bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of aging on tissue-specific noradrenergic activity at rest and during nonexertional heating in rats
Authors: Kregel K. C.
Published: December 2017

The purpose of this study was to test the hypothesis that sympathetic nervous system (SNS) activity to internal organs during nonexertional heat stress is exaggerated with advancing age. Norepinephrine (NE) synthesis was blocked with alpha-methyl-DL-p-tyrosine, and NE turnover rates were determined in the left ventricle, renal cortex, liver, and adrenal gland in groups of conscious unrestrained mature (12-mo-old) and senescent (24-mo-old) Fischer 344 rats before and after whole body heating. Animals were maintained in thermoneutral control conditions (n = 10 per group) or exposed to an ambient temperature of 42 degrees C until colonic temperature (TCO) reached a designated level (39.5 or 41.0 degrees C; n = 10 per group at both temperature levels). NE turnover rates were similar in all four tissues sampled for both mature and senescent rats in the resting condition. Over the course of the heating period, progressive increases in arterial blood pressure and heart rate were observed, with the magnitudes of the pressor and tachycardic responses similar between age groups. At TCO of 39.5 degrees C, calculated NE turnover rates were unchanged from control levels for the senescent and mature animals, whereas animals heated to 41.0 degrees C demonstrated marked elevations in NE turnover in all four tissues for both age groups. In addition, the increase in NE turnover rate at this TCO was significantly higher for senescent rats compared with their younger counterparts in the renal cortex (410 vs. 278%) and liver (557 vs. 170%).(ABSTRACT TRUNCATED AT 250 WORDS)
Assessment of injury in transplanted and nontransplanted lungs after 6 h of cold storage with glutathione
Authors: Bryan C. L. , Patefield A. J. , Cohen D. , Nielsen J. L. , Emanuel B. , Calhoon J. H.
Published: December 2017

Single-lung transplantation after 3 h of hypothermic storage produces bilateral lung injury [pulmonary reimplantation response (PRR)]. We hypothesized that glutathione (GSH) hypothermic storage would protect both lungs from PRR for extended preservation times and that differences in injury and protection would be realized between the graft and the nontransplanted lung. Mongrel dogs underwent left single-lung autotransplantation after preservation for 5–6 h in Euro-Collins (EC) solution, EC plus exogenous GSH (EC+GSH), or Viaspan (VIA) at 4 degrees C. Lung injury was measured in both lungs after 1 h of reperfusion. EC dogs demonstrated significant increases in lung edema, lipid peroxidation, and alveolar neutrophil recruitment in the lung graft and to a less extent in the nontransplanted right lung compared with control dogs (P < 0.05). Edema, lipid peroxidation, and alveolar neutrophils were significantly reduced in both lungs from EC+GSH and VIA dogs compared with lungs from EC dogs (P < 0.05). An increase in large-pore permeability was measured in the lung graft from EC dogs compared with all other lungs. Bronchoalveolar lavage fluid lactate dehydrogenase and total protein concentrations were elevated in both lungs from all three groups of tranplanted dogs compared with those of control dogs (P < 0.05). These data suggest that GSH-containing solutions attenuate the PRR after 6 h of ischemic hypothermic storage but that the protection is incomplete. Mechanisms of injury affecting the lung graft during the PRR appear to differ from those affecting the nontransplanted lung.
Comparison of captive and pulsating bubble surfactometers with use of lung surfactants
Authors: Putz G. , Goerke J. , Taeusch H. W. , Clements J. A.
Published: December 2017

We compared surface tension measures of surfactants with various surface activities by using a pulsating bubble surfactometer (PBS) and a captive bubble surfactometer (CBS). Rabbit lung lavage surfactant (60,000 x average g for 60 min), bovine surfactant extract (Survanta), and a synthetic lipid surfactant mixture (dipalmitoylphosphatidylcholine-egg phosphatidylglycerol-palmitic acid) were studied at 1.25 mg phospholipid/ml. The PBS was used either unmodified according to manufacturer's instructions or with the sample chamber capillary kept dry and the sample adsorbing at maximum bubble size (5 min). The CBS was used in a manner that imitated the unmodified PBS. We found that all three techniques indicated low surface tension on the first cycle for 60K. For Survanta, the CBS and the modified PBS reported low surface tension on the first cycle, whereas the unmodified PBS did not achieve this within 10 cycles. For the synthetic lipid surfactant mixture, only the CBS measured low surface tension within 10 cycles. Video observations indicate that the modified PBS performs better than the unmodified PBS because keeping the capillary dry prevents surface film from occupying this large surface during cycling, thereby allowing larger area compressions.
Increased left atrial pressure inhibits hypoxic pulmonary vasoconstriction
Authors: De Canniere D. , Stefanidis C. , Hallemans R. , Delcroix M. , Lejeune P. , Naeije R.
Published: December 2017

