bluuebunny/crossref_metadata_2025 huggingface dataset:
Sympathetic modulation of renal blood flow by rilmenidine and captopril: central vs. peripheral effects
Authors: Janssen Ben J. A. , Lukoshkova Elena V. , Head Geoffrey A.
Published: March 2015

Renal blood flow (RBF) is modulated by renal sympathetic nerve activity (RSNA). However, agents that are supposed to reduce sympathetic tone, such as rilmenidine and captopril, influence RBF also by direct arteriolar effects. The present study was designed to test to what extent the renal nerves contribute to the renal hemodynamic response to rilmenidine and captopril. We used a technique that allows simultaneous recording of RBF and RSNA to the same kidney in conscious rabbits. We compared the dose-dependent effects of rilmenidine (0.01–1 mg/kg) and captopril (0.03–3 mg/kg) on RBF and RSNA in intact and renal denervated (RNX) rabbits. Because rilmenidine and captopril lower blood pressure, studies were also performed in sinoaortically denervated (SAD) rabbits to determine the role of the baroreflex in the renal hemodynamic response. Rilmenidine reduced arterial pressure, RBF, and RSNA dose dependently. In intact rabbits ( n = 10), renal conductance (RC) remained unaltered (3 ± 5%), even after the 1-mg/kg dose, which completely abolished RSNA. In RNX rabbits ( n = 6), RC fell by 18 ± 5%, whereas in SAD rabbits ( n = 7) RC increased by 30 ± 20% after rilmenidine. In intact rabbits, captopril increased RSNA maximally by 64 ± 8%. RSNA did not rise in SAD rabbits. Despite the differential response or absence of RSNA, captopril increased RC to a comparable degree (maximally 40–50%) in all three groups. Using spectral analysis techniques, we found that in all groups, independently of ongoing RSNA, captopril, but not rilmenidine, attenuated both myogenic (0.07–0.25 Hz) and tubuloglomerular feedback (0.01–0.07 Hz) related fluctuations in RC. We conclude that, in conscious rabbits, the renal vasodilator effect of rilmenidine depends on the level of ongoing RSNA. Its sympatholytic effect is, however, blunted by a direct arteriolar vasoconstrictor effect. In contrast, the renal vasodilator effect of captopril is not modulated by ongoing RSNA and is associated with impairment of autoregulation of RBF.
Determinants of renal microvascular response to ACh: afferent and efferent arteriolar actions of EDHF
Authors: Wang Xuemei , Loutzenhiser Rodger
Published: March 2015

The renal microvascular actions of ACh were investigated using the in vitro perfused hydronephrotic rat kidney. ACh reversed ANG II-induced vasoconstriction in the afferent and efferent arteriole by 106 ± 2 and 75 ± 5%, respectively. Inhibition of nitric oxide synthase [NOS; 100 μmol/l NG-nitro-l-arginine methyl ester (l-NAME)] and cyclooxygenase (COX; 10 μmol/l ibuprofen) prevented the sustained response of the afferent arteriole but did not reduce the magnitude of the initial dilation (97 ± 7%). However, NOS/COX inhibition abolished the response of the efferent arteriole. The underlying mechanisms mediating this endothelium-derived hyperpolarizing factor (EDHF)-like response were characterized using K channel blockers. Ba (100 μmol/l), tetraethylammonium (1 mmol/l), and ouabain (3 mmol/l) had no effect, arguing against a role of an inward rectifier K channel, large-conductance Ca-activated K channel, or Na,K-ATPase. Charybdotoxin (10 nmol/l) and apamin (1.0 μmol/l) attenuated the response when administered alone (63 ± 7% and 37 ± 5%, respectively) and abolished the response when coadministered (0.1 ± 1.0%). These findings indicate that, as in other vascular beds, the renal EDHF-like response to ACh involves K channels that are sensitive to a combination of apamin and charybdotoxin. Our finding that EDHF modulates preglomerular, but not postglomerular, tone is consistent with the evolving concept that vasomotor mechanisms in cortical efferent arterioles do not involve voltage-gated Ca entry.
FcRn-mediated transcytosis of immunoglobulin G in human renal proximal tubular epithelial cells
Authors: Kobayashi Noriyoshi , Suzuki Yusuke , Tsuge Toshinao , Okumura Ko , Ra Chisei , Tomino Yasuhiko
Published: March 2015

In the kidney, proteins filtered through glomeruli are reabsorbed by endocytosis along the proximal tubules to avoid renal loss of large amounts of proteins. Recently, neonatal Fc receptor (FcRn), which is involved in the transport of IgG across several epithelial and endothelial cells, was reported to be expressed in renal proximal tubular epithelial cells (RPTECs). However, there has been no direct evidence for receptor-mediated endocytosis of IgG in human RPTECs. To explore physiological roles of FcRn in the proximal tubules, we used the human RPTECs to examine IgG transport. FcRn was expressed in RPTECs and physically associated with β2-microglobulin, preserving the capacity of specific pH-dependent IgG binding. Human IgG was bound to the cell surface of RPTECs in a pH-dependent manner. The human IgG transport assay revealed that receptor-mediated transepithelial transport of intact IgG in RPTECs is bidirectional and that it requires the formation of acidified intracellular compartments. With the use of double immunofluorescence, the internalized human IgG was marked in cytoplasm of RPTECs and colocalized with FcRn. These data define the mechanisms of FcRn-associated IgG transport in RPTEC monolayers. It was suggested that the intact pathway for human IgG transepithelial transport may avoid lysosomal degradation of IgG.
Urea and hypertonicity increase expression of heme oxygenase-1 in murine renal medullary cells
Authors: Tian Wei , Bonkovsky Herbert L. , Shibahara Shigeki , Cohen David M.
Published: March 2015

