bluuebunny/crossref_metadata_2025 huggingface dataset:
Anaerobic energy provision does not limit Wingate exercise performance in endurance-trained cyclists
Authors: Calbet J. A. L. , De Paz J. A. , Garatachea N. , Cabeza de Vaca S. , Chavarren J.
Published: March 2015

The aim of this study was to evaluate the effects of severe acute hypoxia on exercise performance and metabolism during 30-s Wingate tests. Five endurance- (E) and five sprint- (S) trained track cyclists from the Spanish National Team performed 30-s Wingate tests in normoxia and hypoxia (inspired O2 fraction = 0.10). Oxygen deficit was estimated from submaximal cycling economy tests by use of a nonlinear model. E cyclists showed higher maximal O2 uptake than S (72 ± 1 and 62 ± 2 ml · kg−1 · min−1, P < 0.05). S cyclists achieved higher peak and mean power output, and 33% larger oxygen deficit than E ( P< 0.05). During the Wingate test in normoxia, S relied more on anaerobic energy sources than E ( P < 0.05); however, S showed a larger fatigue index in both conditions ( P < 0.05). Compared with normoxia, hypoxia lowered O2 uptake by 16% in E and S ( P < 0.05). Peak power output, fatigue index, and exercise femoral vein blood lactate concentration were not altered by hypoxia in any group. Endurance cyclists, unlike S, maintained their mean power output in hypoxia by increasing their anaerobic energy production, as shown by 7% greater oxygen deficit and 11% higher postexercise lactate concentration. In conclusion, performance during 30-s Wingate tests in severe acute hypoxia is maintained or barely reduced owing to the enhancement of the anaerobic energy release. The effect of severe acute hypoxia on supramaximal exercise performance depends on training background.
Impact of axial diffusion on nitric oxide exchange in the lungs
Authors: Shin Hye-Won , George Steven C.
Published: March 2015

Nitric oxide (NO) appears in the exhaled breath and is a potentially important clinical marker. The accepted model of NO gas exchange includes two compartments, representing the airway and alveolar region of the lungs, but neglects axial diffusion. We incorporated axial diffusion into a one-dimensional trumpet model of the lungs to assess the impact on NO exchange dynamics, particularly the impact on the estimation of flow-independent NO exchange parameters such as the airway diffusing capacity and the maximum flux of NO in the airways. Axial diffusion reduces exhaled NO concentrations because of diffusion of NO from the airways to the alveolar region of the lungs. The magnitude is inversely related to exhalation flow rate. To simulate experimental data from two different breathing maneuvers, NO airway diffusing capacity and maximum flux of NO in the airways needed to be increased approximately fourfold. These results depend strongly on the assumption of a significant production of NO in the small airways. We conclude that axial diffusion may decrease exhaled NO levels; however, more advanced knowledge of the longitudinal distribution of NO production and diffusion is needed to develop a complete understanding of the impact of axial diffusion.
Rises in whole muscle passive tension of mammalian muscle after eccentric contractions at different lengths
Authors: Whitehead N. P. , Morgan D. L. , Gregory J. E. , Proske U.
Published: March 2015

This is a report of experiments carried out on the medial gastrocnemius muscle of the anesthetized cat, investigating the effects of eccentric contractions carried out at different muscle lengths on the passive and active length-tension relationships. In one series of experiments, the motor supply to the muscle was divided into three approximately equal parts; in the other, whole muscles were used. Fifty eccentric contractions were carried out over different regions of the active length-tension curve for each partial or whole muscle. Active and passive length-tension curves were measured before and after the eccentric contractions. When eccentric contractions were carried out at longer lengths, there was a larger shift of the optimum length for active tension in the direction of longer muscle lengths and a larger fall in peak isometric tension. Passive tension was higher immediately after the eccentric contractions, and if the muscle was left undisturbed for 40 min, it increased further to higher values, particularly after contractions at longer lengths. A series of 20 passive stretches of the same speed and amplitude and covering the same length range as the active stretches, reduced the passive tension which redeveloped over a subsequent 40-min period. It is hypothesized that there are two factors influencing the level of passive tension in a muscle after a series of eccentric contractions. One is injury contractures in damaged muscle fibers tending to raise passive tension; the other is the presence of disrupted sarcomeres in series with still-functioning sarcomeres tending to reduce it.
7-Nitroindazole and posthypoxic ventilatory behavior in the A/J and C57BL/6J mouse strains
Authors: Price Edwin R. , Han Fang , Dick Thomas E. , Strohl Kingman P.
Published: March 2015

Periodic breathing (PB) is a fundamental breathing pattern in many common cardiopulmonary illnesses. The finding of PB in C57BL/6J (B6) mice was previously ascribed to strain differences in posthypoxic ventilatory and frequency decline in the B6 mice (Han F, Subramanian S, Price ER, Nadeau J, and Strohl KP. J Appl Physiol 92: 1133-1140, 2002). We tested whether the induction of posthypoxic frequency decline in A/J mice, through administration of a neuronal nitric oxide synthase blocker [7-nitroindazole (7-NI); 60 mg/kg], would cause A/J mice to exhibit PB and/or alter PB expression in the B6 strain. Recordings of ventilatory behavior by the plethysmography method were made when unanesthetized B6 ( n = 10) or A/J ( n = 6) animals were reoxygenated with 100% O2or room air after exposure to 8% O2. Before undergoing gas challenges, mice were given an intraperitoneal injection of either peanut oil alone (vehicle) or 7-NI suspended in peanut oil. Compared with vehicle, both strains of mice exhibited posthypoxic frequency decline and the absence of short-term potentiation with 7-NI administration. B6 mice continued to exhibit posthypoxic PB; however, the PB was characterized by longer cycle and apnea length. In contrast, A/J mice did not show increased tendency toward posthypoxic PB with 7-NI. We conclude that 7-NI further differentiates the A/J and B6 strains in terms of PB and that strain-related differences in posthypoxic frequency decline are not primary determinants of this strain difference in the occurrence of PB. Metabolism was not associated with either the expression of posthypoxic ventilatory decline or PB. Furthermore, neuronal nitric oxide may be an organizing feature in the presence, length, and/or cycle length of apnea in the susceptible strain.
Carbohydrate supplementation and exercise-induced changes in T-lymphocyte function
Authors: Green Katherine J. , Croaker Susan J. , Rowbottom David G.
Published: March 2015

