bluuebunny/crossref_metadata_2025 huggingface dataset:
Autocrine extracellular purinergic signaling in epithelial cells derived from polycystic kidneys
Authors: Schwiebert Erik M. , Wallace Darren P. , Braunstein Gavin M. , King Sandi R. , Peti-Peterdi Janos , Hanaoka Kazushige , Guggino William B. , Guay-Woodford Lisa M. , Bell P. Darwin , Sullivan Lawrence P. , Grantham Jared J. , Taylor Amanda L.
Published: March 2015

ATP and its metabolites are potent autocrine agonists that act extracellularly within tissues to affect epithelial function. In polycystic kidneys, renal tubules become dilated and/or encapsulated as cysts, creating abnormal microenvironments for autocrine signaling. Previously, our laboratory has shown that high-nanomolar to micromolar quantities of ATP are released from cell monolayers in vitro and detectable in cyst fluids from microdissected human autosomal dominant polycystic kidney (ADPKD) cysts. Here, we show enhanced ATP release from autosomal recessive polycystic kidney (ARPKD) and ADPKD epithelial cell models. RT-PCR and immunoblotting for P2Y G protein-coupled receptors and P2X purinergic receptor channels show expression of mRNA and/or protein for multiple subtypes from both families. Assays of cytosolic Ca2+concentration and secretory Cl−transport show P2Y and P2X purinergic receptor-mediated stimulation of Cl−secretion via cytosolic Ca2+-dependent signaling. Therefore, we hypothesize that autocrine purinergic signaling may augment detrimentally cyst volume expansion in ADPKD or tubule dilation in ARPKD, accelerating disease progression.
ATP inhibits Mg2+uptake in MDCT cells via P2X purinoceptors
Authors: Dai Long-Jun , Kang Hyung Sub , Kerstan Dirk , Ritchie Gordon , Quamme Gary A.
Published: March 2015

First published July 12, 2001; 10.1152/ajprenal.00349.2001.—Nucleotides have diverse effects on water and electrolyte reabsorption within the distal tubule of the nephron. As the distal tubule is important in control of renal Mg2+balance, we determined the effects of ATP on cellular Mg2+uptake in this segment. The effects of ATP on immortalized mouse distal convoluted tubule (MDCT) cells were studied by measuring Mg2+uptake with fluorescence techniques. The mean basal Mg2+uptake rate was 165 ± 6 nM/s. ATP inhibited basal Mg2+uptake and hormone-stimulated Mg2+entry by 40%. Both P2X (P2X1–P2X5 subtypes) and P2Y2 receptor subtypes were identified in MDCT cells using differential RT-PCR. Activation of both receptor subtypes with selective agonists increased intracellular Ca2+concentration, P2X purinoceptors by ionotropic-gated channels, and P2Y receptors via G protein-mediated intracellular Ca2+release. The more relatively selective P2X agonists [β,γ-methylene ATP (β,γ-Me-ATP) and 2′- and -3′- O-(4-benzoyl-benzoyl)-ATP] inhibited arginine vasopressin (AVP)- and parathyroid hormone (PTH)-mediated Mg2+uptake whereas agonists more selective for P2Y purinoceptors (UTP, ADP, and 2-methylthio-ATP) were without effect. Removal of extracellular Ca2+diminished β,γ-Me-ATP-mediated increase in intracellular Ca2+and inhibition of AVP-stimulated Mg2+entry. We conclude from this information that ATP inhibited Mg2+uptake in MDCT cells through P2X purinoceptors expressed in this distal convoluted tubule cell line.
Invited Review: Complexity of factors modulating airway narrowing in vivo: relevance to assessment of airway hyperresponsiveness
Authors: Brusasco Vito , Pellegrino Riccardo
Published: March 2015

In vivo, the airway response to constrictor stimuli is the net result of a complex array of factors, some facilitating and some opposing airway narrowing, which makes the interpretation of bronchial challenges far from being straightforward. This review begins with a short description of the complex mechanisms of airway smooth muscle activation and force generation as the starting events for airway narrowing. It then focuses on gain factors modulating airway smooth muscle shortening and on the geometric factors determining the magnitude of reduction in airway caliber in vivo. Finally, in light of the evidence that mechanical modulation of airway smooth muscle tone and airway narrowing is at least as important as the inflammatory contractile mediators in the pathogenesis of airway hyper-responsiveness, the implications for the interpretation of bronchial challenges in clinical settings are discussed.
Selected Contribution: Lung hypoxia: antioxidant and antiapoptotic effects of liposomal α-tocopherol
Authors: Minko T. , Stefanov A. , Pozharov V.
Published: March 2015

The aim of this study is to examine the antioxidant and antiapoptotic activity of liposomal α-tocopherol (LAT) in anesthetized rats exposed to severe hypoxia. It was shown that intratracheal application of LAT normalized lung phospholipid composition and inhibited lipid peroxidation in lung tissues, which in turn decreased lung edema and damage and improved breathing pattern, oxygen diffusion, and lung gas exchange. LAT also limited the overexpression of genes encoding hypoxia inducible factor-1α and both studied forms of phospholipase A2, and it increased the power of cellular antioxidant and antiapoptotic defense by overexpressing genes encoding Mn- and Cu-Zn-cofactored superoxide dismutases, Bcl-2, and heat shock 70 proteins. The overexpression of studied caspases and their activity were downregulated, which significantly (1.6–2 times) limited apoptosis in lung cells. Finally, all these positive changes decreased mortality during hypoxia from ∼60% in untreated animals to ∼30% in the group of rats treated with LAT. The data obtained indicate that LAT may be useful for the correction of hypoxic lung injury.
Characteristics of surface mechanomyogram are dependent on development of fusion of motor units in humans
Authors: Yoshitake Yasuhide , Shinohara Minoru , Ue Hidetoshi , Moritani Toshio
Published: March 2015