First Published August 15, 2001; 10.1152/ajprenal. 00358.2001.—Epithelial cells derived from the mammalian kidney medulla are responsive to urea at the levels of signal transduction and gene regulation. Hybridization of RNA harvested from control- and urea-treated murine inner medullary collecting duct (mIMCD3) cells with a cDNA expression array encoding stress-responsive genes suggested that heme oxygenase (HO)-1 mRNA was upregulated by urea. RNase protection assay confirmed this upregulation; hypertonicity also increased HO-1 mRNA expression but neither hypertonic NaCl nor urea were effective in the nonrenal 3T3 cell line. The effect on HO-1 expression appeared to be transcriptionally mediated on the basis of mRNA half-life studies and reporter gene analyses using the promoters of both human and chicken HO-1. Although urea signaling resembles that of heavy metal signaling in other contexts, the effect of urea on HO-1 transcription was independent of the cadmium response element in this promoter. Urea-inducible HO-1 expression was sensitive to antioxidants but not to scavengers of nitric oxide. Urea also upregulated HO-1 protein expression and pharmacological inhibition of HO-1 action with zinc protoporphyrin-sensitized mIMCD3 cells to the adverse effects of hypertonicity but not to urea. Coupled with the prior observation of others that HO-1 expression increases along the renal corticomedullary gradient, these data suggest that HO-1 expression may comprise an element of the adaptive response to hypertonicity and/or urea in renal epithelial cells.
Tetracycline-inducible gene expression in cultured rat renal CD cells and in intact CD from transgenic mice
Authors: Puttini Stefania , Beggah Ahmed T. , Ouvrard-Pascaud Antoine , Legris Christine , Blot-Chabaud Marcel , Farman Nicolette , Jaisser Frederic
Published: March 2015

First published August 30, 2001; 10.1152/ajprenal.00360.2000.—The renal collecting duct (CD) plays a key role in the control of ion and fluid homeostasis. Several genetic diseases that involve mutations in genes encoding for ion transporters or hormone receptors specifically expressed in CD have been described. Suitable cellular or transgenic animal models expressing such mutated genes in an inducible manner should represent attractive systems for structure-function relationship analyses and the generation of appropriate physiopathological models of related diseases. Our first goal was to develop a CD cell line that allows inducible gene expression using the tetracycline-inducible system (Tet-On). We designed several strategies aimed at the development of a tight and highly inducible system in RCCD1 cells, a rat cortical collecting duct (CCD) cell line exhibiting several properties of the native CCD. Analysis of reporter gene expression demonstrated that the Tet-On system is suitable for inducible gene expression in these cells. In a second step, we have tested whether transgenic Tet-On mice expressing the tetracycline transactivator under the control of the human cytomegalovirus promoter were suitable for inducible gene expression in tubule epithelial cells. The results indicate that, in vivo , the inducible expression of the lacZ reporter gene appeared to be restricted to the CD. This particular strain of transgenic mice may therefore be useful for the expression of genes of interest in an inducible manner in the collecting duct.
Down training of the elderly soleus H reflex with the use of a spinally induced balance perturbation
Authors: Mynark Richard G. , Koceja David M.
Published: March 2015

The purpose of this study was to determine the ability of the elderly central nervous system to modulate spinal reflex output to functionally decrease a spinally induced balance perturbation. In this case, the soleus H reflex was used as the source of perturbation. Therefore, decreasing (down training) of the soleus H reflex was necessary to counteract this perturbation and to better maintain postural control. In addition to assessing the effect of this perturbation on the H reflex, static postural stability was measured to evaluate possible functional effects. Ten healthy young subjects (age: 27.0 ± 4.6 yr) and 10 healthy elderly subjects (age: 71.4 ± 5.1 yr) participated in this study. Subjects underwent balance perturbation on 2 consecutive days. On day 1 of perturbation, significant down training of the soleus H reflex was demonstrated in both young (−20.4%) and elderly (−18.7%) subjects. On day 2 of perturbation, significant down training of the soleus H reflex was again demonstrated in both young (−24.6%) and elderly (−21.0%) subjects. Analysis of static stability after the 2 days of balance perturbation revealed a significant 10.1% decrease in the area of sway in elderly subjects. In conclusion, this study demonstrated that healthy, elderly subjects compared with young subjects were equally capable of down training the soleus H reflex in response to a balance perturbation. Furthermore, the improvement in static stability through balance training may provide further evidence that balance can be retrained and rehabilitated in subjects with decreased reflex function.
Influence of endurance exercise training status and gender on postexercise hypotension
Authors: Senitko Annette N. , Charkoudian Nisha , Halliwill John R.
Published: March 2015

In sedentary individuals, postexercise hypotension after a single bout of aerobic exercise is due to a peripheral vasodilation. Endurance exercise training has the potential to modify this response and perhaps reduce the degree of postexercise hypotension. We tested the hypothesis that endurance exercise-trained men and women would have blunted postexercise hypotension compared with sedentary subjects but that the mechanism of hypotension would be similar (i.e., vasodilation). We studied 16 endurance-trained and 16 sedentary men and women. Arterial pressure, cardiac output, and total peripheral resistance were determined before and after a single 60-min bout of exercise at 60% peak oxygen consumption. All groups exhibited a similar degree of postexercise hypotension (∼4–5 mmHg; P < 0.05 vs. preexercise). In sedentary men and women, hypotension was the result of vasodilation (Δresistance: −8.9 ± 2.2%). In endurance-trained women, hypotension was also the result of vasodilation (−8.1 ± 4.1%). However, in endurance-trained men, hypotension was the result of a reduced cardiac output (−5.2 ± 2.4%; P < 0.05 vs. all others) and vasodilation was absent (−0.7 ± 3.3%; P < 0.05 vs. all others). Thus we conclude the magnitude of postexercise hypotension is similar in sedentary and endurance-trained men and women but that endurance-trained men and women achieve this fall in pressure via different mechanisms.
The maximally attainable V̇o2during exercise in humans: the peak vs. maximum issue
Authors: Day J. R. , Rossiter H. B. , Coats E. M. , Skasick A. , Whipp B. J.
Published: March 2015

