bluuebunny/crossref_metadata_2025 huggingface dataset:
Respiratory abdominal muscle recruitment and chest wall motion in myotonic muscular dystrophy
Authors: Ugalde Viviane , Walsh Sandra , Abresch R. Ted , Bonekat H. William , Breslin Eileen
Published: December 2017

Abdominal muscles are selectively active in normal subjects during stress and may increase the potential energy for inspiration by reducing the end-expiratory lung volume (EELV). We hypothesized that a similar process would occur in subjects with myotonic muscular dystrophy (MMD), but would be less effective, because of to their weakness and altered chest wall mechanics. Fine-wire electromyography (EMG) of the transversus abdominis (TA), internal oblique (IO), external oblique, and rectus abdominis was recorded in 10 MMD and 10 control subjects. EMG activity, respiratory inductive plethysmography, and gastric pressure were recorded during static pressure measurement and at increasing levels of inspiratory resistance breathing. EELV was reduced and chest wall motion was synchronous only in controls. Although the TA and IO were selectively recruited in both groups, EMG activity of the MMD group was twice that of controls at the same inspiratory pressure. In MMD subjects with mildly reduced forced vital capacity, significant differences can be seen in abdominal muscle recruitment, wall motion, work of breathing, and ventilatory parameters.
Lower inflection point and recruitment with PEEP in ventilated patients with acute respiratory failure
Authors: Mergoni M. , Volpi A. , Bricchi C. , Rossi A.
Published: December 2017

The lower inflection point (LIP) on the total respiratory system pressure-volume (P-V) curve is widely used to set positive end-expiratory pressure (PEEP) in patients with acute respiratory failure (ARF) on the assumption that LIP represents alveolar recruitment. The aims of this work were to study the relationship between LIP and recruited volume (RV) and to propose a simple method to quantify the RV. In 23 patients with ARF, respiratory system P-V curves were obtained by means of both constant-flow and rapid occlusion technique at four different levels of PEEP and were superimposed on the same P-V plot. The RV was measured as the volume difference at a pressure of 20 cmH2O. A third measurement of the RV was done by comparing the exhaled volumes after the same distending pressure of 20 cmH2O was applied (equal pressure method). RV increased with PEEP ( P < 0.0001); the equal pressure method compares favorably with the other methods ( P = 0.0001 by correlation), although individual data cannot be superimposed. No significant difference was found when RV was compared with PEEP in the group of patients with a LIP ≤5 cmH2O and the group with a LIP >5 cmH2O (76.9 ± 94.3 vs. 61.2 ± 51.3, 267.7 ± 109.9 vs. 209.6 ± 73.9, and 428.2 ± 216.3 vs. 375.8 ± 145.3 ml with PEEP of 5, 10, and 15 cmH2O, respectively). A RV was found even when a LIP was not present. We conclude that the recruitment phenomenon is not closely related to the presence of a LIP and that a simple method can be used to measure RV.
Severe diabetes inhibits resistance exercise-induced increase in eukaryotic initiation factor 2B activity
Authors: Kostyak John C. , Kimball Scot R. , Jefferson Leonard S. , Farrell Peter A.
Published: December 2017

Rates of protein synthesis are reduced in severely diabetic rats. A potential mechanism through which insulin can stimulate protein synthesis is modulation of the activity of eukaryotic initiation factor 2B (eIF2B). The activity of this factor is elevated after exercise in nondiabetic rats but is markedly lower in skeletal muscle from nonexercised severely diabetic rats. We tested the hypothesis that a failure to increase eIF2B activity after exercise is one potential reason for a failure of severely diabetic rats to increase rates of protein synthesis after resistance exercise. Diabetic (partial pancreatectomy, plasma glucose >475 mg/dl) and nondiabetic male Sprague-Dawley rats (∼300 g) performed acute moderate-intensity resistance exercise or remained sedentary. Rates of protein synthesis were higher in nondiabetic rats and increased significantly with exercise, while no elevation was found in severely diabetic rats. The activity of eIF2B was higher ( P < 0.05) in exercised nondiabetic than in sedentary nondiabetic rats (0.096 ± 0.016 and 0.064 ± 0.02 pmol GDP exchanged/min, respectively), but no difference was observed between sedentary and exercised diabetic rats (0.037 ± 0.001 and 0.044 ± 0.008 pmol GDP exchanged/min, respectively), and these activities were lower ( P < 0.05) than in nondiabetic animals. These data suggest that severe hypoinsulinemia is associated with an inability to increase eIF2B activity in response to exercise.
Effects of hypergravity and anti-G suit pressure on intraregional ventilation distribution during VC breaths
Authors: Gustafsson Per M. , Eiken Ola , Grönkvist Mikael
Published: December 2017

The effects of increased gravity in the head-to-foot direction (+Gz) and pressurization of an anti-G suit (AGS) on total and intraregional intra-acinar ventilation inhomogeneity were explored in 10 healthy male subjects. They performed vital capacity (VC) single-breath washin/washouts of SF6 and He in +1, +2, or +3 Gz in a human centrifuge, with an AGS pressurized to 0, 6, or 12 kPa. The phase III slopes for SF6 and He over 25–75% of the expired VC were used as markers of total ventilation inhomogeneity, and the (SF6 − He) slopes were used as indicators of intraregional intra-acinar inhomogeneity. SF6 and He phase III slopes increased proportionally with increasing gravity, but the (SF6 − He) slopes remained unchanged. AGS pressurization did not change SF6 or He slopes significantly but resulted in increased (SF6 − He) slope differences at 12 kPa. In conclusion, hypergravity increases overall but not intraregional intra-acinar inhomogeneity during VC breaths. AGS pressurization provokes increased intraregional intra-acinar ventilation inhomogeneity, presumably reflecting the consequences of basilar pulmonary vessel engorgement in combination with compression of the basilar lung regions.
Ventilatory long-term facilitation in unanesthetized rats
Authors: Olson E. B. , Bohne C. J. , Dwinell M. R. , Podolsky A. , Vidruk E. H. , Fuller D. D. , Powell F. L. , Mitchel G. S.
Published: December 2017