An increase in left atrial pressure (Pla) has been reported to either inhibit or not affect hypoxic pulmonary vasoconstriction in intact dogs. We investigated mean pulmonary arterial pressure (Ppa)-flow (Q) relationships at low and high fixed Pla and Ppa-Pla relationships at fixed Q in piglets, which are known to present with a stronger hypoxic pulmonary pressor response than dogs. Seven piglets were anesthetized; equipped with balloon catheters in inferior vena cava and left atrium to control Q and Pla, respectively; and ventilated alternatively in hyperoxia [fractional concn of O2 in inspired air (FIO2) 0.4] and hypoxia (FIO2 0.12). In all experimental conditions, Ppa-Q plots were best described by a linear approximation with extrapolated pressure intercepts (Pi) not different from Pla. Hypoxia increased slope but not Pi of Ppa-Q plots. An increase in Pla from 8 to 17 mmHg induced a parallel shift of Ppa-Q plots to higher Ppa in hyperoxia but did not affect Ppa-Q plots in hypoxia. In hyperoxia, an increase in Pla at constant Q induced an approximately equal increase in Ppa, whereas in hypoxia there was no effect. The hypoxia-induced increase in Ppa was blunted by increased Pla at all levels of Q studied. We conclude that in anesthetized piglets at fixed Pla hypoxia increases the slope of Ppa-Q plots without affecting Pi and an increase in Pla inhibits hypoxic pulmonary vasoconstriction. The results suggest that no closing pressure higher than normal Pla contributes to hyperoxic or hypoxic Ppa in the intact porcine pulmonary circulation.
Inhibition of eicosanoids does not prevent neutrophil injury from phorbol in isolated rabbit lung
Authors: Littner M. R. , Lott F. D.
Published: December 2017

Studies suggest that pulmonary and neutrophil cyclooxygenase and lipoxygenase products (i.e., eicosanoids) play a role in oxidant lung injury. We tested the hypothesis that such eicosanoids contribute to lung injury from activation of rabbit neutrophils by phorbol myristate acetate (PMA) in the pulmonary circulation of salt-perfused isolated rabbit lung preparations. We measured lung injury from PMA-activated neutrophils under zone 2 pulmonary vascular conditions with transvascular albumin flux by 125I-labeled albumin. We found that this flux was increased; catalase prevented the increase, confirming that the increase was from oxidant injury. However, results were inconsistent: about one-half of the preparations showed a marked increase and about one-half were not elevated. In preparations with a > 40-mmHg increase in pulmonary arterial pressure (Ppa), albumin flux increased, and in those with Ppa < 40 mmHg it did not. In those with Ppa > 40 mmHg, vascular volume, and presumably vascular surface area, was markedly reduced. We next studied PMA-activated neutrophils under zone 3 pulmonary vascular conditions in preparations with Ppa that increased < 40 mmHg. Albumin flux or filtration coefficient (Kf,c) was used to measure injury. Both were elevated. As with albumin flux, catalase prevented increases in Kf,c. BW-755C (a dual lipoxygenase and cyclooxygenase inhibitor) prevented increases in cyclooxygenase products and leukotriene B4 (a lipoxygenase product) but did not prevent increases in Kf,c. We conclude that a marked decrease in vascular volume can occur in zone 2 preparations and may mask the presence of injury as measured by transvascular albumin flux. A zone 3 vascular condition overcomes the vasoconstrictor-induced decrease in surface area and unmasks injury. Finally, oxidant injury from PMA-stimulated rabbit neutrophils in isolated rabbit lungs cannot be readily attributed to formation of eicosanoids.
Effect of spaceflight on skeletal muscle: mechanical properties and myosin isoform content of a slow muscle
Authors: Caiozzo V. J. , Baker M. J. , Herrick R. E. , Tao M. , Baldwin K. M.
Published: December 2017

This study examined changes in contractile, biochemical, and histochemical properties of slow antigravity skeletal muscle after a 6-day spaceflight mission. Twelve male Sprague-Dawley rats were randomly divided into two groups: flight and ground-based control. Approximately 3 h after the landing, in situ contractile measurements were made on the soleus muscles of the flight animals. The control animals were studied 24 h later. The contractile measurements included force-velocity relationship, force-frequency relationship, and fatigability. Biochemical measurements focused on the myosin heavy chain (MHC) and myosin light chain profiles. Adenosine-triphosphatase histochemistry was performed to identify cross-sectional area of slow and fast muscle fibers and to determine the percent fiber type distribution. The force-velocity relationships of the flight muscles were altered such that maximal isometric tension (Po) was decreased by 24% and maximal shortening velocity was increased by 14% (P < 0.05). The force-frequency relationship of the flight muscles was shifted to the right of the control muscles. At the end of the 2-min fatigue test, the flight muscles generated only 34% of Po, whereas the control muscles generated 64% of Po. The flight muscles exhibited de novo expression of the type IIx MHC isoform as well as a slight decrease in the slow type I and fast type IIa MHC isoforms. Histochemical analyses of flight muscles demonstrated a small increase in the percentage of fast type II fibers and a greater atrophy of the slow type I fibers. The results demonstrate that contractile properties of slow antigravity skeletal muscle are sensitive to the microgravity environment and that changes begin to occur within the 1st wk. These changes were at least, in part, associated with changes in the amount and type of contractile protein expressed.
Canine model of obstructive sleep apnea: model description and preliminary application
Authors: Kimoff R. J. , Makino H. , Horner R. L. , Kozar L. F. , Lue F. , Slutsky A. S. , Phillipson E. A.
Published: December 2017