The quantification of maximum oxygen uptake (V̇o2 max), a parameter characterizing the effective integration of the neural, cardiopulmonary, and metabolic systems, requires oxygen uptake (V̇o2) to attain a plateau. We were interested in whether a V̇o2plateau was consistently manifest during maximal incremental ramp cycle ergometry and also in ascertaining the relationship between this peak V̇o2(V̇o2 peak) and that determined from one, or several, maximal constant-load tests. Ventilatory and pulmonary gas-exchange variables were measured breath by breath with a turbine and mass spectrometer. On average, V̇o2 peak[3.51 ± 0.8 (SD) l/min] for the ramp test did not differ from that extrapolated from the linear phase of the response in 71 subjects. In 12 of these subjects, the V̇o2 peakwas less than the extrapolated value by 0.1-0.4 l/min (i.e., a “plateau”), and in 19 subjects, V̇o2 peakwas higher by 0.05-0.4 l/min. In the remaining 40 subjects, we could not discriminate a difference. The V̇o2 peakfrom the incremental test also did not differ from that of a single maximum constant-load test in 38 subjects or from the V̇o2 maxin 6 subjects who undertook a range of progressively greater discontinuous constant-load tests. A plateau in the actual V̇o2response is therefore not an obligatory consequence of incremental exercise. Because the peak value attained was not different from the plateau in the plot of V̇o2vs. work rate (for the constant-load tests), the V̇o2 peakattained on a maximum-effort incremental test is likely to be a valid index of V̇o2 max, despite no evidence of a plateau in the data themselves. However, without additional tests, one cannot be certain.
Autonomic control after blockade of the norepinephrine transporter: a model of orthostatic intolerance
Authors: Carson Robert P. , Diedrich André , Robertson David
Published: March 2015

Orthostatic intolerance is a debilitating syndrome characterized by tachycardia on assumption of upright posture. The norepinephrine (NE) transporter (NET) has been implicated in a genetic form of the disorder. We assessed the combined central and peripheral effects of pharmacological NET blockade on cardiovascular regulation and baroreflex sensitivity in rats. NE reuptake was blocked chronically in female Sprague-Dawley rats by the NET antagonist desipramine (DMI). Treated animals demonstrated an elevated supine heart rate, reduced tyramine responsiveness, and a reduced plasma ratio of the intraneuronal NE metabolite dihydroxyphenylglycol relative to NE, all of which are consistent with observations in human NET deficiency. Spectral analysis revealed a dramatic decrease in low-frequency spectral power after DMI that was consistent with decreased sympathetic outflow. Stimulation of the baroreflex with the vasodilator nitroprusside revealed an attenuated tachycardia in DMI-treated animals. This indicated that the DMI-induced sympathoinhibitory effects of increased NE in the brain stem predominates over the functional elevation of NE stimulation of peripheral targets. Thus attenuated baroreflex function and reduced sympathetic outflow may contribute to the orthostatic intolerance of severe NET deficiency.
Exercise-induced immunodepression– plasma glutamine is not the link
Authors: Hiscock Natalie , Pedersen Bente Klarlund
Published: March 2015

The amino acid glutamine is known to be important for the function of some immune cells in vitro. It has been proposed that the decrease in plasma glutamine concentration in relation to catabolic conditions, including prolonged, exhaustive exercise, results in a lack of glutamine for these cells and may be responsible for the transient immunodepression commonly observed after acute, exhaustive exercise. It has been unclear, however, whether the magnitude of the observed decrease in plasma glutamine concentration would be great enough to compromise the function of immune cells. In fact, intracellular glutamine concentration may not be compromised when plasma levels are decreased postexercise. In addition, a number of recent intervention studies with glutamine feeding demonstrate that, although the plasma concentration of glutamine is kept constant during and after acute, strenuous exercise, glutamine supplementation does not abolish the postexercise decrease in in vitro cellular immunity, including low lymphocyte number, impaired lymphocyte proliferation, impaired natural killer and lymphokine-activated killer cell activity, as well as low production rate and concentration of salivary IgA. It is concluded that, although the glutamine hypothesis may explain immunodepression related to other stressful conditions such as trauma and burn, plasma glutamine concentration is not likely to play a mechanistic role in exercise-induced immunodepression.
Effects of hyperthermia on cerebral blood flow and metabolism during prolonged exercise in humans
Authors: Nybo Lars , Møller Kirsten , Volianitis Stefanos , Nielsen Bodil , Secher Niels H.
Published: March 2015