We tested the hypothesis that unanesthetized rats exhibit ventilatory long-term facilitation (LTF) after intermittent, but not continuous, hypoxia. Minute ventilation (V˙e) and carbon dioxide production (V˙co 2) were measured in unanesthetized, unrestrained male Sprague-Dawley rats via barometric plethysmography before, during, and after exposure to continuous or intermittent hypoxia. Hypoxia was either isocapnic [inspired O2 fraction (Fi O2 ) = 0.08–0.09 and inspired CO2 fraction (Fi CO2 ) = 0.04] or poikilocapnic (Fi O2 = 0.11 and Fi CO2 = 0.00). Sixty minutes after intermittent hypoxia, V˙e orV˙e/V˙co 2 was significantly greater than baseline in both isocapnic and poikilocapnic conditions. In contrast, 60 min after continuous hypoxia,V˙e andV˙e/V˙co 2 were not significantly different from baseline values. These data demonstrate ventilatory LTF after intermittent hypoxia in unanesthetized rats. Ventilatory LTF appeared similar in its magnitude (after accounting for CO2 feedback), time course, and dependence on intermittent hypoxia to phrenic LTF previously observed in anesthetized, vagotomized, paralyzed rats.
Multiple firing of single muscle vasoconstrictor neurons during cardiac dysrhythmias in human heart failure
Authors: Elam Mikael , Macefield Vaughan
Published: December 2017

Single vasoconstrictor nerve fibers in humans normally fire only once but have the capacity to fire as many as eight times, per cardiac interval. Our laboratory recently demonstrated that the mean firing frequency of individual vasoconstrictor fibers is more than doubled in the sympathoexcitation associated with congestive heart failure (Macefield VG, Rundqvist B, Sverrisdottir YB, Wallin BG, and Elam M. Circulation 100: 1708–1713, 1999). However, the propensity to fire only once per cardiac interval was retained. In the present retrospective study, we tested the hypothesis that vasoconstrictor fibers fire more than once per cardiac interval in response to transient sympathoexcitatory stimuli, providing one mechanism for further increase of an already augmented sympathetic discharge. Six patients with congestive heart failure (New York Heart Association functional class II–IV; left ventricular ejection range 13–37%, average 22%) were studied at rest and during premature ectopic heartbeats. Analyzed for a total of 60 premature beats, the average firing probability of 10 vasoconstrictor fibers increased from 61 to 80% in the prolonged cardiac interval (i.e., reduced diastolic pressure) after premature beats. The incidence of multiple within-burst firing increased markedly, with two spikes being more common than one. Our results illustrate two different mechanisms (increases in firing probability and multiple within-burst firing), and indirectly indicate a third mechanism (recruitment of previously silent fibers), for acute sympathoexcitatory responses.
Extracellular glutathione inhibits oxygen-induced permeability changes in alveolar epithelial monolayers
Authors: Roum J. H. , Aledia A. S. , Carungcong L. A. , Kim K.-J. , Borok Z.
Published: December 2017

Exposure to high fractional inspired oxygen for 24 h increases permeability of the alveolar epithelium, contributing to the clinical manifestations of oxygen toxicity. Utilizing a model of the alveolar epithelium in which isolated rat type II cells form polarized monolayers on polycarbonate filters [transepithelial resistance ( Rt) > 1 kΩ · cm2by day 4], we evaluated the ability of reduced glutathione (GSH) to ameliorate these changes. On day 4, apical fluid was replaced with culture medium containing 1) no additives, 2) GSH (500 μM), or 3) GSH (500 μM) + glutathione reductase (0.5 U/ml) + nicotinamide adenine dinucleotide phosphate (250 μM). Monolayers were exposed (for 24 h) to room air (control) or 95% O2, each containing 5% CO2. After 24 h of hyperoxia, Rtfor condition 1decreased by 45% compared with control ( P < 0.001). In conditions 2 and 3, Rtdid not decrease significantly ( P = not significant). Hyperoxia-induced decreases in active ion transport were observed for conditions 1 and 2 ( P < 0.05), but not for condition 3 ( P = not significant). These findings indicate that extracellular GSH may protect the alveolar epithelium against hyperoxia-induced injury. Addition of glutathione reductase and nicotinamide adenine dinucleotide phosphate may further augment these protective effects of GSH.
TGF-β1and prepro-ANP mRNAs are differentially regulated in exercise-induced cardiac hypertrophy
Authors: Calderone Angelino , Murphy René J. L. , Lavoie Julie , Colombo Federico , Béliveau Louise
Published: December 2017

The induction of transforming growth factor (TGF)-β and prepro-atrial natriuretic peptide (ANP) mRNAs represent hallmark features of pathological cardiac hypertrophy. The present study examined whether this pattern of mRNA expression was conserved in a physiological model of cardiac hypertrophy. To address this thesis, female Sprague-Dawley rats were individually housed and permitted to run freely. Voluntary exercise for 3 and 6 wk resulted in biventricular hypertrophy and increased cytochrome c oxidase activity in the triceps muscle. In the hypertrophied left ventricle, the steady-state mRNA level of the cardiac fetal gene prepro-ANP and the extracellular matrix proteins preprocollagen-α1and fibronectin were similar in exercise-trained and sedentary rats. By contrast, an increased expression of TGF-β1mRNA was observed, whereas TGF-β3mRNA level was unchanged in the hypertrophied left ventricle of exercise-trained compared with sedentary rats. These data highlight a heterogeneity in the regulation of TGF-β isoforms, and the increased expression of ventricular TGF-β1mRNA in physiological cardiac hypertrophy may contribute to myocardial remodeling.
Simulated microgravity upregulates an endothelial vasoconstrictor prostaglandin
Authors: Sangha Deepali S. , Han Sukgu , Purdy Ralph E.
Published: December 2017