The purpose of this study was to test whether surface mechanomyogram (MMG) recorded on the skin reflects the contractile properties of individual motor units in humans. Eight motor units in the medial gastrocnemius muscle were identified, and trains of stimulation at 5, 10, 15, and 20 Hz were delivered to each isolated motor unit. There was a significant positive correlation between the duration of MMG and twitch duration. MMG amplitude decreased with increasing stimulation frequency. Reductions in MMG amplitude were in parallel with the reductions in force fluctuations, and the rate of change in both was positively correlated across the motor units. Rate of change in MMG amplitude against force was negatively correlated to half relaxation time and twitch duration. Similar negative correlations were found between force fluctuations and contractile properties. These results provide evidence supporting a direct relation between MMG and contractile properties of individual motor units within the gastrocnemius muscle, indicating that surface MMG is dependent on the contractile properties of the activated motor units in humans.
Differential adenosine sensitivity of diaphragm and skeletal muscle arterioles
Authors: Aaker Aaron , Laughlin M. H.
Published: March 2015

The hyperemic response in exercising skeletal muscle is dependent on muscle fiber-type composition and fiber recruitment patterns, but the vascular control mechanisms producing exercise hyperemia in skeletal muscle remain poorly understood. The purpose of this study was to test the hypothesis that arterioles from white, low-oxidative skeletal muscle are less responsive to adenosine-induced dilation than are arterioles from diaphragm (Dia) and red, high-oxidative skeletal muscle. Second-order arterioles (2As) were isolated from the white portion of gastrocnemius muscle (WG; low-oxidative, fast-twitch muscle tissue) and two types of high-oxidative skeletal muscle [Dia and red portion of gastrocnemius muscle (RG)] of rats. Results reveal that 2As from all three types of muscle dilated in response to the endothelium-dependent dilator acetylcholine (WG: 48 ± 3%, Dia: 51 ± 3%, RG: 74 ± 3%). In contrast, adenosine dilated only 2As from WG (48 ± 4%) and Dia (46 ± 5%) but not those from RG (5 ± 5%). Thus adenosine-induced dilator responses differed among 2As of these different types of muscle tissue. However, the results do not support our hypothesis because 2As from Dia and WG dilated in response to adenosine, whereas 2As from RG did not. We conclude that the adenosine responsiveness of 2As from rat skeletal muscle cannot be predicted only by the fiber-type composition or oxidative capacity of the skeletal muscle tissue wherein the arteriole lies.
Systemic vs. local cytokine and leukocyte responses to unilateral wrist flexion exercise
Authors: Nemet Dan , Hong Suzi , Mills Paul J. , Ziegler Michael G. , Hill Maryann , Cooper Dan M.
Published: March 2015

We hypothesized that brief exercise of a small muscle group would lead to local rather than systemic alterations in cytokines, peripheral blood mononuclear cells, and mediators of angiogenesis. Fifteen men and eight women (age range 22–36 yr old) performed 10 min of unilateral wrist flexion exercise. Blood was sampled from venous catheters in the resting and exercising arm at baseline, at the end of exercise, and at 10, 30, 60, and 120 min after exercise. Lactate was significantly elevated in the exercising arm (+276 ± 35%; P < 0.0005) with no change in the resting arm. In contrast, increases in both arms were observed for interleukin-6 (+139 ± 51%; P < 0.0005), growth hormone (+1,104 ± 284%; P < 0.003), natural killer cells (+81 ± 9%; P < 0.0005), and lymphocytes expressing CD62L, CD11a, and CD54. There were no significant differences in these increases between the resting and exercising arm. Catecholamines increased in both arms [epinephrine peak increase, +226 ± 36% ( P < 0.001); norepinephrine peak increase, +90 ± 15% ( P < 0.01)]. Fibroblast growth factor-2 initially decreased with exercise in both arms, and this was followed by a rebound increase. Vascular endothelial growth factor demonstrated a small but significant increase in both arms (+124 ± 31%; P < 0.05). Brief, low-intensity exercise leads to a systemic rather than local response of mediators that could be involved in inflammation, repair, or angiogenic adaptation to physical activity.
Cardiovascular and splenic responses to exercise in humans
Authors: Stewart Ian B. , Warburton Darren E. R. , Hodges Alastair N. H. , Lyster Donald M. , McKenzie Donald C.
Published: March 2015

To investigate splenic erythrocyte volume after exercise and the effect on hematocrit- and hemoglobin-based plasma volume equations, nine men cycled at an intensity of 60% maximal O2 uptake for 5-, 10-, or 15-min duration, followed by an incremental ride to exhaustion. The reduction in spleen volume, calculated using 99mTc-labeled erythrocytes, was not significantly different among the three submaximal rides (5 min = 28%, 10 min = 30%, 15 min = 36%; P = 0.26). The incremental ride to exhaustion resulted in a 56% reduction in spleen volume, which recovered to baseline levels within 20 min. Plasma catecholamines were inversely related to spleen volume after exercise ( r = 0.70–0.84; P < 0.0001). There were no differences in red cell or total blood volume pre- to postexercise; however, a significant reduction in plasma volume was observed (18.9%; P < 0.01). There was no difference between the iodinated albumin and the hematocrit and hemoglobin methods of assessing plasma volume changes. These results suggest that the spleen regulates its volume in response to an intensity-dependent signal, and plasma catecholamines appear partially responsible. Splenic release of erythrocytes has no effect on indirect measures of plasma volume.
Chronic intermittent hypoxia enhances ventilatory long-term facilitation in awake rats
Authors: McGuire Michelle , Zhang Yi , White David P. , Ling Liming
Published: March 2015