The development of hyperthermia during prolonged exercise in humans is associated with various changes in the brain, but it is not known whether the cerebral metabolism or the global cerebral blood flow (gCBF) is affected. Eight endurance-trained subjects completed two exercise bouts on a cycle ergometer. The gCBF and cerebral metabolic rates of oxygen, glucose, and lactate were determined with the Kety-Schmidt technique after 15 min of exercise when core temperature was similar across trials, and at the end of exercise, either when subjects remained normothermic (core temperature = 37.9°C; control) or when severe hyperthermia had developed (core temperature = 39.5°C; hyperthermia). The gCBF was similar after 15 min in the two trials, and it remained stable throughout control. In contrast, during hyperthermia gCBF decreased by 18% and was therefore lower in hyperthermia compared with control at the end of exercise (43 ± 4 vs. 51 ± 4 ml · 100 g−1· min−1; P < 0.05). Concomitant with the reduction in gCBF, there was a proportionally larger increase in the arteriovenous differences for oxygen and glucose, and the cerebral metabolic rate was therefore higher at the end of the hyperthermic trial compared with control. The hyperthermia-induced lowering of gCBF did not alter cerebral lactate release. The hyperthermia-induced reduction in exercise cerebral blood flow seems to relate to a concomitant 18% lowering of arterial carbon dioxide tension, whereas the higher cerebral metabolic rate of oxygen may be ascribed to a Q10(temperature) effect and/or the level of cerebral neuronal activity associated with increased exertion.
Finger dexterity, skin temperature, and blood flow during auxiliary heating in the cold
Authors: Brajkovic Dragan , Ducharme Michel B.
Published: March 2015

The primary purpose of the present study was to compare the effectiveness of two forms of hand heating and to discuss specific trends that relate finger dexterity performance to variables such as finger skin temperature (Tfing), finger blood flow (Q̇fing), forearm skin temperature (Tfsk), forearm muscle temperature (Tfmus), mean weighted body skin temperature (T̄sk), and change in body heat content (ΔHb). These variables along with rate of body heat storage, toe skin temperature, and change in rectal temperature were measured during direct and indirect hand heating. Direct hand heating involved the use of electrically heated gloves to keep the fingers warm (heated gloves condition), whereas indirect hand heating involved warming the fingers indirectly by actively heating the torso with an electrically heated vest (heated vest condition). Seven men (age 35.6 ± 5.6 yr) were subjected to each method of hand heating while they sat in a chair for 3 h during exposure to -25°C air. Q̇fing was significantly ( P < 0.05) higher during the heated vest condition compared with the heated gloves condition (234 ± 28 and 33 ± 4 perfusion units, respectively), despite a similar Tfing (which ranged between 28 and 35°C during the 3-h exposure). Despite the difference in Q̇fing, there was no significant difference in finger dexterity performance. Therefore, finger dexterity can be maintained with direct hand heating despite a low Q̇fing. ΔHb, T̄sk, and Tfmus reached a low of -472 ± 18 kJ, 28.5 ± 0.3°C, and 29.8 ± 0.5°C, respectively, during the heated gloves condition, but the values were not low enough to affect finger dexterity.
Receptor activator of NF-κB ligand arrests bone growth and promotes cortical bone resorption in growing rats
Authors: McHugh Nansie A. , Vercesi Haydee M. , Egan Robert W. , Hey John A.
Published: March 2015

Receptor activator of NF-κB ligand (RANKL), produced by osteoblastic lineage cells and activated T cells, is an essential factor for osteoclast differentiation, activation, and survival. Therefore, RANKL is a focal point of therapies targeting bone diseases where there is an imbalance of bone metabolism in favor of bone resorption. The present study assesses the effects of exogenous RANKL on growing bone. RANKL (100 μg·kg-1·day-1 for 7 days) administered to Sprague-Dawley weanling rats caused major deficits in growth, appearance, and bone mineral densities (BMD). Urinary deoxypyridinoline crosslinks, a measure of bone turnover, were higher in the RANKL-treated rats ( P = 0.031), and the bone mineral content was lower ( P < 0.001). The final BMD in the RANKL-treated rats was lower ( P = 0.039) than in the control rats (19 ± 7 vs. 38 ± 5 mg/cm3). Moreover, calculated cortical bone density in each bone slice (total BMD - trabecular BMD) indicated there was only 5% cortical bone remaining in RANKL-treated rats. We conclude that therapies targeting RANKL are likely to have effects on cortical as well as trabecular bone density.
Waging war on physical inactivity: using modern molecular ammunition against an ancient enemy
Authors: Booth Frank W. , Chakravarthy Manu V. , Gordon Scott E. , Spangenburg Espen E.
Published: March 2015

A hypothesis is presented based on a coalescence of anthropological estimations of Homo sapiens' phenotypes in the Late Paleolithic era 10,000 years ago, with Darwinian natural selection synergized with Neel's idea of the so-called thrifty gene. It is proposed that humans inherited genes that were evolved to support a physically active lifestyle. It is further postulated that physical inactivity in sedentary societies directly contributes to multiple chronic health disorders. Therefore, it is imperative to identify the underlying genetic and cellular/biochemical bases of why sedentary living produces chronic health conditions. This will allow society to improve its ability to effect beneficial lifestyle changes and hence improve the overall quality of living. To win the war against physical inactivity and the myriad of chronic health conditions produced because of physical inactivity, a multifactorial approach is needed, which includes successful preventive medicine, drug development, optimal target selection, and efficacious clinical therapy. All of these approaches require a thorough understanding of fundamental biology and how the dysregulated molecular circuitry caused by physical inactivity produces clinically overt disease. The purpose of this review is to summarize the vast armamentarium at our disposal in the form of the extensive scientific basis underlying how physical inactivity affects at least 20 of the most deadly chronic disorders. We hope that this information will provide readers with a starting point for developing additional strategies of their own in the ongoing war against inactivity-induced chronic health conditions.
Modeling the acute- and late-phase responses to peripheral airway cooling and desiccation
Authors: Davis Michael S. , Royer Chris M. , Payton Mark , Buttress Brian
Published: March 2015