Endothelial nitric oxide contributes to the vascular hyporesponsiveness to norepinephrine (NE) observed in carotid arteries from rats exposed to simulated microgravity. The goal of the present study was to determine whether a cyclooxygenase product of arachidonic acid also influences vascular responsiveness in this setting. Microgravity was simulated in rats by hindlimb unweighting (HU). After 20 days of HU, carotid arteries were isolated from control and HU-treated rats, and vascular rings were mounted in tissue baths for the measurement of isometric contraction. Two cyclooxygenase inhibitors, indomethacin and ibuprofen, and the selective thromboxane A2prostanoid-receptor antagonist, SQ-29548, had no effect on the contraction to NE in control vessels but markedly reduced contraction to NE in HU vessels. When the endothelium was removed, indomethacin no longer had any effect on the NE-induced contraction in HU vessels. In endothelium-intact vessels in the presence of indomethacin, the addition of the nitric oxide synthase inhibitor, NG-l-nitro-arginine methyl ester, to the medium bathing HU vessels increased the contraction to NE to the level of that of the control vessels. These results indicate that HU treatment induced two endothelial changes in carotid artery that opposed each other. Nitric oxide activity was increased and was responsible for the vascular hyporesponsiveness to NE. The activity of a vasoconstrictor prostaglandin was also increased, and attenuated the vasodilating effect of nitric oxide.
Respiratory mechanics and lung histology in normal rats anesthetized with sevoflurane
Authors: Correa Fatima C. F. , Ciminelli Patricia B. , Falcão Haroldo , Alcântara Bruno J. C. , Contador Renata S. , Medeiros Aline S. , Zin Walter A. , Rocco Patricia R. M.
Published: December 2017

Respiratory system, lung, and chest wall mechanical properties were subdivided into their resistive, elastic, and viscoelastic/inhomogeneous components in normal rats, to define the sites of action of sevoflurane. In addition, we aimed to determine the extent to which pretreatment with atropine modified these parameters. Twenty-four rats were divided into four groups of six animals each: in the P group, rats were sedated (diazepam) and anesthetized with pentobarbital sodium; in the S group, sevoflurane was administered; in the AP and AS groups, atropine was injected 20 min before sedation/anesthesia with pentobarbital and sevoflurane, respectively. Sevoflurane increased lung viscoelastic/inhomogeneous pressures and static elastance compared with rats belonging to the P group. In AS rats, lung static elastance increased in relation to the AP group. In conclusion, sevoflurane anesthesia acted not at the airway level but at the lung periphery, stiffening lung tissues and increasing mechanical inhomogeneities. These findings were supported by the histological demonstration of increased areas of alveolar collapse and hyperinflation. The pretreatment with atropine reduced central and peripheral airway secretion, thus lessening lung inhomogeneities.
On the functional consequences of bronchial basement membrane thickening
Authors: Milanese Manlio , Crimi Emanuele , Scordamaglia Antonio , Riccio Annamaria , Pellegrino Riccardo , Canonica G. Walter , Brusasco Vito
Published: December 2017

Reticular basement membrane (RBM) thickness and airway responses to inhaled methacholine (MCh) were studied in perennial allergic asthma ( n = 11), perennial allergic rhinitis ( n = 8), seasonal allergic rhinitis ( n = 5), and chronic obstructive pulmonary disease (COPD, n = 9). RBM was significantly thicker in asthma (10.1 ± 3.7 μm) and perennial rhinitis (11.2 ± 4.2 μm) than in seasonal rhinitis (4.7 ± 0.7 μm) and COPD (5.2 ± 0.7 μm). The dose (geometric mean) of MCh causing a 20% decrease of 1-s forced expiratory volume (FEV1) was significantly higher in perennial rhinitis (1,073 μg) than in asthma (106 μg). In COPD, the slope of the linear regression of all values of forced vital capacity plotted against FEV1 during the challenge was higher, and the intercept less, than in other groups, suggesting enhanced airway closure. In asthma, RBM thickness was positively correlated ( r = 0.77) with the dose (geometric mean) of MCh causing a 20% decrease of FEV1 and negatively correlated ( r = −0.73) with the forced vital capacity vs. FEV1 slope. We conclude that 1) RBM thickening is not unique to bronchial asthma, and 2) when present, it may protect against airway narrowing and air trapping. These findings support the opinion that RBM thickening represents an additional load on airway smooth muscle.
Effect of mechanical deformation of neutrophils on their CD18/ICAM-1-dependent adhesion
Authors: Anderson Gregory J. , Roswit William T. , Holtzman Michael J. , Hogg James C. , Van Eeden Stephan F.
Published: December 2017

Mechanical deformation of polymorphonuclear leukocytes (PMN) changes their expression of the surface adhesion molecule CD11b/CD18. We tested the hypothesis that mechanical deformation of PMN enhances their adhesiveness. Purified human PMN were deformed through either 5- or 3-μm polycarbonate membrane filters and allowed to adhere to 96-well plates coated with human recombinant intercellular adhesion molecule-1 (ICAM-1). Flow cytometric studies showed that deformation of PMN increased CD11b/CD18 expression ( P < 0.01). PMN adhesion to ICAM-1-coated plates was dependent on the magnitude of cell deformation (5 μm, 63.8 ± 8.1%, P < 0.04; 3 μm, 232.4 ± 20.9%, P < 0.01). Priming of PMN (0.5 nM N-formyl-methionyl-leucyl-phenylalanine) before deformation (5 μm) increased PMN adhesion (63.8 ± 8.1 vs. 105.3 ± 16.4%; P < 0.04). Stimulation (5% zymosan-activated plasma) of PMN after deformation resulted in increased adhesion, and the degree of increase was dependent on the magnitude of PMN deformation (stimulation, 50.6 ± 4%; 5-μm filtration and stimulation, 62.9 ± 6.6%; 3-μm filtration and stimulation, 249.9 ± 24.2%; P < 0.01). This study shows that mechanical deformation of PMN causes an increase in PMN adhesiveness to ICAM-1 that was enhanced by both priming of PMN before deformation and stimulation after cell deformation.
Effects of acute exercise on the gluconeogenic capacity of periportal and perivenous hepatocytes
Authors: Désy François , Burelle Yan , Bélanger Patrice , Gascon-Barré Marielle , Lavoie Jean-Marc
Published: December 2017

