands contract bronchial smooth muscle only intermittently and that most of bronchial resting tension may thus be attributed to the summation of rhythmic contractions.
Dynamic markers of altered gait rhythm in amyotrophic lateral sclerosis
Authors: Hausdorff Jeffrey M. , Lertratanakul Apinya , Cudkowicz Merit E. , Peterson Amie L. , Kaliton David , Goldberger Ary L.
Published: December 2017

Amyotrophic lateral sclerosis (ALS) is a disorder marked by loss of motoneurons. We hypothesized that subjects with ALS would have an altered gait rhythm, with an increase in both the magnitude of the stride-to-stride fluctuations and perturbations in the fluctuation dynamics. To test for this locomotor instability, we quantitatively compared the gait rhythm of subjects with ALS with that of normal controls and with that of subjects with Parkinson's disease (PD) and Huntington's disease (HD), pathologies of the basal ganglia. Subjects walked for 5 min at their usual pace wearing an ankle-worn recorder that enabled determination of the duration of each stride and of stride-to-stride fluctuations. We found that the gait of patients with ALS is less steady and more temporally disorganized compared with that of healthy controls. In addition, advanced ALS, HD, and PD were associated with certain common, as well as apparently distinct, features of altered stride dynamics. Thus stride-to-stride control of gait rhythm is apparently compromised with ALS. Moreover, a matrix of markers based on gait dynamics may be useful in characterizing certain pathologies of motor control and, possibly, in quantitatively monitoring disease progression and evaluating therapeutic interventions.
Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle
Authors: Winder W. W. , Holmes B. F. , Rubink D. S. , Jensen E. B. , Chen M. , Holloszy J. O.
Published: December 2017

Muscle contraction causes an increase in activity of 5′-AMP-activated protein kinase (AMPK). This study was designed to determine whether chronic chemical activation of AMPK will increase mitochondrial enzymes, GLUT-4, and hexokinase in different types of skeletal muscle of resting rats. In acute studies, rats were subcutaneously injected with either 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR; 1 mg/g body wt) in 0.9% NaCl or with 0.9% NaCl alone and were then anesthetized for collection and freezing of tissues. AMPK activity increased in the superficial, white region of the quadriceps and in soleus muscles but not in the deep, red region of the quadriceps muscle. Acetyl-CoA carboxylase (ACC) activity, a target for AMPK, decreased in all three muscle types in response to AICAR injection but was lowest in the white quadriceps. In rats given daily, 1 mg/g body wt, subcutaneous injections of AICAR for 4 wk, activities of citrate synthase, succinate dehydrogenase, and malate dehydrogenase were increased in white quadriceps and soleus but not in red quadriceps. Cytochrome c and δ-aminolevulinic acid synthase levels were increased in white, but not red, quadriceps. Carnitine palmitoyl-transferase and hydroxy-acyl-CoA dehydrogenase were not significantly increased. Hexokinase was markedly increased in all three muscles, and GLUT-4 was increased in red and white quadriceps. These results suggest that chronic AMPK activation may mediate the effects of muscle contraction on some, but not all, biochemical adaptations of muscle to endurance exercise training.
Transient enhancement of GLUT-4 levels in rat epitrochlearis muscle after exercise training
Authors: Reynolds Thomas H. , Brozinick Joseph T. , Larkin Lisa M. , Cushman Samuel W.
Published: December 2017

The purpose of the present study was to examine the effect of detraining on the glucose transport system after short-term swim training (5 days), long-term swim training (5 wk), and treadmill run training (5 wk). Skeletal muscles were isolated from female Wistar rats at 24 or 48 h posttraining. SST produces a 48% increase in GLUT-4 mRNA, a 30% increase in GLUT-4 protein, and a 60% increase in insulin-stimulated glucose transport activity at 24 h posttraining but not at 48 h posttraining. Similar to SST, long-term swim training produces a 60% increase in GLUT-4 mRNA and a 30% increase in GLUT-4 protein content at 24 h posttraining but not at 48 h posttraining. Finally, treadmill run training produces a transient 35% increase in GLUT-4 protein content that is completely reversed at 48 h after the last bout of exercise. These results demonstrate that the increase in GLUT-4 mRNA and GLUT-4 protein occurs during the first week of exercise training and is rapidly lost after training cessation. We believe that the transient enhancement in GLUT-4 protein after exercise training is due to a short GLUT-4 half-life, a process that is primarily regulated by pretranslational mechanisms.
Exercise alters fractal dimension and spatial correlation of pulmonary blood flow in the horse
Authors: Sinclair Scott E. , McKinney Steve , Glenny Robb W. , Bernard Susan L. , Hlastala Michael P.
Published: December 2017