Acute bronchoconstriction after isocapnic hyperpnea can be produced in most asthmatic individuals. However, the existence of a late-phase response is less certain. We used a canine model of isocapnic hyperpnea to test the hypothesis that this discrepancy is due to differences in the challenge threshold for the responses. Acute-phase and late-phase bronchoconstriction was measured in nine dogs after peripheral airway exposure to unconditioned air. Additionally, bronchoalveolar lavage fluid (BALF) was obtained during the late-phase response. The acute-phase response was a polynomial function with a decreasing slope at higher challenges, whereas the late-phase response suggested that a minimum threshold of challenge severity was needed to produce late-phase bronchoconstriction. BALF leukocyte and eicosanoid concentrations had linear relationships with challenge severity. Our data support the hypothesis that acute- and late-phase posthyperpnea responses have different dose-response relationships, a fact that may explain the frequent lack of a late-phase response. However, our data suggest that mild inflammation can be induced with relatively lower challenge severity.
Effect of high-intensity hypoxic training on sea-level swimming performances
Authors: Truijens M. J. , Toussaint H. M. , Dow J. , Levine B. D.
Published: March 2015

The objective of this study was to test the hypothesis that high-intensity hypoxic training improves sea-level performances more than equivalent training in normoxia. Sixteen well-trained collegiate and Masters swimmers (10 women, 6 men) completed a 5-wk training program, consisting of three high-intensity training sessions in a flume and supplemental low- or moderate-intensity sessions in a pool each week. Subjects were matched for gender, performance level, and training history, and they were assigned to either hypoxic [Hypo; inspired O2 fraction (Fi O2 ) = 15.3%, equivalent to a simulated altitude of 2,500 m] or normoxic (Norm; Fi O2 = 20.9%) interval training in a randomized, double-blind, placebo-controlled design. All pool training occurred under Norm conditions. The primary performance measures were 100- and 400-m freestyle time trials. Laboratory outcomes included maximal O2 uptake (V˙o 2 max), anaerobic capacity (accumulated O2 deficit), and swimming economy. Significant ( P = 0.02 and <0.001 for 100- and 400-m trials, respectively) improvements were found in performance on both the 100- [Norm: −0.7 s (95% confidence limits: +0.2 to −1.7 s), −1.2%; Hypo: −0.8 s (95% confidence limits: −0.1 to −1.5 s), −1.1%] and 400-m freestyle [Norm: −3.6 s (−1.8 to −5.5 s), −1.2%; Hypo: −5.3 s (−2.3 to −8.3 s), −1.7%]. There was no significant difference between groups for either distance (ANOVA interaction, P = 0.91 and 0.36 for 100- and 400-m trials, respectively). V˙o 2 max was improved significantly (Norm: 0.16 ± 0.23 l/min, 6.4 ±8.1%; Hypo: 0.11 ± 0.18 l/min, 4.2 ± 7.0%). There was no significant difference between groups ( P = 0.58). We conclude that 5 wk of high-intensity training in a flume improves sea-level swimming performances andV˙o 2 max in well-trained swimmers, with no additive effect of hypoxic training.
Maximal rowing has an acute effect on the blood-gas barrier in elite athletes
Authors: Hanel Birgitte , Law Ian , Mortensen Jann
Published: March 2015

The purpose of the study was to evaluate the effects of maximal exercise on the integrity of the alveolar epithelial membrane using the clearance rate of aerosolized 99mTc-labeled diethylenetriaminepentaacetic acid as an index for the permeability of the lung blood-gas barrier. Ten elite rowers (24.3 ± 4.6 yr of age) completed two 20-min pulmonary clearance measurements immediately after and 2 h after 6 min of all-out rowing (initial and late, respectively). All subjects participated in resting control measurements on a separate day. For each 20-min measurement, lung clearance was calculated for 0-7 and 10-20 min. Furthermore, scintigrams were processed from the initial and late measurements of diethylenetriaminepentaacetic acid clearance. Compared with control levels, the pulmonary clearance measurement after rowing was increased from 1.2 ± 0.5 to 2.4 ± 1.0%/min (SD) at 0-7 min ( P < 0.01) and from 0.8 ± 0.3 to 1.5 ± 0.4%/min at 10-20 min ( P < 0.0005), returning to resting levels within 2 h. In 6 of 10 subjects, ventilation distribution on the lung scintigrams was inhomogeneous at the initial measurement. The study demonstrates an acute increased pulmonary clearance after maximal rowing. The ventilation defects identified on the lung scintigrams may represent transient interstitial edema secondary to increased blood-gas barrier permeability induced by mechanical stress.
Segmental analysis of nasal cavity compliance by acoustic rhinometry
Authors: Brugel-Ribere L. , Fodil R. , Coste A. , Larger C. , Isabey D. , Harf A. , Louis B.
Published: March 2015

To explore the determinants of possible collapse of the nasal valve region, a common cause of nasal obstruction, we evaluated the mechanical properties of the nasal wall. In this study, we determined the nasal cross-sectional area-to-negative pressure ratio (nasal wall compliance) in the anterior part of the nose in six healthy subjects by measuring nasal area by acoustic rhinometry at pressures ranging from atmospheric pressure to a negative pressure of −10 cmH2O. Measurements were performed at baseline and after nasal mucosal decongestion (oxymetazoline). At baseline, nasal wall compliance increased progressively from the nasal valve (0.031 ± 0.016 cm2/cmH2O, mean ± SD) to the anterior and medial part of the inferior turbinate (0.045 ± 0.024 cm2/cmH2O) and to the middle meatus region (0.056 ± 0.029 cm2/cmH2O). After decongestant, compliances decreased and became similar in the three regions. On the basis of these results, we hypothesize that compliance of the nasal wall is partly related to mucosal blood volume and quantity of vascular tissue, which differ in the three regions, increasing from the nasal valve to the middle meatus.
Pulmonary gas exchange and acid-base state at 5,260 m in high-altitude Bolivians and acclimatized lowlanders
Authors: Wagner Peter D. , Araoz Mauricio , Boushel Robert , Calbet José A. L. , Jessen Birgitte , Rådegran Göran , Spielvogel Hilde , Søndegaard Hans , Wagner Harrieth , Saltin Bengt
Published: March 2015