This report describes a canine model of obstructive sleep apnea (OSA) developed in our laboratory and the results of its preliminary short-term application. Healthy adult dogs were prepared with a tracheostomy and with implanted electroencephalographic and nuchal electromyographic recording electrodes. A silent occlusion valve was attached to the outer end of the endotracheal tube. The electroencephalogram and electromyogram were monitored continuously by a computer that determined sleep-wake state using software developed in our laboratory. At a predetermined time (e.g., 12 s) after each sleep onset, a signal was transmitted from the computer to the valve controller, resulting in airway occlusion. When the dog aroused from sleep, the occlusion was released. These events therefore mimic those that occur in human OSA. Successful operation of the model was confirmed during 5-day continuous trials in two dogs. During the trials, the dogs became increasingly somnolent both by behavioral observation and objective measurement. The frequency of occlusions increased, and measures of apnea severity, including apnea duration and end-apneic arterial oxygen saturation, worsened. We conclude that this experimental model of repeated airway occlusion during sleep provides a potentially powerful tool for investigating the sequelae of OSA.
Hiccuplike response elicited by mechanical stimulation of dorsal epipharynx of cats
Authors: Oshima T. , Sakamoto M. , Arita H.
Published: December 2017

To identify the site for triggering hiccup, we recorded activities from the diaphragm (DIA), posterior cricoarytenoid muscle (PCA) of the larynx, and abdominal muscle (ABD) along with intrapleural pressure (Ppl) in anesthetized spontaneously breathing cats. To directly access the epipharynx and to observe glottic movement, we made a submental opening at the level rostral to the epiglottis. Mechanical stimulation of the epipharynx evoked a fixed motor pattern of hiccup: DIA showed spasmodic discharge, and Ppl exhibited spiky negative pressure swing; phasic (inspiratory) discharge of PCA was inhibited, and glottic adduction was revealed by direct observation; and ABD remained suppressed during this response. Chlorpromazine hydrochloride or CO2 inhalation suppressed the response, and the intensity of the response varied according to phase of the respiratory cycle, being largest at midinspiration and least at midexpiration. These are compatible with clinical data on human hiccup. Mechanical stimulation of various parts other than the epipharynx failed to evoke the hiccuplike response. The triggering site was located in the dorsal wall of the epipharynx overlying the occipital bone. These results indicate that mechanical irritation of the dorsal epipharynx is essential for triggering hiccup.
Albuminuria and overall capillary permeability of albumin in acute altitude hypoxia
Authors: Hansen J. M. , Olsen N. V. , Feldt-Rasmussen B. , Kanstrup I. L. , Dechaux M. , Dubray C. , Richalet J. P.
Published: December 2017

The mechanism of proteinuria at high altitude is unclear. Renal function and urinary excretion rate of albumin (Ualb) at rest and during submaximal exercise and transcapillary escape rate of 125I-labeled albumin (TERalb) were investigated in 12 normal volunteers at sea level and after rapid and passive ascent to 4,350 m. The calcium antagonist isradipine (5 mg/day; n = 6) or placebo (n = 6) was administered to abolish hypoxia-induced rises in blood pressure. Lithium clearance and urinary excretion of beta 2-microglobulin were used to evaluate renal tubular function. High altitude increased Ualb from 2.8 to > 5.0 micrograms/min in both groups (P < 0.05). In the placebo group, high altitude significantly increased filtration fraction (P < 0.05), but this response was abolished by isradipine. Lithium clearance and urinary excretion of beta 2-microglobulin remained unchanged by hypoxia in both groups. Exercise did not reveal any further renal dysfunction. In both groups, high altitude increased TERalb from 4.8 to > 6.7%/h (P < 0.05). In conclusion, acute altitude hypoxia increases Ualb despite unchanged tubular function and independent of effects of isradipine on filtration fraction. The elevated TERalb suggests an overall increase in capillary permeability, including the glomerular endothelium, as the critical factor in high-altitude induced albuminuria.
Finite-element analysis of stress in the canine diaphragm
Authors: Margulies S. S. , Lei G. T. , Farkas G. A. , Rodarte J. R.
Published: December 2017

Stress in the diaphragm, transdiaphragmatic pressure, and diaphragm shape are interrelated by a balance of forces. Using precise in vivo measurements of diaphragm shape and transdiaphragmatic pressure distribution in combination with finite-element analysis (ANSYS), we determined the direction and magnitude of stress in the passive diaphragm at relaxation volume. Lead spheres sutured along muscle bundles identified muscle bundle location and orientation in vivo. The x, y, and z coordinates of the lead spheres and entire surface of the diaphragm, excluding the zone of apposition, were determined to within 1.4 mm. Thin shell elements were used to construct a finite-element model of the diaphragm with a 2.1- to 4.2-mm internodal spacing. The diaphragm was assumed to have a uniform thickness of 2.5 mm, and magnitude and direction of the principal stresses were computed. The results show that 1) diaphragm stress is nonuniform and anisotropic (i.e., varies both with location on diaphragm surface and direction examined), 2) largest stress (sigma 1) is aligned with muscle bundles and is two to four times larger than sigma 2 (perpendicular to sigma 1 in diaphragm plane), and 3) stress along the muscle bundles is larger in vivo under conditions of biaxial stress than at same length in vitro under uniaxial stress. Although diaphragm stress and tension have often been assumed to be uniform, our finding that stress is oriented primarily along the muscle fibers should be considered in future models of the diaphragm.(ABSTRACT TRUNCATED AT 250 WORDS)
Endothelial cell hyperpolarization increases [Ca2+]i and venular microvessel permeability
Authors: He P. , Curry F. E.
Published: December 2017