The present study was conducted to examine the effect of a single bout of exercise (rodent treadmill, 60 min at 26 m/min, 0% grade) on the gluconeogenic activity of periportal hepatocytes (PP-H) and perivenous hepatocytes (PV-H) in fasted (18 h) rats. Isolated PP-H and PV-H, obtained by selective destruction following liver perfusion with digitonin and collagenase, were incubated with saturating concentrations of alanine (Ala; 20 mM) or a mixture of lactate and pyruvate (Lac+Pyr; 20:2 mM) to determine the glucose production flux ( J glucose) in the incubation medium. Results show that, in the resting conditions, J glucose from all exogenous substrates was significantly higher ( P < 0.01) in PP-H than in PV-H. Exercise, compared with rest, resulted in a higher J glucose ( P < 0.01) from Lac+Pyr substrate in the PV-H but not in the PP-H, resulting in the disappearance of the difference in J glucosebetween PP-H and PV-H. Exercise, compared with rest, led to a higher J glucose ( P < 0.01) from Ala substrate in both PP-H and PV-H. However, the exercise-induced increase in J glucose (gluconeogenic activity) from Ala substrate was higher in PV-H than in PP-H, resulting, as from Lac+Pyr substrate, in the disappearance ( P > 0.05) of the difference of J glucose between PP-H and PV-H. It is concluded that exercise differentially stimulates the gluconeogenic activity of PV-H to a larger extent than PP-H, indicative of a heterogenous metabolic response of hepatocytes to exercise.
Role of airway nitric oxide on the regulation of pulmonary circulation by carbon dioxide
Authors: Yamamoto Yasushi , Nakano Hitoshi , Ide Hiroshi , Ogasa Toshiyuki , Takahashi Toru , Osanai Shinobu , Kikuchi Kenjiro , Iwamoto Jun
Published: December 2017

The effects of hypercapnia (CO2) confined to either the alveolar space or the intravascular perfusate on exhaled nitric oxide (NO), perfusate NO metabolites (NOx), and pulmonary arterial pressure (Ppa) were examined during normoxia and progressive 20-min hypoxia in isolated blood- and buffer-perfused rabbit lungs. In blood-perfused lungs, when alveolar CO2concentration was increased from 0 to 12%, exhaled NO decreased, whereas Ppa increased. Increments of intravascular CO2levels increased Ppa without changes in exhaled NO. In buffer-perfused lungs, alveolar CO2 increased Ppa with reductions in both exhaled NO from 93.8 to 61.7 (SE) nl/min ( P < 0.01) and perfusate NOx from 4.8 to 1.8 nmol/min ( P < 0.01). In contrast, intravascular CO2 did not affect either exhaled NO or Ppa despite a tendency for perfusate NOx to decline. Progressive hypoxia elevated Ppa by 28% from baseline with a reduction in exhaled NO during normocapnia. Alveolar hypercapnia enhanced hypoxic Ppa response up to 50% with a further decline in exhaled NO. Hypercapnia did not alter the apparent K m for O2, whereas it significantly decreased the V max from 66.7 to 55.6 nl/min. These results suggest that alveolar CO2 inhibits epithelial NO synthase activity noncompetitively and that the suppressed NO production by hypercapnia augments hypoxic pulmonary vasoconstriction, resulting in improved ventilation-perfusion matching.
Muscarinic excitation-contraction coupling mechanisms in tracheal and bronchial smooth muscles
Authors: Janssen Luke J. , Wattie Jennifer , Lu-Chao Hwa , Tazzeo Tracy
Published: December 2017

We investigated the mechanisms underlying muscarinic excitation-contraction coupling in canine airway smooth muscle using organ bath, fura 2 fluorimetric, and patch-clamp techniques. Cyclopiazonic acid (CPA) augmented the responses to submaximal muscarinic stimulation in both tracheal (TSM) and bronchial smooth muscles (BSM), consistent with disruption of the barrier function of the sarcoplasmic reticulum. During maximal stimulation, however, CPA evoked substantial relaxation in TSM but not BSM. CPA reversal of carbachol tone persisted in the presence of tetraethylammoium or high KCl, suggesting that hyperpolarization is not involved; CPA relaxations were absent in tissues preconstricted with KCl alone or by permeabilization with β-escin, ruling out a nonspecific effect on the contractile apparatus. Peak contractions were sensitive to inhibitors of tyrosine kinase (genistein) or Rho kinase (Y-27632). Sustained responses were dependent on Ca2+influx in TSM but not BSM; this influx was sensitive to Ni2+ but not La3+. In conclusion, there are several mechanisms underlying excitation-contraction coupling in airway smooth muscle, the relative importance of which varies depending on tissue and degree of stimulation.
Effect of lymphatic outflow pressure on lymphatic albumin transport in humans
Authors: Wu Jauchia , Mack Gary W.
Published: December 2017