Carbohydrate (CHO) ingestion during exercise has been shown to reduce perturbations in immune cell numbers and function, possibly through a reduction in the cortisol response to exercise. We have previously observed that exercise decreases T-lymphocyte responses to mitogen via an increase in cell death of both CD4 and CD8 T lymphocytes (Green KJ and Rowbottom DG. J Appl Physiol. 95: 57-63, 2003). This study tested the hypothesis that CHO ingestion rather than placebo (Pl) would result in an attenuation of the cortisol response to exercise and a reduction of the exercise-associated alterations in cell death. Six well-trained cyclists completed two exercise trials consisting of 2.5 h of cycling at 85% of individual ventilatory threshold. In a random order, trials were completed under either CHO (6% CHO solution, 3.2 g CHO/kg body wt total) or Pl conditions. Blood samples were collected before exercise, midexercise (after 60 min of exercise), immediately after exercise, and after 60 min of recovery. T-lymphocyte responses to mitogen were determined by using carboxyfluorescein diacetate succinimidyl ester fluorescent cell division tracking and expansion rates, and cell death rates were calculated for each sample as well as mitosis rates for each cell generation. Cellular expansion of T lymphocytes was decreased after exercise in Pl only. The reduction in cellular expansion was related to an increase in cell death of both CD4 and CD8 cells in culture rather than a decrease in the ability of cells to undergo mitosis. CHO ingestion compared with Pl was associated with no reductions in cellular expansion or increases in cell death. CHO ingestion during exercise acted to reduce the impairment of T-lymphocyte function by decreasing cell death within mitogen-stimulated cell cultures; however, the mechanism of action appears to be independent of cortisol.
Effects of botulinum toxin A injection and exercise on the growth of juvenile rat gastrocnemius muscle
Authors: Chen Chen-Ming , Stott N. Susan , Smith Heather K.
Published: March 2015

Botulinum toxin A (Btx) injections and supervised exercise are often used concurrently to treat calf muscle spasticity in children. This study has analyzed the early effects of Btx-induced paralysis and increased activity by voluntary wheel running on cell growth-related processes in juvenile rat gastrocnemius muscle. Btx injection at 29 days of age prevented the normal increases in wet mass (50%) and fiber cross-sectional area (34%) seen by 36 days of age in control rats. Btx-injected vs. contralateral muscles had 22% fewer myonuclei per fiber length but greater than twofold the number of MyoD-positive nuclei at 36 days of age. The accretion of 5-bromo-2′-deoxyuridine-labeled newly produced myonuclei did not differ between limbs. Voluntary exercise during the 7 days increased the mass (18%) and fiber size (23%) of Btx-injected and contralateral muscles but did not affect any other variable. Thus Btx injection and exercise had early effects on muscle and fiber size without consistently associated changes in myonuclear production or number. This suggests the presence of noncontractile activity-dependent, growth-promoting cytoplasmic events in juvenile muscle.
Invited Review: Do inflammatory mediators influence the contribution of airway smooth muscle contraction to airway hyperresponsiveness in asthma?
Authors: Fernandes Darren J. , Mitchell Richard W. , Lakser Oren , Dowell Maria , Stewart Alastair G. , Solway Julian
Published: March 2015

It is now accepted that a host of cytokines, chemokines, growth factors, and other inflammatory mediators contributes to the development of nonspecific airway hyperresponsiveness in asthma. Yet, relatively little is known about how inflammatory mediators might promote airway structural remodeling or about the molecular mechanisms by which they might exaggerate smooth muscle shortening as observed in asthmatic airways. Taking a deep inspiration, which provides relief of bronchodilation in normal subjects, is less effective in asthmatic subjects, and some have speculated that this deficiency stems directly from an abnormality of airway smooth muscle and results in airway hyperresponsiveness to constrictor agonists. Here, we consider some of the mechanisms by which inflammatory mediators might acutely or chronically induce changes in the contractile apparatus that in turn might contribute to hyperresponsive airways in asthma.
Regional differences in blood flow and oxygen consumption in resting muscle and their relationship during recovery from exhaustive exercise
Authors: Mizuno Masaki , Kimura Yuichi , Iwakawa Takashi , Oda Keiichi , Ishii Kenji , Ishiwata Kiichi , Nakamura Yoshio , Muraoka Isao
Published: March 2015