We tested the hypothesis that Ca2+ influx into endothelial cells forming the walls of intact venular microvessels was increased when the cell membranes were hyperpolarized. Cytoplasmic free Ca2+ concentration ([Ca2+]i) was measured after the endothelial cells forming the microvessel wall were loaded with fura 2, endothelial cell membrane potential was measured with the membrane potential dye bis-oxonol, and hydraulic conductivity (Lp) of the vessels was measured by the modified Landis technique to follow changes in microvessel permeability. When microvessels were exposed to low-K+ (0.1 mM) Ringer solution, the membrane of the endothelial cells was hyperpolarized approximately 27 mV and [Ca2+]i increased from 47 nM to a peak value of 151 +/- 28 nM. Under the same experimental conditions, Lp increased to a peak 6.3 times control. In the presence of ionomycin (5 microM), the initial peak [Ca2+]i measured with low-K+ Ringer solution was 347 +/- 58 nM compared with 252 +/- 58 nM with ionophore and normal Ringer solution. The corresponding initial increases in Lp were 28 times control and 10 times control, respectively. The results conform to the hypothesis that vasoactive substances that hyperpolarize the endothelial cell membrane may initiate and/or potentiate the inflammatory response in venular microvessels.
Reflex changes in breathing pattern evoked by inhalation of wood smoke in rats
Authors: Kou Y. R. , Lai C. J.
Published: December 2017

The acute ventilatory response to inhalation of wood smoke was studied in 58 anesthetized Sprague-Dawley rats. Wood smoke (approximately 6 ml) was inhaled spontaneously via a tracheal cannula. Within the first two breaths of smoke inhalation, either a slowing of respiration (SR) (n = 39) or an augmented inspiration (AI) (n = 19) was elicited consistently in each rat. The SR was primarily due to a prolongation of expiratory duration, whereas the AI was characterized by a two-step inspiratory flow leading to an exceedingly large tidal volume. Both initial responses, usually accompanied by bradycardia and hypotension, were reduced by inhaling smoke at a decreased concentration. After these initial responses, a delayed tachypnea developed and reached its peak 6–10 breaths after inhalation of smoke. Both the SR and AI were completely abolished by bilateral cervical vagotomy. In contrast, the delayed tachypneic response was not prevented by vagotomy but was significantly attenuated by denervation of peripheral chemoreceptors. We conclude that the initial responses to inhalation of several tidal breaths of wood smoke are mediated through vagal bronchopulmonary afferents, whereas the delayed tachypnea may involve nonvagal mechanisms that include a stimulation of peripheral chemoreceptors.
Influence of carbohydrate ingestion on fuel substrate turnover and oxidation during prolonged exercise
Authors: Bosch A. N. , Dennis S. C. , Noakes T. D.
Published: December 2017

This study examined effects of ingesting a 10% carbohydrate (CHO) drink (CI) or placebo (PI) at 500 ml/h on total (splanchnic) glucose appearance (endogenous+exogenous; Ra), blood glucose oxidation, and muscle glycogen utilization in 14 male endurance-trained cyclists who rode for 180 min at 70% of maximal O2 uptake after CHO loading [starting muscle glycogen 203 +/- 7 (SE) mmol/kg wet wt]. Total CHO oxidation was similar in CI and PI, but Ra increased significantly during the trial in both groups with CI reaching a plateau after 75 min. Ra was significantly greater in CI than in PI at the end of exercise. Blood glucose oxidation also increased significantly during the trial to a plateau in CI and was significantly higher in CI than in PI at the end of exercise. However, mean endogenous Ra was significantly lower in CI than in PI throughout exercise, as was oxidation of endogenous blood glucose, which remained almost constant in CI and reached 43 +/- 8 and 73 +/- 13 mumol.min-1.kg fat-free mass-1 in CI and PI, respectively, at the end of exercise. At 0.83 g/min of CHO ingestion, 0.77 +/- 0.03 g/min was oxidized. Muscle glycogen utilization was identical in both groups and was higher during the 1st h of exercise.(ABSTRACT TRUNCATED AT 250 WORDS)
Control of breathing patterns and abdominal muscles during graded loads and tilt
Authors: Barrett J. , Cerny F. , Hirsch J. A. , Bishop B.
Published: December 2017