This study examined the effect of chronic intermittent hypoxia (CIH: 5 min 11-12% O2/5 min air, 12 h/night, 7 nights) on ventilatory long-term facilitation (LTF) and determined the persistence period of this CIH effect in awake rats. LTF, elicited by 5 or 10 episodes of 5 min 12% O2, was measured four times in the same Sprague-Dawley rats by plethysmography, before and 8 h, 3 days, and 7 days after CIH treatment. Resting ventilation was unchanged after CIH. Five episodes of 12% O2did not initially elicit LTF but elicited LTF (23.5 ± 1.4% above baseline) 8 h after CIH, which partially remained at 3 days (11.4 ± 2.2%, P < 0.05) and disappeared at 7 days. Ten episodes initially elicited LTF (17.7 ± 1.1%, 45-min duration) and elicited an enhanced LTF (29.1 ± 1.5%, 75 min) 8 h after CIH. These results demonstrated that CIH enhanced ventilatory LTF in conscious, freely behaving rats in two ways: 1) a previously ineffective protocol induced LTF; and 2) LTF magnitude was increased and LTF duration prolonged, and this CIH effect on LTF persisted for at least 3 days.
Effects of mode of exercise recovery on thermoregulatory and cardiovascular responses
Authors: Carter Robert , Wilson Thad E. , Watenpaugh Donald E. , Smith Michael L. , Crandall Craig G.
Published: March 2015

To identify the effects of exercise recovery mode on cutaneous vascular conductance (CVC) and sweat rate, eight healthy adults performed two 15-min bouts of upright cycle ergometry at 60% of maximal heart rate followed by either inactive or active (loadless pedaling) recovery. An index of CVC was calculated from the ratio of laser-Doppler flux to mean arterial pressure. CVC was then expressed as a percentage of maximum (%max) as determined from local heating. At 3 min postexercise, CVC was greater during active recovery (chest: 40 ± 3, forearm: 48 ± 3%max) compared with during inactive recovery (chest: 21 ± 2, forearm: 25 ± 4%max); all P < 0.05. Moreover, at the same time point sweat rate was greater during active recovery (chest: 0.47 ± 0.10, forearm: 0.46 ± 0.10 mg · cm−2 · min−1) compared with during inactive recovery (chest: 0.28 ± 0.10, forearm: 0.14 ± 0.20 mg · cm−2 · min−1); all P < 0.05. Mean arterial blood pressure, esophageal temperature, and skin temperature were not different between recovery modes. These data suggest that skin blood flow and sweat rate during recovery from exercise may be modulated by nonthermoregulatory mechanisms and that sustained elevations in skin blood flow and sweat rate during mild active recovery may be important for postexertional heat dissipation.
V̇o2 max is unaffected by altering the temporal pattern of stimulation frequency in rat hindlimb in situ
Authors: Hepple Russell T. , Krause Daniel J. , Hagen Jason L. , Jackson Cory C.
Published: March 2015

It might be anticipated that fatiguing contractions would impair the aerobic metabolic response in skeletal muscle if significant fatigue developed before full activation of aerobic metabolism. On the basis of this premise, we examined two groups of rats to test the hypothesis that a gradual increase in stimulation frequency would yield a higher maximal O2 uptake (V̇o2 max) than beginning immediately with an intense stimulation frequency because of a slower progression of fatigue under the former conditions. In one group of animals, the distal hindlimb muscles were electrically stimulated at a frequency of 60 tetani/min for 4 min (F60; n = 6 rats); in the other group, the muscles were incrementally stimulated for 1 min at each of 7.5, 15, 30, and 60 tetani/min and for 2 min at 90 tetani/min (FInc; n = 5 rats). Despite large differences in rate of fatigue [time to 60% of initial force was 47 ± 3 (SE) vs. 188 ± 1 s in F60 and FInc, respectively] and the time at which V̇o2 max occurred (120 ± 15 vs. 264 ± 6 s), V̇o2 max was not different (419 ± 24 vs. 381 ± 44 μmol · min-1 · 100 g-1). Furthermore, time × tension integral at V̇o2 max (3.82 ± 0.41 vs. 4.07 ± 0.31 N · s) and peak lactate efflux (910 ± 45 vs. 800 ± 98 μmol · min-1 · 100 g-1) were not different between groups. Thus our results show that the more rapid progression of fatigue in F60 did not compromise the aerobic metabolic response in electrically stimulated rat hindlimb muscles. However, in both groups, O2 uptake and lactate efflux declined after V̇o2 max was attained in similar proportion to a further fall in force, suggesting that ongoing fatigue with intense contractions reduced ATP demand below that requiring maximal aerobic and glycolytic metabolic responses once V̇o2 max was reached.
Effects of exercise training and antioxidantR-ALA on glucose transport in insulin-sensitive rat skeletal muscle
Authors: Saengsirisuwan Vitoon , Perez Felipe R. , Kinnick Tyson R. , Henriksen Erik J.
Published: March 2015