This investigation evaluated regional differences in blood flow and oxygen consumption and their relationship in exercised muscle during recovery from exhaustive exercise. Five healthy men performed exhaustive one-legged cycling exercise. Positron emission tomography was used to measure blood flow, oxygen uptake, and oxygen extraction in the quadriceps femoris muscle before and after exercise. Regions of interest included five areas of the muscle (two proximal, one central, and two distal), which were evenly spaced across the muscle. Before exercise, blood flow and oxygen consumption decreased significantly ( P < 0.05) in the direction from the proximal to the distal portions; blood flow declined from 2.0 ± 0.5 to 1.4 ± 0.3 ml·100 g–1·min–1, and oxygen consumption decreased from 0.21 ± 0.04 to 0.17 ± 0.02 ml·100 g–1·min–1. In contrast, these gradients in blood flow and oxygen consumption diminished during recovery after exercise. Consequently, there was a positive relationship between changes in blood flow and oxygen consumption in an exercised muscle during recovery after exercise ( r = 0.963, P < 0.01). These changes became larger in the direction from proximal to distal portions: blood flow increased from 2.9 ± 0.7 to 3.9 ± 0.8 and oxygen consumption from 1.4 ± 0.1 to 1.8 ± 0.4 times resting values. These results suggest that hemodynamic variables are heterogeneous within a muscle both at rest and during recovery from exercise and that there is a systematic difference in these variables in the direction from proximal to distal regions within the quadriceps femoris muscle.
Effects of albumin supplementation on microvascular permeability in septic patients
Authors: Margarson Michael P. , Soni Neil C.
Published: March 2015

Albumin has a stabilizing effect on endothelium and helps maintain capillary permeability to macromolecules. Critically ill patients with sepsis may have profound hypoalbuminemia, but the effect of this hypoalbuminemia on microvascular permeability is unknown. To determine the degree and potential importance of this effect, we measured the transcapillary escape rate (TER) of 125I-labeled albumin in 12 adult patients fulfilling American College of Chest Physicians/Society of Critical Care Medicine criteria for septic shock. We measured TER over a 90-min baseline period and then repeated these measurements immediately after the rapid infusion of 200 ml of 20% albumin. At baseline, patients had a mean serum albumin concentration of 10.3 ± 3.8 g/l, which, at 30 min after the albumin infusion, was 18.5 ± 3.7 g/l. The baseline TER was 6.7 ± 1.5%/h, with a postinfusion TER of 6.4 ± 2.1%/h ( P = 0.550). Albumin supplementation sufficient to nearly double serum concentrations in profoundly hypoalbuminemic septic patients had no clinically significant effect in reducing microvascular permeability.
Regenerated mdx mouse skeletal muscle shows differential mRNA expression
Authors: Tseng B. S. , Zhao P. , Pattison J. S. , Gordon S. E. , Granchelli J. A. , Madsen R. W. , Folk L. C. , Hoffman E. P. , Booth F. W.
Published: March 2015

Despite over 3,000 articles published on dystrophin in the last 15 years, the reasons underlying the progression of the human disease, differential muscle involvement, and disparate phenotypes in different species are not understood. The present experiment employed a screen of 12,488 mRNAs in 16-wk-old mouse mdx muscle at a time when the skeletal muscle is avoiding severe dystrophic pathophysiology, despite the absence of a functional dystrophin protein. A number of transcripts whose levels differed between the mdx and human Duchenne muscular dystrophy were noted. A fourfold decrease in myostatin mRNA in the mdx muscle was noted. Differential upregulation of actin-related protein 2/3 (subunit 4), β-thymosin, calponin, mast cell chymase, and guanidinoacetate methyltransferase mRNA in the more benign mdx was also observed. Transcripts for oxidative and glycolytic enzymes in mdx muscle were not downregulated. These discrepancies could provide candidates for salvage pathways that maintain skeletal muscle integrity in the absence of a functional dystrophin protein in mdx skeletal muscle.
Upper airway response to electrical stimulation of the genioglossus in obstructive sleep apnea
Authors: Oliven Arie , O'Hearn Daniel J. , Boudewyns An , Odeh Majed , De Backer Wilfried , van de Heyning Paul , Smith Philip L. , Eisele David W. , Allan Larry , Schneider Hartmut , Testerman Roy , Schwartz Alan R.
Published: March 2015

Contraction of the genioglossus (GG) has been shown to improve upper airway patency. In the present study, we evaluated responses in upper airway pressure-flow relationships during sleep to electrical stimulation (ES) of the GG in patients with obstructive sleep apnea. Five patients with chronically implanted hypoglossal nerve (HG) electrodes and nine patients with fine-wire electrodes inserted into the GG were studied. Airflow was measured at multiple levels of nasal pressure, and upper airway collapsibility was defined by the nasal pressure below which airflow ceased [“critical” pressure (Pcrit)]. ES shifted the pressure-flow relationships toward higher flow levels in all patients over the entire range of nasal pressure applied. Pcrit decreased similarly during both HG-ES and GG-ES (ΔPcrit was 3.98 ± 2.31 and 3.18 ± 1.70 cmH2O, respectively) without a significant change in upstream resistance. The site of collapse (velo- vs. oropharynx) did not influence the response to GG-ES. Moreover, ES-induced reductions in the apnea-hypopnea index of the HG-ES patients were associated with substantial decreases in Pcrit. Our findings imply that responses in apnea severity to HG-ES can be predicted by characterizing the patient's baseline pressure-flow relationships and response to GG-ES.
Deep breaths, methacholine, and airway narrowing in healthy and mild asthmatic subjects
Authors: Crimi Emanuele , Pellegrino Riccardo , Milanese Manlio , Brusasco Vito
Published: March 2015