Tilting from supine to upright purportedly enhances both segmental and pulmonary proprioceptive feedback, whereas an expiratory threshold load (ETL) preferentially enhances pulmonary feedback. To test this we studied 13 adults when supine and 60 degrees and 90 degrees head up. We measured tidal volume, inspiratory duration (TI), and expiratory duration (TE) from flow; estimated end-expiratory lung volume from inspiratory capacity; and determined burst amplitudes and durations from abdominal electromyograms (EMGs). ETLs were incremented from 0 (control) to 25 cmH2O in 5-cmH2O steps. Tidal volume was significantly increased by ETL but was unaffected by body position. Every load prolonged TE, whereas TI remained unchanged. When subjects were supine, abdominal EMGs were silent but became tonically active when subjects were upright. During ETL, abdominal activity became rhythmical and phase locked to expiration. Bursts amplitudes were enhanced with each increment in ETL, but burst durations did not change even though TE was prolonged. The altered breathing pattern and active expiration augmented inspiratory flow and decreased end-tidal PCO2. Responses were greatest when subjects were 90 degrees head up. The load-related increments in abdominal recruitment, with no change in burst durations, fit the concept of two central pattern generators: one controlling pattern and the other controlling rhythm of the central respiratory drive.
Reflex modulation of airflow dynamics through the upper airway
Authors: Seelagy M. M. , Schwartz A. R. , Russ D. B. , King E. D. , Wise R. A. , Smith P. L.
Published: December 2017

We studied the effect of respiratory reflexes on maximal inspiratory flow (VImax) and its mechanical determinants, pharyngeal critical pressure (Pcrit) and nasal resistance, in an isolated feline upper airway preparation. Chemoreceptor reflexes were evaluated by varying inspired oxygen and end-tidal CO2 concentrations. At each gas concentration, we found that changes in VImax were related to changes in Pcrit. As CO2 increased, Pcrit became increasingly subatmospheric (P < 0.02), indicating reductions in pharyngeal collapsibility. In contrast, progressive hypoxia had no effect on Pcrit. We then examined the effects of vagal afferents and upper airway mucosal receptors on airflow dynamics at three levels of CO2. We confirmed that CO2 increased VImax (P < 0.01) and decreased Pcrit to more subatmospheric levels (P < 0.05) in both the presence and absence of vagal and airway mucosal afferent activity. Moreover, airway mucosal afferents led to smaller reductions in Pcrit (a less collapsible airway) (P < 0.05), whereas vagal afferents led to a larger increase in Pcrit (a more collapsible pharynx) under hypercapnic conditions (P < 0.01). We conclude that CO2 had a major effect on pharyngeal collapsability and that its effect was modulated by vagal and mucosal afferents. We speculate that the sensitivity and threshold to reflex CO2 responses play a major role in the maintenance of airway patency.
Hydroxymalonate inhibits lactate uptake by the rabbit hindlimb
Authors: Gutierrez G. , Fernandez E. , Hurtado F. J. , Kiiski R. , Chakravarthy S. , Ronco J. J. , Arbelaez G.
Published: December 2017

Lactate uptake by skeletal muscle occurs under diverse conditions, including hypoxia and electrical stimulation. A possible metabolic fate of lactate in resting muscle is its conversion to pyruvate followed by carboxylation to malate in the cytosolic malic reaction. To test this hypothesis, we measured hindlimb lactate uptake in hypoxic mechanically ventilated rabbits. Rabbits were given intravenous infusions of hydroxymalonate, an inhibitor of the malic reaction (200 mM; n = 7), or normal saline (n = 7) at 1.1 ml/min. Hindlimb lactate uptake/release was calculated as femoral blood flow times the arteriovenous lactate difference. Saline or hydroxymalonate was infused continuously during sequential 30-min periods of normoxia (arterial PO2 approximately 150 Torr), hypoxemia (arterial PO2 approximately 30 Torr), and reoxygenation (arterial PO2 approximately 150 Torr). Hindlimb O2 transport decreased with hypoxemia, but O2 consumption remained unchanged in both groups. During hypoxemia there was net uptake of lactate by the hindlimb of the group given normal saline [4.5 +/- 0.9 (SE) mumol/min]. The hindlimb of the hydroxymalonate group continued to release lactate (-0.5 +/- 1.0 mumol/min). The inhibition of lactate uptake by hydroxymalonate supports the hypothesis that the malic reaction plays a major role in the metabolism of lactate by resting rabbit skeletal muscle.
pH and temperature modulate norepinephrine-dependent changes in endothelial permeability
Authors: Griffin M. P. , Moorman J. R.
Published: December 2017

To evaluate the role of pH and temperature in norepinephrine (NE)-mediated decreases in endothelial permeability, we studied bovine pulmonary arterial endothelial monolayers at pH values of 4–9 and at temperatures of 35–39 degrees C. Only extremes of pH-modulated endothelial permeability and temperature had no effect. Although both NE and 3-isobutyl-1-methylxanthine decreased endothelial permeability, their effects were diminished by low pH and high temperature. Fever and acidosis may contribute to the edema seen in septic shock by a novel mechanism: attenuation of the barrier-improving function of NE.
Ventilatory variability induced by spontaneous variations of PaCO2 in humans
Authors: Modarreszadeh M. , Bruce E. N.
Published: December 2017