The effects of posture on the lymphatic outflow pressure and lymphatic return of albumin were examined in 10 volunteers. Lymph flow was stimulated with a bolus infusion of isotonic saline (0.9%, 12.6 ml/kg body wt) under four separate conditions: upright rest (Up), upright rest with lower body positive pressure (LBPP), supine rest (Sup), and supine rest with lower body negative pressure (LBNP). The increase in plasma albumin content (ΔAlb) during the 2 h after bolus saline infusion was greater in Up than in LBPP: 82.9 ± 18.5 vs. −28.4 mg/kg body wt. ΔAlb was greater in LBNP than in Sup: 92.6 vs. −22.5 ± 18.9 mg/kg body wt ( P < 0.05). The greater ΔAlb in Up and Sup with LBNP were associated with a lower estimated lymphatic outflow pressure on the basis of the difference in central venous pressure (ΔCVP). During LBPP, CVP was increased compared with Up: 3.8 ± 1.4 vs. −1.2 ± 1.2 mmHg. During LBNP, CVP was reduced compared with Sup: −3.0 ± 2.2 vs. 1.7 ± 1.0 mmHg. The translocation of protein into the vascular space after bolus saline infusion reflects lymph return of protein and is higher in Up than in Sup. Modulation of CVP with LBPP or LBNP in Up and Sup, respectively, reversed the impact of posture on lymphatic outflow pressure. Thus posture-dependent changes in lymphatic protein transport are modulated by changes in CVP through its mechanical impact on lymphatic outflow pressure.
Increased renal tubular sodium reabsorption during exercise-induced hypervolemia in humans
Authors: Nagashima Kei , Wu Jauchia , Kavouras Stavros A. , Mack Gary W.
Published: December 2017

We tested the hypothesis that renal tubular Na+ reabsorption increased during the first 24 h of exercise-induced plasma volume expansion. Renal function was assessed 1 day after no-exercise control (C) or intermittent cycle ergometer exercise (Ex, 85% of peak O2 uptake) for 2 h before and 3 h after saline loading (12.5 ml/kg over 30 min) in seven subjects. Ex reduced renal blood flow ( p-aminohippurate clearance) compared with C (0.83 ± 0.12 vs. 1.49 ± 0.24 l/min, P < 0.05) but did not influence glomerular filtration rates (97 ± 10 ml/min, inulin clearance). Fractional tubular reabsorption of Na+ in the proximal tubules was higher in Ex than in C ( P < 0.05). Saline loading decreased fractional tubular reabsorption of Na+ from 99.1 ± 0.1 to 98.7 ± 0.1% ( P < 0.05) in C but not in Ex (99.3 ± 0.1 to 99.4 ± 0.1%). Saline loading reduced plasma renin activity and plasma arginine vasopressin levels in C and Ex, although the magnitude of decrease was greater in C ( P < 0.05). These results indicate that, during the acute phase of exercise-induced plasma volume expansion, increased tubular Na+ reabsorption is directed primarily to the proximal tubules and is associated with a decrease in renal blood flow. In addition, saline infusion caused a smaller reduction in fluid-regulating hormones in Ex. The attenuated volume-regulatory response acts to preserve distal tubular Na+ reabsorption during saline infusion 24 h after exercise.
New method of cardiac output measurement using ultrasound velocity dilution in rats
Authors: Veal Nary , Moal Frédéric , Wang Jinhua , Vuillemin Eric , Oberti Frédéric , Roy Emmanuel , Kaassis Mehdi , Trouvé Renaud , Saumet Jean-Louis , Calès Paul
Published: December 2017

The aim of this study was to validate a new technique for the measurement of cardiac output (CO) based on ultrasound and dilution (COUD) in anesthetized rats. A transit time ultrasound (TTU) probe was placed around the rat carotid artery, and ultrasound velocity dilution curves were generated on intravenous injections of saline. CO by COUD were calculated from the dilution curves for normal and portal hypertensive rats in which CO was known to be increased. COUD was compared with the radiolabeled microsphere method and with direct aortic TTU flowmetry for baseline CO and drug-induced CO variations. CO in direct aortic TTU flowmetry was the ascending aorta blood flow measured directly by TTU probe (normal use of TTU flowmetry). The reproducibility of COUD within the same animal was also determined under baseline conditions. COUD detected the known CO increase in portal hypertensive rats compared with normal rats. CO values by COUD were correlated with those provided by microsphere technique or direct aortic TTU flowmetry (adjusted r = 0.76, P < 10−4 and r = 0.79, P < 0.05, respectively). Baseline CO values and terlipressin-induced CO variations were detected by COUD and the other techniques. Intra- and interobserver agreements for COUD were excellent (intraclass r = 0.99 and 0.98, respectively). COUD was reproducible at least 10 times in 20 min. COUD is an accurate and reproducible method providing low-cost, repetitive CO measurements without open-chest surgery. It can be used in rats as an alternative to the microsphere method and to direct aortic flowmetry.
Evidence of LPL gene-exercise interaction for body fat and LPL activity: the HERITAGE Family Study
Authors: Garenc Christophe , Pérusse Louis , Bergeron Jean , Gagnon Jacques , Chagnon Yvon C. , Borecki Ingrid B. , Leon Arthur S. , Skinner James S. , Wilmore Jack H. , Rao D. C. , Bouchard Claude
Published: December 2017

Evidence of a gene-exercise interaction for traits related to body composition is limited. Here, the association between the lipoprotein lipase (LPL) S447X polymorphism and changes in body mass index, fat mass, percent body fat, abdominal visceral fat measured by computed tomography, and post-heparin plasma LPL activity in response to 20 wk of endurance training was investigated in 741 adult white and black subjects. Changes were compared between carriers and noncarriers of the X447 allele after adjustment for the effects of age and pretraining values. No evidence of association was observed in men. However, white women carrying the X447 allele exhibited greater reductions of body mass index ( P= 0.01), fat mass ( P = 0.01), and percent body fat ( P = 0.03); in black women, the carriers exhibited a greater reduction of abdominal visceral fat ( P = 0.05) and a greater increase in post-heparin LPL activity ( P = 0.02). These results suggest that the LPL S447X polymorphism influences the training-induced changes in body fat and post-heparin LPL activity in women but not in men.
β1-subunit of BK channels regulates arterial wall [Ca2+] and diameter in mouse cerebral arteries
Authors: Löhn Matthias , Lauterbach Birgit , Haller Hermann , Pongs Olaf , Luft Friedrich C. , Gollasch Maik
Published: December 2017