Deep breaths taken before inhalation of methacholine attenuate the decrease in forced expiratory volume in 1 s and forced vital capacity in healthy but not in asthmatic subjects. We investigated whether this difference also exists by using measurements not preceded by full inflation, i.e., airway conductance, functional residual capacity, as well as flow and residual volume from partial forced expiration. We found that five deep breaths preceding a single dose of methacholine 1) transiently attenuated the decrements in forced expiratory volume in 1 s and forced vital capacity in healthy ( n = 8) but not in mild asthmatic ( n = 10) subjects and 2) increased the areas under the curve of changes in parameters not preceded by a full inflation over 40 min, during which further deep breaths were prohibited, without significant difference between healthy ( n = 6) and mild asthmatic ( n = 16) subjects. In conclusion, a series of deep breaths preceding methacholine inhalation significantly enhances bronchoconstrictor response similarly in mild asthmatic and healthy subjects but facilitates bronchodilatation on further full inflation in the latter.
Topographical distribution of pulmonary perfusion and ventilation, assessed by PET in supine and prone humans
Authors: Musch Guido , Layfield J. Dominick H. , Harris R. Scott , Melo Marcos F. Vidal , Winkler Tilo , Callahan Ronald J. , Fischman Alan J. , Venegas Jose G.
Published: March 2015

Using positron emission tomography (PET) and intravenously injected 13N2, we assessed the topographical distribution of pulmonary perfusion (Q˙) and ventilation (V˙) in six healthy, spontaneously breathing subjects in the supine and prone position. In this technique, the intrapulmonary distribution of 13N2, measured during a short apnea, is proportional to regional Q˙. After resumption of breathing, regional specific alveolar V˙(sV˙a, ventilation per unit of alveolar gas volume) can be calculated from the tracer washout rate. The PET scanner imaged 15 contiguous, 6-mm-thick, slices of lung. Vertical gradients ofQ˙ and sV˙a were computed by linear regression, and spatial heterogeneity was assessed from the squared coefficient of variation (CV2). Both CV[Formula: see text] and CV[Formula: see text] were corrected for the estimated contribution of random imaging noise. We found that 1) both Q˙ and V˙ had vertical gradients favoring dependent lung regions, 2) vertical gradients were similar in the supine and prone position and explained, on average, 24% ofQ˙ heterogeneity and 8% of V˙ heterogeneity, 3) CV[Formula: see text] was similar in the supine and prone position, and 4) CV[Formula: see text] was lower in the prone position. We conclude that, in recumbent, spontaneously breathing humans, 1) vertical gradients favoring dependent lung regions explain a significant fraction of heterogeneity, especially ofQ˙, and 2) although Q˙ does not seem to be systematically more homogeneous in the prone position, differences in individual behaviors may make the prone position advantageous, in terms of V˙-to-Q˙ matching, in selected subjects.
A5 cells are silenced when REM sleep-like signs are elicited by pontine carbachol
Authors: Fenik Victor , Marchenko Vitaliy , Janssen Patrick , Davies Richard O. , Kubin Leszek
Published: March 2015

The A5 noradrenergic neurons are considered important for cardiorespiratory regulation. We hypothesized that A5 cells are silenced during rapid eye movement (REM) sleep, thereby contributing to cardiorespiratory changes and suppression of hypoglossal (XII) motoneuronal activity. We used an anesthetized, paralyzed, and artificially ventilated rat in which pontine microinjections of carbachol trigger signs of REM sleep, including hippocampal theta rhythm, motor suppression, and silencing of locus coeruleus neurons. All 16 putative noradrenergic A5 cells recorded were strongly suppressed when the REM sleep-like episodes were elicited and also after intravenous clonidine. Antidromic mapping showed that none of six neurons tested projected to the XII nucleus, whereas three of five projected to the nucleus of the solitary tract and two of four to the rostral ventrolateral medulla. Bilateral microinjections of clonidine into the A5 regions did not alter XII nerve activity. These data suggest that A5 neurons are silenced during natural REM sleep. This will lead to decreased norepinephrine release and may alter synaptic transmission in the nucleus of the solitary tract and rostral ventrolateral medulla without, however, a detectable impact on XII motoneurons.
Intensity-controlled treadmill running in mice: cardiac and skeletal muscle hypertrophy
Authors: Kemi Ole Johan , Loennechen Jan P. , Wisløff Ulrik , Ellingsen Øyvind
Published: March 2015

Whereas novel pathways of pathological heart enlargement have been unveiled by thoracic aorta constriction in genetically modified mice, the molecular mechanisms of adaptive cardiac hypertrophy remain virtually unexplored and call for an effective and well-characterized model of physiological mechanical loading. Experimental procedures of maximal oxygen consumption (V˙o2 max) and intensity-controlled treadmill running were established in 40 female and 36 male C57BL/6J mice. An inclination-dependent V˙o2 maxwith 0.98 test-retest correlation was found at 25° treadmill grade. Running for 2 h/day, 5 days/wk, in intervals of 8 min at 85–90% of V˙o2 maxand 2 min at 50% (adjusted to weekly V˙o2 maxtesting) increasedV˙o2 maxto a plateau 49% above sedentary females and 29% in males. Running economy improved in both sexes, and echocardiography indicated significantly increased left ventricle posterior wall thickness. Ventricular weights increased by 19–29 and 12–17% in females and males, respectively, whereas cardiomyocyte dimensions increased by 20–32, and 17–23% in females and males, respectively; skeletal muscle mass increased by 12–18%. Thus the model mimics human responses to exercise and can be used in future studies of molecular mechanisms underlying these adaptations.
Therapeutic effects of DCDDP, a calcium channel blocker, on chronic pulmonary hypertension in rat
Authors: Li Zhi-Chao , Zhang Fu-Qin , Song Jing-Chun , Mei Qi-Bing , Zhao De-Hua
Published: March 2015