We tested the hypothesis that breath-to-breath variations in arterial CO2 partial pressure (PaCO2) during spontaneous breathing of awake humans cause a significant portion of spontaneous ventilatory variability (including periodic oscillations). This hypothesis was tested in two ways. First, using a recently developed adaptive PaCO2 buffering technique we reduced the spontaneous variability in PaCO2 of six awake normal young human subjects during hyperoxia and observed a corresponding decrease in their breath-to-breath ventilatory variations. Second, we predicted the ventilatory responses to CO2 disturbances by using a model of chemical control of ventilation, both examining the hyperoxic condition (similar to experimental studies) and predicting the responses to CO2 variations of a normal subject breathing room air. In all experimental and theoretical studies, we found that small random disturbances to PaCO2 have significant effects on ventilation, including the potential for such PaCO2 disturbances to elicit oscillatory fluctuations in ventilation even though the ventilatory chemical control system was stable (i.e., a brief disturbance to PaCO2 did not elicit sustained ventilatory oscillations). On the basis of these results we propose that the stability of chemoreflex ventilatory control loops depends on both “loop gain” factors and the characteristics of random disturbances to PaCO2.
In vivo adenovirus-mediated gene transfer to lungs via pulmonary artery
Authors: Lemarchand P. , Jones M. , Danel C. , Yamada I. , Mastrangeli A. , Crystal R. G.
Published: December 2017

On the basis of the knowledge that the pulmonary and bronchial circulations have extensive anastomoses, we hypothesized that gene transfer to the endothelium of both pulmonary and bronchial circulations might be achieved with replication-deficient recombinant adenovirus (Ad) vectors administered to the pulmonary circulation. To evaluate this concept, the right upper lobe branches of the sheep pulmonary artery and vein were temporarily occluded and a replication-deficient recombinant Ad vector containing the Escherichia coli lacZ reporter gene coding for beta-galactosidase (beta-Gal) was infused into the lumen of the occluded pulmonary artery. After 15 min, the pulmonary circulation was restored, and 1 or 4 days later the lungs were evaluated by histochemical analysis for beta-Gal activity. Gene transfer and expression were positive in 13 of 17 evaluated sheep. No beta-Gal activity was detected in any category of cells of uninfected lobes. As hypothesized, beta-Gal activity was detected in endothelial cells of the right upper lobe pulmonary and bronchial circulations. Unexpectedly, gene transfer was also observed in epithelial cells of the alveoli and the airways (bronchi and bronchioles) as well as in the epithelium of submucosal glands. These studies demonstrate that it is possible to use Ad vectors for transfer and expression of genes to lung parenchymal cells served by both the pulmonary and bronchial circulations. Furthermore, whereas administration of such vectors via the airways results in gene transfer only to the epithelium, pulmonary artery administration permits gene transfer to both endothelium and epithelium, thus expanding the target range of Ad gene transfer to the lungs.
Role of EDRF in the regulation of regional blood flow and vascular resistance at rest and during exercise in conscious dogs
Authors: Shen W. , Lundborg M. , Wang J. , Stewart J. M. , Xu X. , Ochoa M. , Hintze T. H.
Published: December 2017

The contribution of endothelium-derived relaxing factor (EDRF) to the regulation of regional vascular resistance and tissue blood flow at rest and during acute moderate exercise was studied in chronically instrumented conscious dogs. Radioactive microspheres were injected before and during exercise to measure regional blood flow. An infusion of nitro-L-arginine (L-NA), an analogue of L-arginine, was used to inhibit the synthesis of EDRF and resulted in a significant increase in mean arterial pressure, associated with significantly elevated vascular resistance in heart, skeletal muscle, renal and splanchnic circulations and with decreases in tissue blood flow in those regions at rest. Acute exercise caused a typical redistribution of blood flow, in which there was vasodilation in heart and working skeletal muscles, accompanied by vasoconstriction in kidney and splanchnic circulations. L-NA resulted in significantly elevated vascular resistance during vasodilation in heart and working skeletal muscles and also significantly increased vasoconstriction in renal cortex, stomach, pancreas, liver, and colon during exercise. Blood flows during exercise were largely unaffected by L-NA treatment. Our results suggest that whereas EDRF functions to regulate basal vascular tone and vascular resistance during exercise, EDRF has a minor role in determining the pattern of the redistribution of tissue blood flow during exercise.
Different effects of respiratory and metabolic acidosis on preganglionic sympathetic nerve activity
Authors: Offner B. , Czachurski J. , Konig S. A. , Seller H.
Published: December 2017