We have recently demonstrated (Saengsirisuwan V, Kinnick TR, Schmit MB, and Henriksen EJ, J Appl Physiol 91: 145–153, 2001) that exercise training (ET) and the antioxidant R-(+)-α-lipoic acid ( R-ALA) interact in an additive fashion to improve insulin action in insulin-resistant obese Zucker ( fa/fa) rats. The purpose of the present study was to assess the interactions of ET and R-ALA on insulin action and oxidative stress in a model of normal insulin sensitivity, the lean Zucker ( fa/−) rat. For 6 wk, animals either remained sedentary, received R-ALA (30 mg · kg body wt−1· day−1), performed ET (treadmill running), or underwent both R-ALA treatment and ET. ET alone or in combination with R-ALA significantly increased ( P < 0.05) peak oxygen consumption (28–31%) and maximum run time (52–63%). During an oral glucose tolerance test, ET alone or in combination with R-ALA resulted in a significant lowering of the glucose response (17–36%) at 15 min relative to R-ALA alone and of the insulin response (19–36%) at 15 min compared with sedentary controls. Insulin-mediated glucose transport activity was increased by ET alone in isolated epitrochlearis (30%) and soleus (50%) muscles, and this was associated with increased GLUT-4 protein levels. Insulin action was not improved by R-ALA alone, and ET-associated improvements in these variables were not further enhanced with combined ET and R-ALA. Although ET and R-ALA caused reductions in soleus protein carbonyls (an index of oxidative stress), these alterations were not significantly correlated with insulin-mediated soleus glucose transport. These results indicate that the beneficial interactive effects of ET and R-ALA on skeletal muscle insulin action observed previously in insulin-resistant obese Zucker rats are not apparent in insulin-sensitive lean Zucker rats.
Age effects on force produced by intrinsic and extrinsic hand muscles and finger interaction during MVC tasks
Authors: Shinohara Minoru , Latash Mark L. , Zatsiorsky Vladimir M.
Published: March 2015

Finger-pressing forces are produced by activation of the intrinsic hand muscles, which are finger specific, and the extrinsic muscles that connect to multiple fingers. We tested a hypothesis of greater weakening of intrinsic hand muscles with age and quantified associated indexes of finger interaction such as enslaving (force production by unintended fingers) and force deficit (loss of finger force in multifinger tasks compared with single-finger tasks). Twelve young (23-35 yr old) and 12 elderly (70-95 yr old) men and women performed single-finger and four-finger maximal pressing tasks, in which force was applied at the proximal phalanges (PP, the intrinsic muscles are major focal force generators) and at the distal phalanges (DP, the extrinsic muscles are focal force generators). The decline in the peak force with age was greater at PP (30%) than at DP (19%). Larger indexes of finger interaction were observed at PP (enslaving = 17.2 ± 9.4%, force deficit = 36.1 ± 11.1%) than at DP (enslaving = 14.9 ± 8.8%, force deficit = 27.7 ± 10.8%) across ages and genders. We conclude that intrinsic hand muscles show disproportionate weakening with age. The greater indexes of finger interaction in PP tests with greater involvement of intrinsic hand muscles suggest that the finger interactions are predominantly of a central origin across ages and genders.
Changes in regional cerebral metabolism during systemic hyperthermia in humans
Authors: Nunneley Sarah A. , Martin Charles C. , Slauson James W. , Hearon Christopher M. , Nickerson Lisa D. H. , Mason Patrick A.
Published: March 2015

Whole body hyperthermia may produce vasodialation, nausea, and altered cognitive function. Animal research has identified brain regions that have important roles in thermoregulation. However, differences in both the cognitive and sweating abilities of humans and animals implicate the need for human research. Positron emission tomography (PET) was used to identify brain regions with altered activity during systemic hyperthermia. Human subjects were studied under cool (control) conditions and during steady-state hyperthermia induced by means of a liquid-conditioned suit perfused with hot water. PET images were obtained by injecting [18F]fluorodeoxyglucose, waiting 20 min for brain uptake, and then scanning for 10 min. Heating was associated with a 23% increase in resting metabolic rate. Significant increases in cerebral metabolic rate occurred in the hypothalamus, thalamus, corpus callosum, cingulate gyrus, and cerebellum. In contrast, significant decreases occurred in the caudate, putamen, insula, and posterior cingulum. These results are important for understanding the mechanisms responsible for altered cognitive and systemic responses during hyperthermia. Novel regions (e.g., lateral cerebellum) with possible thermoregulatory roles were identified.
Chronic hypoxia upregulates connexin43 expression in rat carotid body and petrosal ganglion
Authors: Chen J. , He L. , Dinger B. , Stensaas L. , Fidone S.
Published: March 2015

Recent studies have demonstrated that oxygen-sensitive type I cells in the carotid body express the gap junction-forming protein connexin43 (Cx43). In the present study, we examined the hypothesis that chronic exposure to hypoxia increases Cx43 expression in type I cells as well as in chemoafferent neurons in the petrosal ganglion. Immunocytochemical studies in tissues from normal rats revealed diffuse and granular Cx43-like immunoreactivity in the cytoplasm of type I cells and dense punctate spots of immunoreactive product at the margins of type I cells and near the borders of chemosensory cell lobules. Cx43-like immunoreactivity was not detectable in petrosal ganglion neurons from normal animals. After a 2-wk exposure to hypobaric (380 Torr) hypoxia, Cx43 immunostaining was substantially enhanced in and around type I cells. Moreover, chronic hypoxia elicited the expression of Cx43-like immunoreactivity in the cytoplasm of afferent neurons throughout the petrosal ganglion. Quantitative RT-PCR studies indicate that chronic hypoxia evokes a substantial increase in Cx43 mRNA levels in the carotid body, along with a marked elevation of Cx43 expression in the petrosal ganglion. Increased Cx43 expression and gap junction formation in type I cells and sensory neurons may contribute to carotid body adaptation during sustained stimulation in extreme physiological conditions.
Selected Contribution: Bone adaptation with aging and long-term caloric restriction in Fischer 344 × Brown-Norway F1-hybrid rats
Authors: LaMothe Jeremy M. , Hepple Russell T. , Zernicke Ronald F.
Published: March 2015