To explore the effect of dimethyl 4-(2-chlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (DCDDP) on pulmonary hypertension (PH) induced by monocrotaline (MCT), the parameters of pulmonary hemodynamics, the contents of endothelin-like immunoreactivity, nitric oxide (NO), malondialdehyde, and superoxide dismutase in plasma and pulmonary homogenate were measured. DCDDP was administered in 5, 50, and 500 μg · kg−1 · day−1ip doses, once a day for 28 days. The antiserotonin effect of DCDDP was investigated by using immunohistochemistry, image analysis, and cell culture technique. The results showed that pulmonary arterial pressure was significantly dropped and pulmonary resistance was decreased in DCDDP groups, compared with the MCT group. DCDDP had no influence on endothelin-like immunoreactivity levels in plasma and pulmonary homogenate but reduced the contents of NO, superoxide dismutase, and malondialdehyde in pulmonary homogenate enhanced by MCT. DCDDP also significantly inhibited the increase in numbers of 5-hydroxytryptamine (5-HT) and 5-HT receptor-positive cells in pulmonary tissue of PH rats induced by MCT. The proliferation and contraction of pulmonary arterial smooth muscle cells and the increase in concentration of free Ca2+ in them evoked by 5-HT were inhibited significantly by DCDDP. The results suggest that DCDDP reduces the production of free radicals and content of 5-HT and 5-HT receptor and the increase in NO in pulmonary tissue, which underlies the mechanisms of DCDDP against MCT-induced PH.
Effects of ET-A receptor blockade on eNOS gene expression in chronic hypoxic rat lungs
Authors: Blumberg Friedrich C. , Wolf Konrad , Arzt Michael , Lorenz Cornelia , Riegger Günter A. J. , Pfeifer Michael
Published: March 2015

We tested the hypothesis that pulmonary endothelial nitric oxide synthase (eNOS) gene expression is primarily regulated by hemodynamic factors and is thus increased in rats with chronic hypoxic pulmonary hypertension. Furthermore, we examined the role of endothelin (ET)-1 in this regulatory process, since ET-1 is able to induce eNOS via activation of the ET-B receptor. Therefore, chronic hypoxic rats (10% O2) were treated with the selective ET-A receptor antagonist LU-135252 (50 mg · kg−1 · day−1). Right ventricular systolic pressure and cross-sectional medial vascular wall area of pulmonary arteries rose significantly, and eNOS mRNA levels increased 1.8- and 2.6-fold after 2 and 4 wk of hypoxia, respectively (each P < 0.05). Pulmonary ET-1 mRNA and ET-1 plasma levels increased significantly after 4 wk of hypoxia (each P < 0.05). LU-135252 reduced right ventricular systolic pressure, vascular remodeling, and eNOS gene expression in chronic hypoxic rats (each P < 0.05), whereas ET-1 production was not altered. We conclude that eNOS expression in chronic hypoxic rat lungs is modified predominantly by hemodynamic factors, whereas the ET-B receptor-mediated pathway and hypoxia seem to be less important.
Computational modeling of cardiovascular response to orthostatic stress
Authors: Heldt Thomas , Shim Eun B. , Kamm Roger D. , Mark Roger G.
Published: March 2015

The objective of this study is to develop a model of the cardiovascular system capable of simulating the short-term (≤5 min) transient and steady-state hemodynamic responses to head-up tilt and lower body negative pressure. The model consists of a closed-loop lumped-parameter representation of the circulation connected to set-point models of the arterial and cardiopulmonary baroreflexes. Model parameters are largely based on literature values. Model verification was performed by comparing the simulation output under baseline conditions and at different levels of orthostatic stress to sets of population-averaged hemodynamic data reported in the literature. On the basis of experimental evidence, we adjusted some model parameters to simulate experimental data. Orthostatic stress simulations are not statistically different from experimental data (two-sided test of significance with Bonferroni adjustment for multiple comparisons). Transient response characteristics of heart rate to tilt also compare well with reported data. A case study is presented on how the model is intended to be used in the future to investigate the effects of postspaceflight orthostatic intolerance.
Adaptations in human muscle sarcoplasmic reticulum to prolonged submaximal training
Authors: Green H. J. , Ballantyne C. S. , MacDougall J. D. , Tarnopolsky M. A. , Schertzer J. D.
Published: March 2015

In this study, we employed single-leg submaximal cycle training, conducted over a 10-wk period, to investigate adaptations in sarcoplasmic reticulum (SR) Ca2+-regulatory proteins and processes of the vastus lateralis. During the final weeks, the untrained volunteers (age 21.4 ± 0.3 yr; means ± SE, n = 10) were exercising 5 times/wk and for 60 min/session. Analyses were performed on tissue extracted by needle biopsy ∼4 days after the last training session. Compared with the control leg, the trained leg displayed a 19% reduction ( P < 0.05) in homogenate maximal Ca2+-ATPase activity (192 ± 11 vs. 156 ± 18 μmol · g protein−1· min−1), a 4.3% increase ( P < 0.05) in pCa50, defined as the Ca2+concentration at half-maximal activity (6.01 ± 0.05 vs. 6.26 ± 0.07), and no change in the Hill coefficient (1.75 ± 0.15 vs. 1.76 ± 0.21). Western blot analysis using monoclonal antibodies (7E6 and A52) revealed a 13% lower ( P < 0.05) sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) 1 in trained vs. control in the absence of differences in SERCA2a. Training also resulted in an 18% lower ( P < 0.05) SR Ca2+uptake and a 26% lower ( P < 0.05) Ca2+release. It is concluded that a downregulation in SR Ca2+cycling in vastus lateralis occurs with aerobic-based training, which at least in the case of Ca2+uptake can be explained by reduction in Ca2+-ATPase activity and SERCA1 protein levels.
Blood flow and oxygen uptake increase with total power during five different knee-extension contraction rates
Authors: Sjøgaard Gisela , Hansen Ernst A. , Osada Takuya
Published: March 2015