We studied sympathetic nerve activity (SNA) responses, recorded in multifiber preparations of left third thoracic white ramus, to respiratory or isocapnic metabolic acidosis or to CO2 enhancement at constant pH in chloralose-anesthetized paralyzed artificially ventilated cats. Cardiopulmonary, baro-, and peripheral chemoreceptors were denervated by bilaterally cutting vagus and carotid sinus nerves. Acidosis was induced by either decreasing artificial ventilation or infusing HCl (0.5 M i.v.). Both respiratory and isocapnic metabolic acidosis induced a decrease in local extracellular pH, measured directly with pH-sensitive microelectrodes within medulla region containing sympathoexcitatory bulbospinal neurons. The magnitude of changes in medullary pH was independent of the way systemic acidosis was generated. Despite uniformity of changes in local medullary extracellular pH due to systemic respiratory or isocapnic metabolic acidosis, different responses were observed in preganglionic SNA. Isocapnic metabolic acidosis resulted in a slight increase in SNA, averaging 6.4% per 0.05 systemic pH unit decrease. In contrast, respiratory acidosis induced by decreasing artificial ventilation produced a more pronounced increase of SNA, reaching peak changes of approximately 70% compared with control level with normal blood gases, an average increase of 13% per 0.05 systemic pH unit decrease. We conclude that systemic CO2 and H+ concentrations represent different stimuli to sympathetic nervous system. Despite similar changes of local extracellular pH within rostral ventrolateral medulla during systemic acidosis, different responses of SNA suggest other sites or as yet unknown additional effects of CO2 as being responsible for excitation of sympathetic activity.
Biexponential pulmonary clearance of 99mTc-DTPA induced by detergent aerosol
Authors: Evander E. , Wollmer P. , Valind S. , Sornmo L. , John J. , Jonson B.
Published: December 2017

We measured the pulmonary clearance of technetium-99m-labeled diethylenetriamine pentaacetatic acid (99mTc-DTPA) for 3 h after perturbation of the surfactant system by administration of the detergent dioctyl sodium sulfosuccinate in aerosol. Forty-two rabbits were anesthetized with pentobarbital sodium. Tracheostomies were performed, and the rabbits were mechanically ventilated. Increasing concentrations of detergent (0.125–2%) or vehicle were given for 5 min, and clearance measurements were performed immediately or 60 min after detergent administration. No animals developed respiratory distress. After vehicle, the clearance was monoexponential with a half-life of 153 min. Detergent induced a biexponential clearance with a rapidly clearing additional pool of radioactivity with a half-life of 5–15 min. The relative amount of radioactivity clearing rapidly increased with detergent concentration. The detergent effect was partly reversible. We conclude that detergent induces a biexponential clearance of 99mTc-DTPA by accelerating the transfer of tracer across the alveolocapillary barrier in a proportion of lung units in a dose-related manner.
Mechanism of respiratory arrest in an animal model of acute fatal bronchoconstriction
Authors: Yanos J. , Patti M. J. , Banner A. S.
Published: December 2017

The cause of respiratory arrest in acute asthma is not known. By its nature, respiratory arrest is difficult to study clinically. The possible causes of respiratory arrest include cardiovascular dysfunction, respiratory muscle fatigue, and central respiratory failure. We used a dog model of respiratory arrest in acute bronchoconstriction that examined the effects of hypoxemia and intrinsic loading in an attempt to establish the mechanism. Our hypothesis was that, in a setting of hypoxemia and intrinsic loading similar to human fatal asthma, respiratory arrest is caused by a central respiratory failure, more specifically, failure of the central rhythm generator. We studied 18 dogs divided into 1) an intrinsically loaded group, 2) a hypoxemic group, and 3) both a loaded and a hypoxemic group. Intrinsic loading was induced with methacholine combined with selective beta 2-blockade, and the hypoxemia was controlled by varying inspired O2 fraction. Respiratory arrest occurred only in animals with both hypoxemia and intrinsic loading. We found no evidence of hemodynamic instability or respiratory muscle fatigue. Instead, there was an abrupt cessation of ventilation while the intensity of the central neural output was maintained. Our results are consistent with a failure of the central rhythm generator as the causal agent in respiratory arrest.
Relationships between energy expenditure and positive and negative mechanical work in repetitive lifting and lowering
Authors: De Looze M. P. , Toussaint H. M. , Commissaris D. A. , Jans M. P. , Sargeant A. J.
Published: December 2017

Determining the separate energy costs of the positive and negative mechanical work in repetitive lifting or lowering is quite complex, as a mixture of both work components will always be involved in the up- and downward motion of the lifter's body mass. In the current study, a new method was tested in which coefficients specifically related to the positive and negative work were estimated by multiple regression on a data set of weight-lifting and weight-lowering tasks. The energy cost was obtained from oxygen uptake measurements. The slopes of the regression lines for energy cost and mechanical work were steeper for positive than for negative work. The cost related to the negative work was approximately 0.3–0.5 times the cost of the positive work. This finding is well in line with data obtained directly from other isolated activities of either positive or negative work (e.g., ladder climbing vs. descending). However, the intercept values of the regression lines were not significantly different from zero or were even negative. This was most likely due to the metabolic energy not related to processes that yield mechanical work (e.g., isometric muscle actions) that was not constant among trials.
Proposed nomenclature for quantifying subdivisions of the bronchial wall
Authors: Bai A. , Eidelman D. H. , Hogg J. C. , James A. L. , Lambert R. K. , Ludwig M. S. , Martin J. , McDonald D. M. , Mitzner W. A. , Okazawa M. , et al.
Published: December 2017

There is increasing interest in the structural components of the airway wall because of the airway remodeling that is observed in conditions such as asthma and chronic obstructive pulmonary disease and because of their contribution to changes in airway mechanics. This interest has stimulated several groups to make morphometric measurements on airway cross sections, and their results have been reported using a variety of nomenclature. We propose the adoption of a standard system of nomenclature that is based on accepted terms for subdivisions of the airway wall and has been agreed to by several groups working in this field.
Carotid baroreflex control of blood pressure and heart rate in men during dynamic exercise
Authors: Papelier Y. , Escourrou P. , Gauthier J. P. , Rowell L. B.
Published: December 2017