Pulmonary gas exchange and acid-base state were compared in nine Danish lowlanders (L) acclimatized to 5,260 m for 9 wk and seven native Bolivian residents (N) of La Paz (altitude 3,600–4,100 m) brought acutely to this altitude. We evaluated normalcy of arterial pH and assessed pulmonary gas exchange and acid-base balance at rest and during peak exercise when breathing room air and 55% O2. Despite 9 wk at 5,260 m and considerable renal bicarbonate excretion (arterial plasma HCO3 − concentration = 15.1 meq/l), resting arterial pH in L was 7.48 ± 0.007 (significantly greater than 7.40). On the other hand, arterial pH in N was only 7.43 ± 0.004 (despite arterial O2 saturation of 77%) after ascent from 3,600–4,100 to 5,260 m in 2 h. Maximal power output was similar in the two groups breathing air, whereas on 55% O2only L showed a significant increase. During exercise in air, arterial Pco 2 was 8 Torr lower in L than in N ( P < 0.001), yet Po 2 was the same such that, at maximal O2 uptake,alveolar-arterial Po 2 difference was lower in N (5.3 ± 1.3 Torr) than in L (10.5 ± 0.8 Torr), P = 0.004. Calculated O2 diffusing capacity was 40% higher in N than in L and, if referenced to maximal hyperoxic work, capacity was 73% greater in N. Buffering of lactic acid was greater in N, with 20% less increase in base deficit per millimole per liter rise in lactate. These data show in L persistent alkalosis even after 9 wk at 5,260 m. In N, the data show 1) insignificant reduction in exercise capacity when breathing air at 5,260 m compared with breathing 55% O2; 2) very little ventilatory response to acute hypoxemia (judged by arterial pH and arterial Pco 2 responses to hyperoxia); 3) during exercise, greater pulmonary diffusing capacity than in L, allowing maintenance of arterial Po 2despite lower ventilation; and 4) better buffering of lactic acid. These results support and extend similar observations concerning adaptation in lung function in these and other high-altitude native groups previously performed at much lower altitudes.
Ambient oxygen regulates epithelial metabolism and nitric oxide production in the human nose
Authors: Nakano Hitoshi , Ide Hiroshi , Ogasa Toshiyuki , Osanai Shinobu , Imada Masanobu , Nonaka Satoshi , Kikuchi Kenjiro , Iwamoto Jun
Published: March 2015

The effects of ambient O2tension on epithelial metabolism and nitric oxide (NO) production (V˙no) in the nasal airway were examined in nine healthy volunteers. Nasal V˙no, O2consumption (V˙o2), and CO2production (V˙co2) were measured during normoxia followed by gradual hypoxia from 21 to 0% O2concentration. Nasal V˙o2,V˙co2, and respiratory quotient during normoxia were determined to be 1.19 ± 0.04 ml/min, 1.60 ± 0.04 ml/min, and 1.35 ± 0.04, respectively. Hypoxia exposure to the nasal cavity significantly decreased bothV˙co2and V˙no[V˙co2: 1.60 ± 0.04 to 0.96 ± 0.03 ml/min ( P < 0.01), V˙no: 530 ± 15 to 336 ± 9 nl/min ( P < 0.01)].V˙no was reduced commensurately with gradual decline in O2tension, and the apparent Kmvalue for O2was determined to be 23.0 μM. These results indicate that the nasal epithelial cells exchange O2and CO2with ambient air in the course of their metabolism and that nasal epithelial cells can synthesize NO by using ambient O2as a substrate. We conclude that air-borne O2diffuses into the epithelium where it may be utilized for either cell metabolism or NO synthesis.
Effect of alcohol intake on muscle glycogen storage after prolonged exercise
Authors: Burke Louise M. , Collier Greg R. , Broad Elizabeth M. , Davis Peter G. , Martin David T. , Sanigorski Andrew J. , Hargreaves Mark
Published: March 2015

We studied the effects of alcohol intake on postexercise muscle glycogen restoration with samples from vastus lateralis being collected immediately after glycogen-depleting cycling and after a set recovery period. Six well-trained cyclists undertook a study of 8-h recovery (2 meals), and another nine cyclists undertook a separate 24-h protocol (4 meals). In each study, subjects completed three trials in crossover order: control (C) diet [meals providing carbohydrate (CHO) of 1.75 g/kg]; alcohol-displacement (A) diet (1.5 g/kg alcohol displacing CHO energy from C) and alcohol + CHO (AC) diet (C + 1.5 g/kg alcohol). Alcohol intake reduced postmeal glycemia especially in A trial and 24-h study, although insulin responses were maintained. Alcohol intake increased serum triglycerides, particularly in the 24-h study and AC trial. Glycogen storage was decreased in A diets compared with C at 8 h (24.4 ± 7 vs. 44.6 ± 6 mmol/kg wet wt, means ± SE, P < 0.05) and 24 h (68 ± 5 vs. 82 ± 5 mmol/kg wet wt, P < 0.05). There was a trend to reduced glycogen storage with AC in 8 h (36.2 ± 8 mmol/kg wet wt, P = 0.1) but no difference in 24 h (85 ± 9 mmol/kg wet wt). We conclude that 1) the direct effect of alcohol on postexercise glycogen synthesis is unclear, and 2) the main effect of alcohol intake is indirect, by displacing CHO intake from optimal recovery nutrition practices.
Bioenergetic adaptation of individual human diaphragmatic myofibers to severe COPD
Authors: Levine Sanford , Gregory Chris , Nguyen Taitan , Shrager Joseph , Kaiser Larry , Rubinstein Neal , Dudley Gary
Published: March 2015