Rodents are commonly used as models for human aging because of their relatively short life span, the ease of obtaining age-specific tissue samples, and lower cost. However, age-associated disease may confound inbred animal studies. For example, numerous physiologically significant lesions, such as chronic nephropathy, are more common in aged Fischer 344 (F344) rats than in other strains (Bronson RT, Genetic Effects of Aging, 1990). Conversely, F344 × Brown-Norway F1-hybrid (F344BN) rats, developed by the National Institute on Aging for aging research, live considerably longer and have fewer pathologies at any given age vs. inbred strains (Lipman RD, Chrisp CE, Hazzard DG, and Bronson RT, J Gerontol A Biol Sci Med Sci 51: 54-59, 1996). To our knowledge, there are no data regarding the effect of age on bone geometry and mechanics in this strain of rat. Furthermore, caloric restriction (CR) extends the mean and maximal life span of animals and significantly reduces age-associated disease but may have adverse consequences for bone growth and mechanics. Thus we investigated the effects of age and CR on bone geometry and mechanics in the axial and appendicular skeleton of F344 Brown-Norway rats. Ad libitum fed rats were assessed at 8 mo (young adult; n = 6), 28 mo (late middle age; n = 5), and 36 mo (senescence; n = 6). CR rats were assessed at 28 mo ( n = 6). Tibiae and the sixth lumbar vertebrae (L6) were dissected, scanned (micro-computed tomography) to determine geometry, and tested mechanically. From 8 to 36 mo, there were no significant changes in L6 geometry, and only the cross-sectional moment of inertia changed (increased) with the tibia. CR-induced body mass reductions accounted for changes in L6 load at proportional limit, maximal load, and stiffness (structural properties), but altered tibial structural properties were independent of body mass. In tibiae, geometric changes dominated alterations in structural properties. Those data demonstrated that, whereas aging in ad libitum-fed animals induced minor changes in bone mechanics, axial and appendicular bones were adversely influenced by CR in late-middle-aged animals in different manners.
Serotonergic modulation of respiratory motor output during tadpole development
Authors: Kinkead Richard , Belzile Olivier , Gulemetova Roumiana
Published: March 2015

To test the hypothesis that serotonin (5-hydroxytryptamine; 5-HT)-receptor activation elicits age-dependent changes in respiratory motor output, we compared the effects of 5-HT bath application (5-HT concentration = 0.5–25 μM) onto in vitro brain stem preparations from pre- and postmetamorphic bullfrog tadpoles. Recording of motor output related to gill and lung ventilation showed that 5-HT elicits a dose-dependent depression of gill burst frequency in both groups. In contrast, the lung burst frequency response was stage dependent; an increase in lung burst frequency at low 5-HT concentration (≤0.5 μM) was observed only in the postmetamorphic group. Higher 5-HT concentrations decreased lung burst frequency in all preparations. Gill burst frequency attenuation is mediated (at least in part) by 5-HT1A-receptor activation in an age-dependent fashion. We conclude that serotonergic modulation of respiratory motor output 1) changes during tadpole development and 2) is distinct for gill and lung ventilation.
Effects on fetal and maternal body temperatures of exposure of pregnant ewes to heat, cold, and exercise
Authors: Laburn Helen P. , Faurie Alida , Goelst Kathleen , Mitchell Duncan
Published: March 2015

We exposed Dorper-cross ewes at ∼120–135 days of gestation to a hot (40°C, 60% relative humidity) and a cold (4°C, 90% relative humidity) environment and to treadmill exercise (2.1 km/h, 5° gradient) and measured fetal lamb and ewe body temperatures using previously implanted abdominal radiotelemeters. When ewes were exposed to 2 h of heat or 30 min of exercise, body temperature rose less in the fetus than in the mother, such that the difference between fetal and maternal body temperature, on average 0.6°C before the thermal stress, fell significantly by 0.54 ± 0.06°C (SE, n = 8) during heat exposure and by 0.21 ± 0.08°C ( n = 7) during exercise. During 6 h of maternal exposure to cold, temperature fell significantly less in the fetus than in the ewe, and the difference between fetal and maternal body temperature rose to 1.16 ± 0.26°C ( n = 9). Thermoregulatory strategies used by the pregnant ewe for thermoregulation during heat or cold exposure appear to protect the fetus from changes in its thermal environment.
Glutamate ingestion and its effects at rest and during exercise in humans
Authors: Mourtzakis Marina , Graham Terry E.
Published: March 2015

Glutamate is central to several transamination reactions that affect the production of ammonia, alanine, glutamine, as well as TCA cycle intermediates during exercise. To further study glutamate metabolism, we administered 150 mg/kg body wt of monosodium glutamate (MSG) and placebo to seven male subjects who then either rested or exercised (15-min cycling at ∼85% maximal oxygen consumption). MSG ingestion resulted in elevated plasma glutamate, aspartate, and taurine, both at rest and during exercise ( P < 0.05), whereas most other amino acids were unchanged. Neither plasma alanine nor ammonia was altered at rest. During exercise and after glutamate ingestion, alanine was increased ( P < 0.05) and ammonia was attenuated ( P < 0.05). Glutamine was also elevated after glutamate ingestion during rest and exercise trials. MSG administration also resulted in elevated insulin levels ( P < 0.05), which were parallel to the trend in C-peptide levels. Thus MSG can successfully elevate plasma glutamate, both at rest and during exercise. The plasma amino acid responses suggest that increased glutamate availability during exercise alters its distribution in transamination reactions within active muscle, which results in elevated alanine and decreased ammonia levels.
Alterations of neuromuscular function after an ultramarathon
Authors: Millet G. Y. , Lepers R. , Maffiuletti N. A. , Babault N. , Martin V. , Lattier G.
Published: March 2015