Controversies exist regarding quantification of internal power (IP) generated by the muscles to overcome energy changes of moving body segments when external power (EP) is performed. The aim was to 1) use a kinematic model for estimation of IP during knee extension, 2) validate the model by independent calculation of IP from metabolic variables (IPmet), and 3) analyze the relationship between total power (TP = EP + IP) and physiological responses. IP increased in a curvilinear manner (5, 7, 13, 21, and 34 W) with contraction rate (45, 60, 75, 90, and 105 contrations/min), but it was independent of EP. Correspondingly, IPmetwas 5, 7, 10, 19, and 28 W, supporting the kinematic model. Heart rate, pulmonary oxygen uptake, and leg blood flow plotted vs. TP fell on the same line independent of contraction rate, and muscular mechanical efficiency as well as delta efficiency remained remarkably constant across contraction rates. It is concluded that the novel metabolic validation of the kinematic model supports the model assumptions, and physiological responses proved to be closely related to TP, supporting the legitimacy of IP estimates.
Active hexose correlated compound enhances resistance to Klebsiella pneumoniae infection in mice in the hindlimb-unloading model of spaceflight conditions
Authors: Aviles Hernan , Belay Tesfaye , Fountain Kimberly , Vance Monique , Sun Buxiang , Sonnenfeld Gerald
Published: March 2015

Previous studies have demonstrated that resistance to infection is decreased in Swiss Webster female mice maintained in the hindlimb-unloading model (Aviles H, Belay T, Fountain K, Vance M, and Sonnenfeld G. J Appl Physiol 95: 73–80, 2003; Belay T, Aviles H, Vance M, Fountain K, and Sonnenfeld G. J Allergy Clin Immunol 110: 262–268, 2002). This is a model of some of the aspects of spaceflight conditions, including lack of load bearing on hindlimbs and a fluid shift to the head. Active hexose correlated compound (AHCC), extracted from Basidiomycete mushrooms, has been shown to induce enhancement of immune responses, including enhanced natural killer activity. In the present study, AHCC was orally administered to mice to determine whether the treatment could decrease immunosuppression and mortality of mice maintained in the hindlimb-unloaded model and infected with Klebsiella pneumoniae. The results of the present study showed that administration of AHCC by gavage for 1 wk (1 g/kg body wt) before suspension and throughout the 10-day suspension period yielded significant beneficial effects for the hindlimb-unloaded group, including 1) decreased mortality, 2) increased time to death, and 3) increased ability to clear bacteria. The results suggest that AHCC can decrease the deleterious effects of the hindlimb-unloading model on immunity and resistance to infection.
Exercise causes a tissue-specific change of NO production in the kidney and lung
Authors: Miyauchi Takashi , Maeda Seiji , Iemitsu Motoyuki , Kobayashi Tsutomu , Kumagai Yoshito , Yamaguchi Iwao , Matsuda Mitsuo
Published: March 2015

Nitric oxide (NO) is produced in the vascular endothelium and is a potent vasodilator substance that participates in the regulation of local vascular tone. Exercise causes peculiar changes in systemic and regional blood flow, i.e., an increase of systemic blood flow and a redistribution of local tissue blood flow, by which the blood flow is greatly increased in the working muscles, whereas it is decreased in some organs such as the kidney and intestine. Thus we hypothesized that exercise causes a tissue-specific change of NO production in some internal organs. We studied whether exercise affects expression of NO synthase (NOS) mRNA and protein, NOS activity, and tissue level of nitrite/nitrate (stable end products of NO) in the kidneys (in which blood flow during exercise is decreased) and lungs (in which blood flow during exercise is increased with the increase of cardiac output) of rat. Rats ran on a treadmill for 45 min at a speed of 25 m/min. Immediately after this exercise, kidneys and lungs were quickly removed. Control rats remained at rest during this 45-min period. Expression of endothelial NOS (eNOS) mRNA in the kidneys was markedly lower in exercise rats than in control rats, whereas that in the lungs was significantly higher in exercise rats than in control rats. Western blot analysis confirmed down- and upregulation of eNOS protein in the kidney and lung, respectively, after exercise. On the other hand, neither expression of neuronal NOS (nNOS) mRNA and nNOS protein nor inducible NOS (iNOS) mRNA and iNOS protein in the kidneys and lungs differed between exercise and control rats. NOS activity in the kidney was significantly lower in exercise rats than in control rats, whereas that in the lung was significantly higher in exercise rats than in control rats. On the other hand, the iNOS activity in the kidneys and lungs did not differ between exercise rats and control rats. Tissue nitrite/nitrate level in the kidneys was markedly lower in exercise rats, whereas that in the lungs was significantly higher in exercise rats. The present results show that production of NO is markedly and tissue-specifically changed in the kidney and lung by exercise.
Training-induced changes in skeletal muscle Na+-K+pump number and isoform expression in rats with chronic heart failure
Authors: Helwig Bryan , Schreurs Katherine M. , Hansen Joslyn , Hageman K. Sue , Zbreski Michael G. , McAllister Richard M. , Mitchell Kathy E. , Musch Timothy I.
Published: March 2015