We determined the changes in fractal dimensions and spatial correlations of regional pulmonary blood flow with increasing exercise in race horses ( n= 4) by using 15-μm fluorescent microspheres. Fluorescence was measured to quantitate regional blood to 1.3-cm3 samples ( n = 1,621–2,503). Perfusion distributions were characterized with fractal dimensions (a measure of spatial variability) and spatial correlations. On average, the fractal dimension decreased with exercise (trot 1.216 to gallop 1.173; P < 0.05) despite a variable fractal dimension at rest. Spatial correlation of flow to neighboring pieces increased with exercise (trot 0.57 ± 0.074 to gallop 0.73 ± 0.051) and was inversely correlated with fractal dimension, indicating better spatial correlation as blood flow distribution becomes more uniform. This is the first study to document a change in fractal dimension as a result of increasing pulmonary blood flow. Spatial differences in response to vasoregulatory mediators may play a role in this phenomenon.
Shape of the canine diaphragm
Authors: Angelillo Maurizio , Boriek Aladin M. , Rodarte Joseph R. , Wilson Theodore A.
Published: December 2017

In an earlier study (Angelillo M, Boriek AM, Rodarte JR, and Wilson TA. J Appl Physiol83: 1486–1491, 1997), we proposed a mathematical theory for the structure and shape of the diaphragm. Muscle bundles were assumed to lie on lines that are simultaneously geodesics and lines of principal curvature of the diaphragm surface, and the class of surfaces that are formed by line elements that are both geodesics and lines of principal curvature was described. Here we present data on the shape of the canine diaphragm that were obtained by the radiopaque marker technique, and we describe a surface that fits the data and satisfies the requirements of the theory. The costal and crural diaphragms are fit by cyclides with radii of 3.7 and 2.3 cm, respectively. In addition, the theory is extended to include the description of a joint between cyclides, and the observed properties of the joint between the costal and crural diaphragms at the dorsal end of the costal diaphragm match those required by the theory.
Preventing mediastinal shift after pneumonectomy does not abolish physiological compensation
Authors: Wu E. Y. , Hsia C. C. W. , Estrera A. S. , Epstein R. H. , Ramanathan M. , Johnson R. L.
Published: December 2017

To determine the role of mediastinal shift after pneumonectomy (PNX) on compensatory responses, we performed right PNX in adult dogs and replaced the resected lung with a custom-shaped inflatable silicone prosthesis. Prosthesis was inflated (Inf) to prevent mediastinal shift, or deflated (Def), allowing mediastinal shift to occur. Thoracic, lung air, and tissue volumes were measured by computerized tomography scan. Lung diffusing capacities for carbon monoxide (DlCO) and its components, membrane diffusing capacity for carbon monoxide (DmCO) and capillary blood volume (Vc), were measured at rest and during exercise by a rebreathing technique. In the Inf group, lung air volume was significantly smaller than in Def group; however, the lung became elongated and expanded by 20% via caudal displacement of the left hemidiaphragm. Consequently, rib cage volume was similar, but total thoracic volume was higher in the Inf group. Extravascular septal tissue volume was not different between groups. At a given pulmonary blood flow, DlCOand DmCOwere significantly lower in the Inf group, but Vc was similar. In one dog, delayed mediastinal shift occurred 9 mo after PNX; both lung volume and DlCOprogressively increased over the subsequent 3 mo. We conclude that preventing mediastinal shift after PNX impairs recruitment of diffusing capacity but does not abolish expansion of the remaining lung or the compensatory increase in extravascular septal tissue volume.