Neuromuscular fatigue of the knee extensor (KE) and plantar flexor (PF) muscles was characterized after a 65-km ultramarathon race in nine well-trained runners by stimulating the femoral and tibial nerves, respectively. One week before and immediately after the ultramarathon, maximal twitches were elicited from the relaxed KE and PF. Electrically evoked superimposed twitches of the KE were also elicited during maximal voluntary contractions (MVCs) to determine maximal voluntary activation. MVC and maximal voluntary activation decreased significantly after the ultramarathon (−30.2 ± 18.0% and −27.7 ± 13.0%, respectively; P < 0.001). Surprisingly, peak twitch increased after the ultramarathon from 15.8 ± 6.3 to 19.7 ± 3.3 N · m for PF ( P < 0.01) and from 131.9 ± 21.2 to 157.1 ± 35.9 N for KE ( P < 0.05). Also, shorter contraction and half-relaxation times were observed for both muscles. The compound muscle action potentials (M wave) were not significantly altered by the ultramarathon with the exception of the soleus, which showed a slightly higher M-wave amplitude after the running. From these results, it can be concluded that 65 km of running 1) severely depressed the maximal voluntary force capacity mainly because of a decrease in maximal voluntary activation, 2) potentiated the twitch mechanical response, and 3) did not change significantly the M-wave characteristics.
Zero-stress state of intra- and extraparenchymal airways from human, pig, rabbit, and sheep lung
Authors: McKay Karen O. , Wiggs Barry R. , Paré Peter D. , Kamm Roger D.
Published: March 2015

Alterations in airway wall anatomic properties and the consequential effects on airway narrowing have been assessed by use of computational models. In these models, it is generally assumed that at zero transmural pressure the airway wall exists in a zero-stress state. Many studies have shown that this is often not the case, as evidenced by a nonzero opening angle. In this study, we measured the opening angle of airway rings at zero transmural pressure to test this assumption. The airway tree was dissected from human, pig, sheep, and rabbit lungs. Airways were excised from the tree, and the opening angle was measured. There were obvious species and regional differences in opening angle. Rabbit airways from both extraparenchymal and intraparenchymal sites exhibited marked opening angles (7–82°). Extraparenchymal airways from sheep had large opening angles (up to 50°), but ovine intraparenchymal airways had small opening angles. Measurable opening angles were rarely observed in human and porcine airways of any size. The assumption of a stable zero-stress state at zero transmural pressure is therefore valid for human and porcine, but not rabbit and sheep, airways.
ACE insertion/deletion polymorphism and submaximal exercise hemodynamics in postmenopausal women
Authors: Hagberg James M. , McCole Steve D. , Brown Michael D. , Ferrell Robert E. , Wilund Kenneth R. , Huberty Andrea , Douglass Larry W. , Moore Geoffrey E.
Published: March 2015

We sought to determine whether the angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism is associated with submaximal exercise cardiovascular hemodynamics. Postmenopausal healthy women (20 sedentary, 20 physically active, 22 endurance athletes) had cardiac output (acetylene rebreathing) measured during 40, 60, and 80%V˙o 2 max exercise. The interaction of ACE genotype and habitual physical activity (PA) level was significantly associated with submaximal exercise systolic blood pressure, with only sedentary women exhibiting differences among genotypes. No significant effects of ACE genotype or its interaction with PA levels was observed for submaximal exercise diastolic blood pressure. ACE genotype was significantly associated with submaximal exercise heart rate (HR) with ACE II having ∼10 beats/min higher HR than ACE ID/DD genotype women. ACE genotype did not interact significantly with habitual PA level to associate with submaximal exercise HR. ACE genotype was not independently, but was interactively with habitual PA levels, associated with differences in submaximal exercise cardiac output and stroke volume. For cardiac output, ACE II genotype women athletes had ∼25% greater cardiac output than ACE DD genotype women athletes, whereas for stroke volume genotype-dependent differences were observed in both the physically active and athletic women. ACE genotype was not significantly associated, either independently or interactively with habitual PA levels, with submaximal exercise total peripheral resistance or arteriovenous O2 difference. Thus the common ACE locus polymorphic variation is associated with many submaximal exercise cardiovascular hemodynamic responses.
Long-term facilitation of ventilation is not present during wakefulness in healthy men or women
Authors: Jordan A. S. , Catcheside P. G. , O'Donoghue F. J. , McEvoy R. D.
Published: March 2015

Obstructive sleep apnea (OSA) is more common in men than in women for reasons that are unclear. The stability of the respiratory controller has been proposed to be important in OSA pathogenesis and may be involved in the gender difference in prevalence. Repetitive hypoxia elicits a progressive rise in ventilation in animals [long-term facilitation (LTF)]. There is uncertainty whether LTF occurs in humans, but if present it may stabilize respiration and possibly also the upper airway. This study was conducted to determine 1) whether LTF exists during wakefulness in healthy human subjects and, if so, whether it is more pronounced in women than men and 2) whether inspiratory pump and upper airway dilator muscle activities are affected differently by repetitive hypoxia. Twelve healthy young men and ten women in the luteal menstrual phase were fitted with a nasal mask and intramuscular genioglossal EMG (EMGgg) recording electrodes. After 5 min of rest, subjects were exposed to ten 2-min isocapnic hypoxic periods (∼9% O2 in N2, arterial O2 saturation ∼80%) separated by 2 min of room air. Inspired minute ventilation (V˙i) and peak inspiratory EMGgg activity were averaged over 30-s intervals, and respiratory data were compared between genders during and after repetitive hypoxia by using ANOVA for repeated measures. V˙i during recovery from repetitive hypoxia was not different from the resting level and not different between genders. There was no facilitation of EMGgg activity during or after repetitive hypoxia. EMGgg activity was reduced below baseline during recovery from repetitive hypoxia in women. In conclusion, we have found no evidence of LTF of ventilation or upper airway dilator muscle activity in healthy subjects during wakefulness.
Cardiac outflow of amino acids and purines during myocardial ischemia and reperfusion
Authors: Bäckström Tobias , Goiny Michel , Lockowandt Ulf , Liska Jan , Franco-Cereceda Anders
Published: March 2015