The mechanisms responsible for the decrements in exercise performance in chronic heart failure (CHF) remain poorly understood, but it has been suggested that sarcolemmal alterations could contribute to the early onset of muscular fatigue. Previously, our laboratory demonstrated that the maximal number of ouabain binding sites (Bmax) is reduced in the skeletal muscle of rats with CHF (Musch TI, Wolfram S, Hageman KS, and Pickar JG. J Appl Physiol 92: 2326–2334, 2002). These reductions may coincide with changes in the Na+-K+-ATPase isoform (α and β) expression. In the present study, we tested the hypothesis that reductions in Bmaxwould coincide with alterations in the α- and β-subunit expression of the sarcolemmal Na+-K+-ATPase of rats with CHF. Moreover, we tested the hypothesis that exercise training would increase Bmaxalong with producing significant changes in α- and β-subunit expression. Rats underwent a sham operation (sham; n = 10) or a surgically induced myocardial infarction followed by random assignment to either a control (MI; n = 16) or exercise training group (MI-T; n = 16). The MI-T rats performed exercise training (ET) for 6–8 wk. Hemodynamic indexes demonstrated that MI and MI-T rats suffered from severe left ventricular dysfunction and congestive CHF. Maximal oxygen uptake (V˙o2 max) and endurance capacity (run time to fatigue) were reduced in MI rats compared with sham. Bmaxin the soleus and plantaris muscles and the expression of the α2-isoform of the Na+-K+-ATPase in the red portion of the gastrocnemius (gastrocnemiusred) muscle were reduced in MI rats. After ET, V˙o2 maxand run time to fatigue were increased in the MI-T group of rats. This coincided with increases in soleus and plantaris Bmaxand the expression of the α2-isoform in the gastrocnemiusredmuscle. In addition, the expression of the β2-isoform of the gastrocnemiusredmuscle was increased in the MI-T rats compared with their sedentary counterparts. This study demonstrates that CHF-induced alterations in skeletal muscle Na+-K+-ATPase, including Bmaxand isoform expression, can be partially reversed by ET.
Maximal lactate steady state declines during the aging process
Authors: Mattern Craig O. , Gutilla Margaret J. , Bright Darrin L. , Kirby Timothy E. , Hinchcliff Kenneth W. , Devor Steven T.
Published: March 2015

Increased participation of aged individuals in athletics warrants basic research focused on delineating age-related changes in performance variables. On the basis of potential age-related declines in aerobic enzyme activities and a shift in the expression of myosin heavy chain (MHC) isoforms, we hypothesized that maximal lactate steady-state (MLSS) exercise intensity would be altered as a function of age. Three age groups [young athletes (YA), 25.9 ± 1.0 yr, middle-age athletes (MA), 43.2 ± 1.0 yr, and older athletes (OA), 64.6 ± 2.7 yr] of male, competitive cyclists and triathletes matched for training intensity and duration were studied. Subjects performed a maximal O2 consumption (V̇o2 max) test followed by a series of 30-min exercise trials to determine MLSS. A muscle biopsy of the vastus lateralis was procured on a separate visit. There were differences ( P < 0.05) in V̇o2 max among all age groups (YA = 67.7 ± 1.2 ml · kg-1 · min-1, MA = 56.0 ± 2.6 ml · kg-1 · min-1, OA = 47.0 ± 2.6 ml · kg-1 · min-1). When expressed as a percentage of V̇o2 max, there was also an age-related decrease ( P < 0.05) in the relative MLSS exercise intensity (YA = 80.8 ± 0.9%, MA = 76.1 ± 1.4%, OA = 69.9 ± 1.5%). There were no significant age-related changes in citrate synthase activity or MHC isoform profile. The hypothesis is supported as there is an age-related decline in MLSS exercise intensity in athletes matched for training intensity and duration. Although type I MHC isoform, combined with age, is helpful in predicting ( r = 0.76, P < 0.05) relative MLSS intensity, it does not explain the age-related decline in MLSS.
Validity of fluorescent microspheres method for bone blood flow measurement during intentional arterial hypotension
Authors: Anetzberger H. , Thein E. , Becker M. , Walli A. K. , Messmer K.
Published: March 2015

In this study, we compared bone blood flow values obtained by simultaneously injected fluorescent (FM) and radiolabeled microspheres (RM) at stepwise reduced arterial blood pressure. Ten anesthetized female New Zealand White rabbits received simultaneous left ventricular injections of FM and RM at 90, 70, and 50 mmHg mean arterial blood pressure (MAP). After the experiments, both kidneys and long bones of all four limbs were removed and dissected in a standardized manner. Radioactivity (corrected for decay, background, and spillover) and fluorescence were determined, and blood flow values were calculated. Relative blood flow values estimated for each bone sample by RM and FM were significantly correlated ( r = 0.98, slope = 0.99, and intercept = 0.04 for 90 mmHg; r = 0.98, slope = 0.94, and intercept = 0.09 for 70 mmHg; r = 0.98, slope = 0.96, and intercept = 0.07 for 50 mmHg). Blood flow values (ml · min-1 · 100 g-1) of right and left bone samples determined at the different arterial blood pressures were identical. During moderate hypotension (70 mmHg MAP), blood flow in all bone samples remained unchanged compared with 90 mmHg MAP, whereas a significant decrease of bone blood flow was observed at severe hypotension (50 mmHg MAP). Our results demonstrate that the FM technique is valid for measuring bone blood flow. Differences in bone blood flow during altered hemodynamic conditions can be detected reliably. In addition, changes in bone blood flow during hypotension indicate that vasomotor control mechanisms, as well as cardiac output, play a role in setting bone blood flow.
Endotoxemia and hepatic injury in a rodent model of hindlimb unloading
Authors: Rivera C. A. , Tcharmtchi M. H. , Mendoza L. , Smith C. W.
Published: March 2015