To assess the effect of severe chronic obstructive pulmonary disease (COPD) on the ability of human diaphragmatic myofibers to aerobically generate ATP relative to ATP utilization, we obtained biopsy specimens of the costal diaphragm from seven patients with severe COPD (mean ± SE; age 56 ± 1 yr; forced expiratory volume in 1 s 23 ± 2% predicted; residual volume 267 ± 30% predicted) and seven age-matched control subjects. We categorized all fibers in these biopsies by using standard techniques, and we carried out the following quantitative histochemical measurements by microdensitometry: 1) succinate dehydrogenase (SDH) activity as an indicator of mitochondrial oxidative capacity and 2) calcium-activated myosin ATPase (mATPase) activity, the ATPase that represents a major portion of ATP consumption by contracting muscle. We noted the following: 1) COPD diaphragms had a larger proportion of type I fibers, a lesser proportion of type IIax fibers, and the same proportion of type IIa fibers as controls. 2) SDH activities of each of the fiber types were higher in COPD than control diaphragms ( P < 0.0001); the mean increases (expressed as percent of control values) in types I, IIa, and IIax were 84, 114, and 130%, respectively. 3) COPD elicited no change in mATPase activity of type I and IIa fibers, but mATPase decreased in type IIax fibers ( P = 0.02). 4) Mitochondrial oxidative capacity relative to ATP demand (i.e., SDH/mATPase) was higher ( P = 0.03) in each of the fiber types in COPD diaphragms than in controls. These results demonstrate that severe COPD elicits an increase in aerobic ATP generating capacity relative to ATP utilization in all diaphragmatic fiber types as well as the previously described fast-to-slow fiber type transformation (Levine S, Kaiser L, Leferovich J, and Tikunov B, N Engl J Med 337: 1799–1806, 1997).
A feedback-controlled treadmill (treadmill-on-demand) and the spontaneous speed of walking and running in humans
Authors: Minetti Alberto E. , Boldrini Lorenzo , Brusamolin Laura , Zamparo Paola , McKee Tom
Published: March 2015

A novel apparatus, composed by a controllable treadmill, a computer, and an ultrasonic range finder, is here proposed to help investigation of many aspects of spontaneous locomotion. The acceleration or deceleration of the subject, detected by the sensor and processed by the computer, is used to accelerate or decelerate the treadmill in real time. The system has been used to assess, in eight subjects, the self-selected speed of walking and running, the maximum “reasonable” speed of walking, and the minimum reasonable speed of running at different gradients (from level up to +25%). This evidenced the speed range at which humans neither walk nor run, from 7.2 ± 0.6 to 8.4 ± 1.1 km/h for level locomotion, slightly narrowing at steeper slopes. These data confirm previous results, obtained indirectly from stride frequency recordings. The self-selected speed of walking decreases with increasing gradient (from 5.0 ± 0.8 km/h at 0% to 3.0 ± 0.9 km/h at +25%) and seems to be ∼30% higher than the speed that minimizes the metabolic energy cost of walking, obtained from the literature, at all the investigated gradients. The advantages, limitations, and potential applications of the newly proposed methodology in physiology, biomechanics, and pathology of locomotion are discussed in this paper.
Invited Review: Intracellular signaling in contracting skeletal muscle
Authors: Sakamoto Kei , Goodyear Laurie J.
Published: March 2015

Physical exercise is a significant stimulus for the regulation of multiple metabolic and transcriptional processes in skeletal muscle. For example, exercise increases skeletal muscle glucose uptake, and, after exercise, there are increases in the rates of both glucose uptake and glycogen synthesis. A single bout of exercise can also induce transient changes in skeletal muscle gene transcription and can alter rates of protein metabolism, both of which may be mechanisms for chronic adaptations to repeated bouts of exercise. A central issue in exercise biology is to elucidate the underlying molecular signaling mechanisms that regulate these important metabolic and transcriptional events in skeletal muscle. In this review, we summarize research from the past several years that has demonstrated that physical exercise can regulate multiple intracellular signaling cascades in skeletal muscle. It is now well established that physical exercise or muscle contractile activity can activate three of the mitogen-activated protein kinase signaling pathways, including the extracellular signal-regulated kinase 1 and 2, the c-Jun NH2-terminal kinase, and the p38. Exercise can also robustly increase activity of the AMP-activated protein kinase, as well as several additional molecules, including glycogen synthase kinase 3, Akt, and the p70 S6 kinase. A fundamental goal of signaling research is to determine the biological consequences of exercise-induced signaling through these molecules, and this review also provides an update of progress in this area.
Measurement of hemodynamics in human carotid artery using ultrasound and computational fluid dynamics
Authors: Starmans-Kool Mirian J. , Stanton Alice V. , Zhao Shunzhi , Xu X. Yun , Thom Simon A. M. , Hughes Alun D.
Published: March 2015