A novel application of microdialysis was studied, in which myocardial outflow of amino acids and purines was monitored by intravasal microdialysis in the myocardial venous outflow during ischemia and reperfusion. Microdialysis catheters were introduced into the great cardiac vein, pulmonary artery, and external jugular vein in 20 anesthetized pigs. The left anterior descending artery was occluded in four groups of pigs for 0, 10, 15, and 60 min. Ischemia was followed by 120 min of reperfusion. Microdialysis samples were analyzed for taurine, aspartate, glutamate, hypoxanthine, inosine, and guanosine. Myocardial infarction developed when ischemia exceeded 10 min. Taurine, aspartate, inosine, and guanosine increased early in the great cardiac vein during ischemia. We found the outflow patterns of amino acids and purines to be graded in response to different lengths of ischemia. In this study we have demonstrated a graded outflow of amino acids and purines in response to ischemia and a positive correlation between infarct size and myocardial outflow of amino acids and purines. This could be of value in a clinical setting to quantify the extent of myocardial damage.
Oxidation rate of exogenous carbohydrate during exercise is higher in boys than in men
Authors: Timmons Brian W. , Bar-Or Oded , Riddell Michael C.
Published: March 2015

To determine whether the relative utilization of exogenous carbohydrate (CHOexo) differs between children and adults, substrate utilization during 60 min of cycling at 70% peak O2 uptake was studied in 12 pre- and early pubertal boys (9.8 ± 0.1 yr) and 10 men (22.1 ± 0.5 yr) on two occasions. Subjects consumed either a placebo or a13C-enriched 6% CHOexo beverage (total volume per trial: 24 ml/kg). Substrate utilization was calculated for the final 30 min of exercise. During both trials, total fat oxidation was higher (5.4 ± 0.5 vs. 3.0 ± 0.4 mg · kg−1 · min−1, P < 0.001) and total CHO oxidation lower (27.4 ± 1.5 vs. 34.8 ± 1.2 mg · kg−1 · min−1, P < 0.001) in boys than in men, respectively. During the CHOexo trial, CHOexo oxidation was higher ( P < 0.001) in boys (8.8 ± 0.5 mg · kg−1 · min−1) than in men (6.2 ± 0.5 mg · kg−1 · min−1) and provided a greater ( P < 0.001) relative proportion of total energy in boys (21.8 ± 1.4%) than in men (14.6 ± 0.9%). These results suggest that, although endogenous CHO utilization during exercise is lower, the relative oxidation of ingested CHO is considerably higher in boys than in men. The greater reliance on CHOexo in boys may be important in preserving endogenous fuels and may be related to pubertal status.
Selected Contribution: TNF-α modulates murine tracheal rings responsiveness to G-protein-coupled receptor agonists and KCl
Authors: Chen Hang , Tliba Omar , Van Besien Christopher R. , Panettieri Reynold A. , Amrani Yassine
Published: March 2015

Although the mechanisms that underlie airway hyperresponsiveness in asthma are complex and involve a variety of factors, evidence now suggests that intrinsic abnormalities in airway smooth muscle (ASM) may play an important role. We previously reported that TNF-α, a cytokine involved in asthma, augments G-protein-coupled receptor (GPCR) agonist-evoked calcium responses in cultured ASM cells. Here we have extended our previous studies by investigating whether TNF-α also modulates the contractile and relaxant responses to GPCR activation using cultured murine tracheal rings. We found that in tracheal rings treated with 50 ng/ml TNF-α, carbachol-induced isometric force was significantly increased by 30% compared with those treated with diluent alone ( P < 0.05). TNF-α also augmented KCl-induced force generation by 70% compared with rings treated with diluent alone ( P < 0.01). The enhancing effect of TNF-α on carbachol-induced isometric force generation was completely abrogated in the tracheal rings obtained from TNF-α receptor (TNFR)1-deficient mice and in control rings treated with a TNF-α mutant that solely activates TNFR2. TNF-α also attenuated relaxation responsiveness to isoproterenol but not to PGE2or forskolin. TNF-α modulatory effects on GPCR-induced ASM responsiveness were completely abrogated by pertussis toxin, an inhibitor of Giα proteins. Taken together, these data suggest that TNF-α may participate in the development of airway hyperresponsiveness in asthma via the modulation of ASM responsiveness to both contractile and β-adrenoceptor GPCR agonists.
Physical capacity influences the response of insulin-like growth factor and its binding proteins to training
Authors: Rosendal Lars , Langberg Henning , Flyvbjerg Allan , Frystyk Jan , Ørskov Hans , Kjær Michael
Published: March 2015

The influence of initial training status on the response of circulating insulin-like growth factor (IGF) and its binding proteins (IGFBP) to prolonged physical training was studied in young men. It was hypothesized that highly standardized training would result in more extensive changes in the circulating IGF system in untrained subjects because of lower fitness level. Seven untrained (UT) and 12 well-trained (WT) individuals performed 11 wk of intense physical training (2–4 h daily). Fasting serum samples were analyzed for total and free IGF-I and -II, for IGFBP-1 to -4, as well as for IGFBP-3 proteolysis. Eleven weeks of physical training resulted in decreased levels of total IGF-I, free IGF-I, and IGFBP-4 in both the UT and WT groups. In the UT group, IGFBP-2 increased, IGFBP-3 decreased [from 4,255 ± 410 (baseline) to 3,896 ± 465 (SD) μg/l ( week 4); P < 0.05], and IGFBP-3 proteolysis increased [from 28 ± 8% (baseline) to 37 ± 7% ( week 4) and 39 ± 12% ( week 11); P < 0.05], whereas no significant changes were found in the WT group. In conclusion, intense physical training results in a marked influence on the IGF system and its binding proteins with generally more extensive changes seen in the untrained individuals. Also, prolonged physical training resulted in increased IGFBP-3 proteolysis in previously untrained individuals only, indicating that intense physical training affects trained and untrained individuals differently.
Termination of inspiration by phase-dependent respiratory vagal feedback in awake normal humans
Authors: BuSha Brett F. , Stella Martha H. , Manning Harold L. , Leiter J. C.
Published: March 2015