Mice with a disrupted β1(BKβ1)-subunit of the large-conductance Ca2+-activated K+ (BK) channel gene develop systemic hypertension and cardiac hypertrophy, which is likely caused by uncoupling of Ca2+ sparks to BK channels in arterial smooth muscle cells. However, little is known about the physiological levels of global intracellular Ca2+ concentration ([Ca2+]i) and its regulation by Ca2+ sparks and BK channel subunits. We utilized a BKβ1 knockout C57BL/6 mouse model and studied the effects of inhibitors of ryanodine receptor and BK channels on the global [Ca2+]i and diameter of small cerebral arteries pressurized to 60 mmHg. Ryanodine (10 μM) or iberiotoxin (100 nM) increased [Ca2+]i by ∼75 nM and constricted +/+ BKβ1 wild-type arteries (pressurized to 60 mmHg) with myogenic tone by ∼10 μm. In contrast, ryanodine (10 μM) or iberiotoxin (100 nM) had no significant effect on [Ca2+]i and diameter of −/− BKβ1-pressurized (60 mmHg) arteries. These results are consistent with the idea that Ca2+ sparks in arterial smooth muscle cells limit myogenic tone through activation of BK channels. The activation of BK channels by Ca2+ sparks reduces the voltage-dependent Ca2+ influx and [Ca2+]i through tonic hyperpolarization. Deletion of BKβ1 disrupts this negative feedback mechanism, leading to increased arterial tone through an increase in global [Ca2+]i.
Mechanism of inhibition of matrix metalloproteinase-9 induction by NO in vascular smooth muscle cells
Authors: Gurjar Milind V. , DeLeon Jason , Sharma Ram V. , Bhalla Ramesh C.
Published: December 2017

Vascular smooth muscle (VSM) cell migration is a critical step in the development of a neointima after angioplasty. Matrix metalloproteinases (MMPs) degrade the basement membrane and extracellular matrix, facilitating VSM cell migration. Recently, we demonstrated that nitric oxide (NO) inhibits interleukin-1β (IL-1β)-stimulated MMP-9 induction in rat aortic VSM cells. In this study, we examined the hypothesis that NO inhibits MMP-9 induction by attenuating superoxide generation and extracellular signal-regulated kinase (ERK) activation. Stimulation of VSM cells with IL-1β significantly ( P < 0.05) increased superoxide production, ERK activation, and MMP-9 induction. Pretreatment of VSM cells with the NO donor DETA NONOate significantly ( P< 0.05) decreased IL-1β-stimulated superoxide generation. In addition, pretreatment of VSM cells with a specific ERK pathway inhibitor, PD-98059, or DETA NONOate inhibited IL-1β-stimulated ERK activation and MMP-9 induction. Direct exposure of VSM cells to increased superoxide levels by treatment with xanthine/xanthine oxidase increased ERK activation and MMP-9 induction, whereas pretreatment of cells with PD-98059 significantly ( P < 0.05) inhibited xanthine/xanthine oxidase-stimulated ERK activation and MMP-9 induction. We conclude that NO inhibits IL-1β-stimulated MMP-9 induction by inhibiting superoxide generation and subsequent ERK activation.
Activation of MAPK by modified low-density lipoproteins in vascular smooth muscle cells
Authors: Velarde Victoria , Jenkins Alicia J. , Christopher Julie , Lyons Timothy J. , Jaffa Ayad A.
Published: December 2017

A high concentration of circulating low-density lipoproteins (LDL) is a major risk factor for atherosclerosis. Native LDL and LDL modified by glycation and/or oxidation are increased in diabetic individuals. LDL directly stimulate vascular smooth muscle cell (VSMC) proliferation; however, the mechanisms remain undefined. The extracellular signal-regulated kinase (ERK) pathway mediates changes in cell function and growth. Therefore, we examined the cellular effects of native and modified LDL on ERK phosphorylation in VSMC. Addition of native, mildly modified (oxidized, glycated, glycoxidized) and highly modified (highly oxidized, highly glycoxidized) LDL at 25 μg/ml to rat VSMC for 5 min induced a fivefold increase in ERK phosphorylation. To elucidate the signal transduction pathway by which LDL phosphorylate ERK, we examined the roles of the Ca2+/calmodulin pathway, protein kinase C (PKC), src kinase, and mitogen-activated protein kinase kinase (MEK). Treatment of VSMC with the intracellular Ca2+chelator EGTA-AM (50 μmol/l) significantly increased ERK phosphorylation induced by native and mildly modified LDL, whereas chelation of extracellular Ca2+by EGTA (3 mmol/l) significantly reduced LDL-induced ERK phosphorylation. The calmodulin inhibitor N-(6-aminohexyl)-1-naphthalenesulfonamide (40 μmol/l) significantly decreased ERK phosphorylation induced by all types of LDL. Downregulation of PKC with phorbol myristate acetate (5 μmol/l) markedly reduced LDL-induced ERK phosphorylation. Pretreatment of VSMC with a cell-permeable MEK inhibitor (PD-98059, 40 μmol/l) significantly decreased ERK phosphorylation in response to native and modified LDL. These findings indicate that native and mildly and highly modified LDL utilize similar signaling pathways to phosphorylate ERK and implicate a role for Ca2+/calmodulin, PKC, and MEK. These results suggest a potential link between modified LDL, vascular function, and the development of atherosclerosis in diabetes.
Historical aspects of the early Soviet/Russian manned space program
Authors: West John B.
Published: December 2017