The objective of the study was to investigate the feasibility of using computational fluid dynamic modeling (CFD) with noninvasive ultrasound measurements to determine time-variant three-dimensional (3D) carotid arterial hemodynamics in humans in vivo. The effects of hyperoxia and hypoxic hypercapnia on carotid artery local hemodynamics were examined by use of this approach. Six normotensive volunteers followed a double-blind randomized crossover design. Blood pressure, heart rate, and carotid blood flow were measured while subjects breathed normal air, a mixture of 5% CO2 and 15% O2 (hypoxic hypercapnia), and 100% O2 (hyperoxia). Carotid artery geometry was reconstructed on the basis of B-mode ultrasound images by using purpose-built image processing software. Time-variant 3D carotid hemodynamics were estimated by using finite volume-based CFD. Systemic blood pressure was not significantly affected by hyperoxia or hypoxic hypercapnia, but heart rate decreased significantly with hyperoxia. There was an increase in diastolic flow velocity in the external carotid artery after hypoxic hypercapnia, but otherwise carotid blood flow velocities did not change significantly. Compared with normal air, hyperoxic conditions were associated with a decrease in the width of the region of flow separation in the external carotid artery. During hyperoxia, there was also an increase in the minimum and a decrease in maximum shear stress in the bifurcation and hence a reduction in cyclic variation in shear stress. Hypoxic hypercapnia was associated with a reduced duration of flow separation in the external carotid artery and an increase in the minimum shear stress without affecting the cyclic variation in shear stress. This study demonstrates the feasibility of using noninvasive ultrasound techniques in conjunction with CFD to describe time-variant 3D hemodynamics in the human carotid arterial bifurcation in vivo.
Vasoconstriction in active skeletal muscles: a potential role for P2X purinergic receptors?
Authors: Buckwalter John B. , Hamann Jason J. , Clifford Philip S.
Published: March 2015

There is evidence that ATP acts as a neurotransmitter in vascular smooth muscle and is coreleased with norepinephrine from sympathetic nerves. We hypothesized that P2X-receptor stimulation with the selective P2X-receptor agonist α,β-methylene ATP would produce vasoconstriction in resting and exercising skeletal muscle. Six mongrel dogs were instrumented chronically with flow probes on the external iliac arteries of both hindlimbs and a catheter in one femoral artery. The selective P2X agonist α,β-methylene ATP was infused as a bolus into the femoral artery catheter at rest and during mild, moderate, and heavy exercise. Intra-arterial infusions of α,β-methylene ATP elicited reductions in vascular conductance of 54 ± 5, 49 ± 8, 39 ± 8, and 30 ± 6% at rest, 3 miles/h, 6 miles/h, and 6 miles/h at a 10% grade, respectively. The agonist infusions did not affect blood flow in the contralateral iliac artery. To examine whether nitric oxide is responsible for the attenuated vasoconstrictor response to P2X stimulation, the infusions were repeated in the presence of NG-nitro-l-arginine methyl ester. After nitric oxide synthase blockade, intra-arterial infusions of α,β-methylene ATP elicited reductions in vascular conductance of 56 ± 7, 61 ± 8, 52 ± 9, and 40 ± 7% at rest, 3 miles/h, 6 miles/h, and 6 miles/h at a 10% grade, respectively. P2X-receptor responsiveness was attenuated during exercise compared with rest. Blockade of nitric oxide production did not affect the attenuation of P2X-receptor responsiveness during exercise. These data support the hypothesis that P2X purinergic receptors can produce vasoconstriction in exercising skeletal muscle.
Cerebral cortical respiratory-related evoked potentials elicited by inspiratory occlusion in lambs
Authors: Davenport Paul W. , Hutchison Alastair A.
Published: March 2015

Respiratory-related evoked potentials (RREP) elicited by inspiratory mechanical loads have been recorded in humans. Early RREP peaks were hypothesized to be generated by activation of neurons in the somatosensory cortex. An animal model was developed to test this hypothesis in chronically instrumented, awake, spontaneously breathing lambs. Electrocorticogram (ECoG) was recorded bilaterally with ball electrodes on the dural surface over the somatosensory region. Inspiratory occlusions were presented through a face mask or endotracheal tube as interruptions of inspiration. Occlusion-elicited evoked potentials were obtained by computer-signal averaging the ECoG activity. A short-latency positive peak was observed bilaterally in the averaged occlusion-elicited evoked potentials in all animals breathing with the facemask and 5 of 8 lambs with the endotracheal tube. Postmortem identification of the electrode location demonstrated that the ECoG was recorded in the caudal-lateral portion of the somatosensory cortex. These results demonstrate that inspiratory occlusion elicits an evoked potential in the somatosensory cortical region of awake, spontaneously breathing lambs. The lamb cortical RREP is similar to human RREP.
Alveolar sphingolipids generated in response to TNF-α modifies surfactant biophysical activity
Authors: Ryan Alan J. , McCoy Diann M. , McGowan Stephen E. , Salome Ronald G. , Mallampalli Rama K.
Published: March 2015

Sphingolipids represent a diverse group of bioactive lipid species that are generated intracellularly in response to tumor necrosis factor-α (TNF-α) and are implicated as potential mediators of acute lung injury. The purpose of these studies was to determine whether there was an extracellular, TNF-α-regulated pool of sphingolipids in the alveolus that modulates the surface tension lowering capacity of pulmonary surfactant. Intratracheal instillation of TNF-α in adult rats led to a twofold increase in the amount of surfactant-associated ceramide and tended to decrease levels of sphingomyelin without significantly altering sphingosine or sphinganine content. TNF-α induction of alveolar ceramide was associated with nearly an 80% increase in acid sphingomyelinase activity recovered in cell-free alveolar lavage. Ceramide administered in a dose-dependent manner potently antagonized the surface tension lowering effects of natural surfactant in vitro. Intratracheal TNF-α and ceramide treatment of rats significantly increased lung permeability, as was evidenced by extravasation of Evans blue dye into alveolar lavage and lung tissue. Thus these studies are the first to demonstrate the existence of a cytokine-regulated alveolar pool of sphingomyelin hydrolysis products that impairs the biophysical properties of the alveolar surfactant film. The results also suggest the presence of a secretory alveolar sphingomylinase that is TNF-α responsive and mediates effects of the cytokine on alveolar sphingolipid metabolism.