Hindlimb unloading (HU) is known to induce physiological alterations in various organ systems that mimic some responses observed after exposure to microgravity. In the present study, the effects of up to 4 wk of HU on the liver were assessed in male Wistar rats and two mouse strains: endotoxin-sensitive C57BL/6 mice and endotoxin-resistant C3H/HEJ mice. Plasma levels of endotoxin, a known stimulator of hepatic injury, were measured in portal and systemic blood samples. Endotoxin was elevated by ∼50% in portal blood samples of mice and rats but was not detectable in systemic blood. This low-grade portal endotoxemia was associated with hepatic injury in rats and C57BL/6 mice as indicated by inflammation and elevated serum transaminase activities. Blood levels of the cytokine TNF-α were increased by ∼50% in C57BL/6 mice; no significant elevation of this cytokine was detected in rats. Messenger RNA levels of the acute-phase proteins serum amyloid A, haptoglobin, and lipopolysaccharide binding protein were significantly enhanced after 3 wk of HU in endotoxin-sensitive rodents. In contrast, no histological changes or significant increases in serum enzyme activity were detected after HU in C3H/HEJ mice despite portal endotoxin levels of 222 ± 83.4 pg/ml. At the 3-wk time point, expression of acute-phase proteins was not elevated in C3H/HEJ mice; however, expression after 4 wk of HU was similar to endotoxin-sensitive rodents. In conclusion, these findings indicate that HU induced mild portal endotoxemia, which contributed to the observed hepatic injury in endotoxin-sensitive rodents.
Role of the autonomic nervous system in the reduced maximal cardiac output at altitude
Authors: Bogaard Harm J. , Hopkins Susan R. , Yamaya Yoshiki , Niizeki Kyuichi , Ziegler Michael G. , Wagner Peter D.
Published: March 2015

After acclimatization to high altitude, maximal exercise cardiac output (Q˙t) is reduced. Possible contributing factors include 1) blood volume depletion, 2) increased blood viscosity, 3) myocardial hypoxia, 4) altered autonomic nervous system (ANS) function affecting maximal heart rate (HR), and 5) reduced flow demand from reduced muscle work capability. We tested the role of the ANS reduction of HR in this phenomenon in five normal subjects by separately blocking the sympathetic and parasympathetic arms of the ANS during maximal exercise after 2-wk acclimatization at 3,800 m to alter maximal HR. We used intravenous doses of 8.0 mg of propranolol and 0.8 mg of glycopyrrolate, respectively. At altitude, peak HR was 170 ± 6 beats/min, reduced from 186 ± 3 beats/min ( P = 0.012) at sea level. Propranolol further reduced peak HR to 139 ± 2 beats/min ( P = 0.001), whereas glycopyrrolate increased peak HR to sea level values, 184 ± 3 beats/min, confirming adequate dosing with each drug. In contrast, peak O2 consumption, work rate, and Q˙t were similar at altitude under all drug treatments [peak Q˙t = 16.2 ± 1.2 (control), 15.5 ± 1.3 (propranolol), and 16.2 ± 1.1 l/min (glycopyrrolate)]. All Q˙t results at altitude were lower than those at sea level (20.0 ± 1.8 l/min in air). Therefore, this study suggests that, whereas the ANS may affect HR at altitude, peak Q˙t is unaffected by ANS blockade. We conclude that the effect of altered ANS function on HR is not the cause of the reduced maximal Q˙t at altitude.
Chest wall kinematic determinants of diaphragm length by optoelectronic plethysmography and ultrasonography
Authors: Aliverti A. , Ghidoli G. , Dellacà R. L. , Pedotti A. , Macklem P. T.
Published: March 2015

To estimate diaphragm fiber length from thoracoabdominal configuration, we measured axial motion of the right-sided area of apposition by ultrasonography and volumes displaced by chest wall compartments [pulmonary, abdominal rib cage, and abdomen (Vab)] by optoelectronic plethysmography in four normal men during quiet breathing and incremental exercise without and with expiratory flow limitation. Points at the cephalic area of apposition border were digitized from echo images and mapped into three-dimensional space, and the axial distance from the xyphoidal transverse plane (Dap) was measured simultaneously with the volumes. Linear regression analysis between changes (Δ) in Dap and the measured volume changes under all conditions showed that 1) ΔDap was linearly related more to ΔVab than to changes in pulmonary and abdominal rib cage volumes; and 2) this was highly repeatable between measures. Multiple stepwise regression analysis showed that ΔVab accounted for 89–96% of the variability of ΔDap, whereas the rib cage compartments added <1%. We conclude that, under conditions of quiet breathing and exercise, with and without expiratory flow limitation, instantaneous ΔDap can be estimated from ΔVab.
Activation of thalamic ventroposteriolateral neurons by phrenic nerve afferents in cats and rats
Authors: Zhang Weirong , Davenport Paul W.
Published: March 2015

It has been demonstrated that phrenic nerve afferents project to somatosensory cortex, yet the sensory pathways are still poorly understood. This study investigated the neural responses in the thalamic ventroposteriolateral (VPL) nucleus after phrenic afferent stimulation in cats and rats. Activation of VPL neurons was observed after electrical stimulation of the contralateral phrenic nerve. Direct mechanical stimulation of the diaphragm also elicited increased activity in the same VPL neurons that were activated by electrical stimulation of the phrenic nerve. Some VPL neurons responded to both phrenic afferent stimulation and shoulder probing. In rats, VPL neurons activated by inspiratory occlusion also responded to stimulation on phrenic afferents. These results demonstrate that phrenic afferents can reach the VPL thalamus under physiological conditions and support the hypothesis that the thalamic VPL nucleus functions as a relay for the conduction of proprioceptive information from the diaphragm to the contralateral somatosensory cortex.