Human spaceflight was one of the great physiological and engineering triumphs of the 20th century. Although the history of the United States manned space program is well known, the Soviet program was shrouded in secrecy until recently. Konstantin Edvardovich Tsiolkovsky (1857–1935) was an extraordinary Russian visionary who made remarkable predictions about space travel in the late 19th century. Sergei Pavlovich Korolev (1907–1966) was the brilliant “Chief Designer” who was responsible for many of the Soviet firsts, including the first artificial satellite and the first human being in space. The dramatic flight of Sputnik 1 was followed within a month by the launch of the dog Laika, the first living creature in space. Remarkably, the engineering work for this payload was all done in less than 4 wk. Korolev's greatest triumph was the flight of Yuri Alekseyevich Gagarin (1934–1968) on April 12, 1961. Another extraordinary feat was the first extravehicular activity by Aleksei Arkhipovich Leonov (1934–) using a flexible airlock that emphasized the entrepreneurial attitude of the Soviet engineers. By the mid-1960s, the Soviet program was overtaken by the United States program and attempts to launch a manned mission to the Moon failed. However, the early Soviet manned space program has a preeminent place in the history of space physiology.
Thermoregulatory and aerobic changes after endurance training in a hypobaric hypoxic and warm environment
Authors: Takeno Yoshiaki , Kamijo Yoshi-Ichiro , Nose Hiroshi
Published: December 2017

Plasma volume (PV) expansion by endurance training and/or heat acclimatization is known to increase aerobic and thermoregulatory capacities in humans. Also, higher erythrocyte volume (EV) fractions in blood are known to improve these capacities. We tested the hypothesis that training in a hypobaric hypoxic and warm environment would increase peak aerobic power (V˙o 2 peak) and forearm skin vascular conductance (FVC) response to increased esophageal temperature (Tes) more than training in either environment alone, by increasing both PV and EV. Twenty men were divided into four training regimens ( n = 5 each): low-altitude cool (610-m altitude, 20°C ambient temperature, 50% relative humidity), high-altitude cool (2,000 m, 20°C), low-altitude warm (610 m, 30°C), and high-altitude warm (HW; 2,000 m, 30°C). They exercised on a cycle ergometer at 60%V˙o 2 peak for 1 h/day for 10 days in a climate chamber. After training, PV increased in all trials, but EV increased in only high-altitude trials (both P < 0.05). V˙o 2 peak increased in all trials ( P < 0.05) but without any significant differences among trials. FVC response to increased Tes was measured during exercise at 60% of the pretrainingV˙o 2 peak at 610 m and 30°C. After the training, Tes threshold for increasing FVC decreased in warm trials ( P < 0.05) but not in cool trials and was significantly lower in HW than in cool trials ( P < 0.05). The slope of FVC increase/Tes increase increased in all trials ( P < 0.05) except for high-altitude cool ( P > 0.4) and was significantly higher in HW than in cool trials ( P < 0.05). Thus, against our hypothesis, the V˙o 2 peak for HW did not increase more than in other trials. Moreover, slope of FVC increase/Tes increase in HW increased most, despite the similar increase in blood volume, suggesting that factors other than blood volume were involved in the highest FVC response in HW.
Protein kinase B/Akt activates c-Jun NH2-terminal kinase by increasing NO production in response to shear stress
Authors: Go Young-Mi , Boo Yong Chool , Park Heonyong , Maland Matthew C. , Patel Rakesh , Pritchard Kirkwood A. , Fujio Yasushi , Walsh Kenneth , Darley-Usmar Victor , Jo Hanjoong
Published: December 2017

Laminar shear stress activates c-Jun NH2-terminal kinase (JNK) by the mechanisms involving both nitric oxide (NO) and phosphatidylinositide 3-kinase (PI3K). Because protein kinase B (Akt), a downstream effector of PI3K, has been shown to phosphorylate and activate endothelial NO synthase, we hypothesized that Akt regulates shear-dependent activation of JNK by stimulating NO production. Here, we examined the role of Akt in shear-dependent NO production and JNK activation by expressing a dominant negative Akt mutant (AktAA) and a constitutively active mutant (AktMyr) in bovine aortic endothelial cells (BAEC). As expected, pretreatment of BAEC with the PI3K inhibitor (wortmannin) prevented shear-dependent stimulation of Akt and NO production. Transient expression of AktAA in BAEC by using a recombinant adenoviral construct inhibited the shear-dependent stimulation of NO production and JNK activation. However, transient expression of AktMyr by using a recombinant adenoviral construct did not induce JNK activation. This is consistent with our previous finding that NO is required, but not sufficient on its own, to activate JNK in response to shear stress. These results and our previous findings strongly suggest that shear stress triggers activation of PI3K, Akt, and endothelial NO synthase, leading to production of NO, which (along with O[Formula: see text], which is also produced by shear) activates Ras-JNK pathway. The regulation of Akt, NO, and JNK by shear stress is likely to play a critical role in its antiatherogenic effects.
Historical Perspectives: An abridged history of sex steroid hormone receptor action
Authors: Fannon Stacey A. , Vidaver Regina M. , Marts Sherry A.
Published: December 2017

The field of steroid hormone action is well established, although it is barely more than four decades old. Pivotal experiments in the late 1950s and 1960s showed that hormone-binding components exist within nuclei of target tissues and that steroid hormones act by regulating gene expression, rather than directly influencing enzymatic processes. The understanding that steroid hormone receptors interact with the general transcription machinery and alter chromatin structure came in the 1970s and 1980s, and details of this mechanism continue to be elucidated. In addition, the discovery of rapid cellular responses to steroid hormones has led to the identification of putative membrane-bound steroid receptors that act without affecting gene transcription. As noted in the recent Institute of Medicine report Exploring the Biological Contributions to Human Health: Does Sex Matter?, the effects of steroid hormones and defects in steroid hormone receptor action have a profound impact on human health and disease. Future research directives include the development of potent, selective steroid receptor modulators, the elucidation of nongenomic steroid hormone effects, and further exploration of hormone-genome interactions.
Chemiluminescent measurements of nitric oxide pulmonary diffusing capacity and alveolar production in humans
Authors: Perillo Irene B. , Hyde Richard W. , Olszowka Albert J. , Pietropaoli Anthony P. , Frasier Lauren M. , Torres Alfonso , Perkins Peter T. , Forster Robert E. , Utell Mark J. , Frampton Mark W.
Published: December 2017