Imperceptible levels of proportional assist ventilation applied throughout inspiration reduced inspiratory time (Ti) in awake humans. More recently, the reduction in Ti was associated with flow assist, but flow assist also reaches a maximum value early during inspiration. To test the separate effects of flow assist and timing of assist, we applied a pseudorandom binary sequence of flow-assisted breaths during early, late, or throughout inspiration in eight normal subjects. We hypothesized that imperceptible flow assist would shorten Ti most effectively when applied during early inspiration. Tidal volume, integrated respiratory muscle pressure per breath, Ti, and Te were recorded. All stimuli (early, late, or flow assist applied throughout inspiration) resulted in a significant increase in inspiratory flow; however, only when the flow assist was applied during early inspiration was there a significant reduction in Tiand the integrated respiratory muscle pressure per breath. These results provide further evidence that vagal feedback modulates breathing on a breath-by-breath basis in conscious humans within a physiological range of breath sizes.
A synthetic surfactant based on a poly-Leu SP-C analog and phospholipids: effects on tidal volumes and lung gas volumes in ventilated immature newborn rabbits
Authors: Johansson Jan , Some Margareta , Linderholm Britt-Marie , Almlén Andreas , Curstedt Tore , Robertson Bengt
Published: March 2015

Available surfactants for treatment of respiratory distress syndrome in newborn infants are derived from animal lungs, which limits supply and poses a danger of propagating infectious material. Poly-Val→poly-Leu analogs of surfactant protein (SP)-C can be synthesized in large quantities and exhibit surface activity similar to SP-C. Here, activity of synthetic surfactants containing a poly-Leu SP-C analog (SP-C33) was evaluated in ventilated premature newborn rabbits. Treatment with 2.5 ml/kg body wt of 2% (wt/wt) SP-C33 in 1,2-dipalmitoyl- sn-3-glycero phosphoryl choline (DPPC)-1-palmitoyl-2-oleoyl- sn-3-glycero phosphoryl choline (POPC)-1-palmitoyl-2-oleoyl- sn-3-glycero phosphoryl glycerol (POPG), 68:0:31, 68:11:20, or 68:16:15 (wt/wt/wt) suspended at 80 mg/ml gave tidal volumes (Vt) of 20-25 ml/kg body wt, with an insufflation pressure of 25 cmH2O and no positive end-expiratory pressure (PEEP), comparable to the Vt for animals treated with the porcine surfactant Curosurf. Nontreated littermates had a Vt of ∼2 ml/kg body wt. The Vt for SP-C33 in DPPC-egg phosphatidylglycerol-palmitic acid [68:22:9 (wt/wt/wt)], DPPC-POPG-palmitic acid [68:22:9 (wt/wt/wt)], and DPPC-POPC-POPG [6:2:2 (wt/wt/wt)] was 15-20 ml/kg body wt. Histological examination of lungs from animals treated with SP-C33-based surfactants showed incomplete, usually patchy air expansion of alveolar spaces associated with only mild airway epithelial damage. Lung gas volume after 30 min of mechanical ventilation were more than threefold larger in animals treated with Curosurf than in those receiving SP-C33 in DPPC-POPC-POPG, 68:11:20. This difference could be largely counterbalanced by ventilation with PEEP (3-4 cmH2O). An artificial surfactant based on SP-C33 improves Vt in immature newborn animals ventilated with standardized peak pressure but requires PEEP to build up adequate lung gas volumes.
Effects of ion transport inhibitors on MCh-mediated secretion from porcine airway submucosal glands
Authors: Phillips Jonathan E. , Hey John A. , Corboz Michel R.
Published: March 2015

Submucosal glands secrete macromolecules and liquid that are essential for normal airway function. To determine the mechanisms responsible for airway gland secretion and the interaction between gland secretion and epithelial ion transport, studies were performed in porcine tracheal epithelia by using the hillocks and Ussing techniques. No significant baseline gland fluid flux ( J G) was measured by the hillocks technique after 3 min, and the epithelia had an average potential difference of 7.5 ± 0.5 mV (lumen negative) with a short-circuit current of 73 ± 4 μA/cm2, as measured by the Ussing technique. The secretagogue methacholine induced concentration-dependent increases in J G after 3 min from 0.003 μl · min−1 · cm−2 at 0.1 μM to 0.41 ± 0.04 μl · min−1 · cm−2 at 1,000 μM, with a 0.9 ± 0.1 mV hyperpolarization of the epithelium at 1,000 μM. When the epithelium was pretreated for 3 min with the sodium channel blocker amiloride, the methacholine (1,000 μM)-induced J G increased to 0.67 ± 0.09 μl · min−1 · cm−2, and the hyperpolarization increased to 2.2 ± 0.5 mV over the amiloride-pretreated level. When pretreated for 3 min with the chloride channel blocker diphenylamine-2-carboxylic acid, the methacholine (1,000 μM)-induced J G was inhibited to 0.20 ± 0.06 μl · min−1 · cm−2, and the methacholine-induced hyperpolarization was abolished. These data indicate that, in porcine airways, methacholine-induced J G may be increased by inhibition of sodium absorption and decreased by inhibition of chloride secretion.