Measurements of nitric oxide (NO) pulmonary diffusing capacity (DlNO) multiplied by alveolar NO partial pressure (PaNO) provide values for alveolar NO production (V˙aNO). We evaluated applying a rapidly responding chemiluminescent NO analyzer to measure DlNOduring a single, constant exhalation (DexNO) or by rebreathing (DrbNO). With the use of an initial inspiration of 5–10 parts/million of NO with a correction for the measured NO back pressure, DexNOin nine healthy subjects equaled 125 ± 29 (SD) ml · min−1· mmHg−1and DrbNOequaled 122 ± 26 ml · min−1· mmHg−1. These values were 4.7 ± 0.6 and 4.6 ± 0.6 times greater, respectively, than the subject's single-breath carbon monoxide diffusing capacity (DsbCO). Coefficients of variation were similar to previously reported breath-holding, single-breath measurements of DsbCO. PaNOmeasured in seven of the subjects equaled 1.8 ± 0.7 mmHg × 10−6and resulted in V˙aNOof 0.21 ± 0.06 μl/min using DexNOand 0.20 ± 0.6 μl/min with DrbNO. DexNOremained constant at end-expiratory oxygen tensions varied from 42 to 682 Torr. Decreases in lung volume resulted in falls of DexNOand DrbNOsimilar to the reported effect of volume changes on DsbCO. These data show that rapidly responding chemiluminescent NO analyzers provide reproducible measurements of DlNOusing single exhalations or rebreathing suitable for measuring V˙aNO.
Ventilatory behavior after hypoxia in C57BL/6J and A/J mice
Authors: Han Fang , Subramanian Shyam , Dick Thomas E. , Dreshaj Ismail A. , Strohl Kingman P.
Published: December 2017

Given the environmental forcing by extremes in hypoxia-reoxygenation, there might be no genetic effect on posthypoxic short-term potentiation of ventilation. Minute ventilation (V˙e), respiratory frequency (f), tidal volume (Vt), and the airway resistance during chemical loading were assessed in unanesthetized unrestrained C57BL/6J (B6) and A/J mice using whole body plethysmography. Static pressure-volume curves were also performed. In 12 males for each strain, after 5 min of 8% O2 exposure, B6 mice had a prominent decrease inV˙e on reoxygenation with either air (−11%) or 100% O2 (−20%), due to the decline of f. In contrast, A/J animals had no ventilatory undershoot or f decline. After 5 min of 3% CO2-10% O2 exposure, B6 exhibited significant decrease in V˙e (−28.4 vs. −38.7%, air vs. 100% O2) and f (−13.8 vs. −22.3%, air vs. 100% O2) during reoxygenation with both air and 100% O2; however, A/J mice showed significant increase inV˙e (+116%) and f (+62.2%) during air reoxygenation and significant increase in V˙e (+68.2%) during 100% O2 reoxygenation. There were no strain differences in dynamic airway resistance during gas challenges or in steady-state total respiratory compliance measured postmortem. Strain differences in ventilatory responses to reoxygenation indicate that genetic mechanisms strongly influence posthypoxic ventilatory behavior.
Muscle chemoreflex elevates muscle blood flow and O2 uptake at exercise onset in nonischemic human forearm
Authors: Perrey Stéphane , Tschakovsky Michael E. , Hughson Richard L.
Published: December 2017

We tested the hypothesis that increases in forearm blood flow (FBF) during the adaptive phase at the onset of moderate exercise would allow a more rapid increase in muscle O2 uptake (V˙o 2  mus). Fifteen subjects completed forearm exercise in control (Con) and leg occlusion (Occ) conditions. In Occ, exercise of ischemic calf muscles was performed before the onset of forearm exercise to activate the muscle chemoreflex evoking a 25-mmHg increase in mean arterial pressure that was sustained during forearm exercise. Eight subjects who increased FBF during Occ compared with Con in the adaptation phase by >30 ml/min were considered “responders.” For the responders, a higherV˙o 2  mus accompanied the higher FBF only during the adaptive phase of the Occ tests, whereas there was no difference in the baseline or steady-state FBF orV˙o 2  mus between Occ and Con. Supplying more blood flow at the onset of exercise allowed a more rapid increase in V˙o 2  mussupporting our hypothesis that, at least for this type of exercise, O2 supply might be limiting.
Regional expiratory flow limitation studied with Technegas in asthma
Authors: Pellegrino Riccardo , Biggi Alberto , Papaleo Alberto , Camuzzini Gianfranco , Rodarte Joseph R. , Brusasco Vito
Published: December 2017

Regional expiratory flow limitation (EFL) may occur during tidal breathing without being detected by measurements of flow at the mouth. We tested this hypothesis by using Technegas to reveal sites of EFL. A first study ( study 1) was undertaken to determine whether deposition of Technegas during tidal breathing reveals the occurrence of regional EFL in induced bronchoconstriction. Time-activity curves of Technegas inhaled during 12 tidal breaths were measured in four asthmatic subjects at control conditions and after exposure to inhaled methacholine at a dose sufficient to abolish expiratory flow reserve near functional residual capacity. A second study ( study 2) was conducted in seven asthmatic subjects at control and after three increasing doses of methacholine to compare the pattern of Technegas deposition in the lung with the occurrence of EFL. The latter was assessed at the mouth by comparing tidal with forced expiratory flow or with the flow generated on application of a negative pressure. Study 1 documented enhanced and spotty deposition of Technegas in the central lung regions with increasing radioactivity during tidal expiration. This is consistent with increased impaction of Technegas on the airway wall downstream from the flow-limiting segment. Study 2 showed that both methods based on analysis of flow at the mouth failed to detect EFL at the time spotty deposition of Technegas occurred. We conclude that regional EFL occurs asynchronously across the lung and that methods based on mouth flow measurements are insensitive to it.