The degree of control of blood pressure (BP) and heart rate (HR) by arterial baroreflex during exercise is still controversial. We studied baroreflex control of BP and HR in seven normal young men by a noninvasive procedure employing a neck suction chamber that delivers pulsatile positive and negative pressures to the carotid sinus (CS). Pressures applied to the CS ranged from -80 to +60 Torr in steps of 20 Torr. Pressure stimuli were triggered by electrocardiogram R wave, and each pressure step was maintained for 20 s in a continuous sequence. One baroreflex-response curve was obtained during the last 3 min of each 6-min period of exercise. The four levels of upright (cycle) exercise were 60, 120, 180, and 240 W, the highest requiring approximately 75% of maximal O2 uptake. The sensitivity of the HR baroreflex response assessed by linear regression of HR vs. CS pressure (CSP) did not significantly decrease from rest (-0.09 +/- 0.053 beat/Torr) to 240 W (-0.06 +/- 0.025 beat/Torr). The BP above or below which CSP was increased or decreased by neck collar pressure was significantly increased from rest (76 +/- 6.5 Torr) to 240 W (111.2 +/- 4.0 Torr). The sensitivity of baroreflex response was assessed by linear regression of BP vs. CSP and was not significantly different from rest (-0.29 +/- 0.054 Torr/Torr) up to exercise at 240 W (-0.29 +/- 0.048 Torr/Torr). We conclude that mild to severe exercise does not reduce the gain of the CS reflex below resting values.(ABSTRACT TRUNCATED AT 250 WORDS)
Longitudinal distribution of ozone absorption in the lung: effects of respiratory flow
Authors: Hu S. C. , Ben-Jebria A. , Ultman J. S.
Published: December 2017

In our previous work, we developed a bolus inhalation apparatus and measured the longitudinal distribution of ozone (O3) uptake in intact human lungs at a quiet respiratory flow of 250 ml/min. The objective of the present study was to determine the effect of alternative respiratory flows between 150 and 1,000 ml/s. Uptake was expressed as the O3 absorbed during a single breath relative to the amount of O3 in the inhaled bolus (lambda). Measurements of lambda were correlated with the penetration volume of the bolus into the respiratory tract (Vp). Vp in the range of 20–70 ml was considered to indicate upper airways (UA), the Vp interval of 70–180 ml was identified as lower conducting airways (CA), and Vp > 180 ml was associated with the respiratory air spaces (RA). During quiet oral breathing at 250 ml/s, lambda increased smoothly as Vp increased, with 50% of the inhaled O3 absorbed in the UAs and the remainder absorbed within the CAs such that no O3 reached the RAs. The effect of increasing the respiratory flow was to shift the lambda-Vp distribution distally such that significantly less O3 was absorbed in the UAs and CAs and some O3 reached the RAs. For example, at 1,000 ml/s, only 10% of the inhaled O3 was absorbed in UAs and 65% was absorbed in the CAs such that 25% reached the RAs.(ABSTRACT TRUNCATED AT 250 WORDS)
Role of nitric oxide and prostaglandins in the regulation of diaphragmatic arteriolar tone in the rat
Authors: Boczkowski J. , Vicaut E. , Danialou G. , Aubier M.
Published: December 2017

We evaluated by intravital microscopy in rats the relative importance of nitric oxide (NO) and prostaglandins in 1) the maintenance of basal diaphragmatic arteriolar tone and 2) the response of diaphragmatic arterioles to the endothelium-dependent vasodilator acetylcholine (ACh). One hundred two mechanically ventilated rats were studied. Separate applications of N omega-nitro-L-arginine (L-NNA) and mefenamic acid (MA), which are specific inhibitors of NO and prostaglandin synthesis, respectively, elicited a significant reduction in basal diaphragmatic arteriolar diameter. A dramatic potentiation of the effect of each inhibitor was observed when both agents were applied simultaneously. ACh application induced a significant and dose-dependent increase in arteriolar diameter that was not significantly modified by the separate application of L-NNA or MA. Conversely, the simultaneous administration of L-NNA and MA almost completely prevented ACh-induced arteriolar dilatation. Dilatation in response to sodium nitroprusside was not significantly modified in the presence of both inhibitors. These results suggest that NO and prostaglandins act in concert to regulate basal diaphragmatic arteriolar tone and to mediate diaphragmatic arteriolar response to ACh.
Pressure-flow specificity of inspiratory muscle training
Authors: Tzelepis G. E. , Vega D. L. , Cohen M. E. , Fulambarker A. M. , Patel K. K. , McCool F. D.
Published: December 2017

The inspiratory muscles (IM) can be trained by having a subject breathe through inspiratory resistive loads or by use of unloaded hyperpnea. These disparate training protocols are characterized by high inspiratory pressure (force) or high inspiratory flow (velocity), respectively. We tested the hypothesis that the posttraining improvements in IM pressure or flow performance are specific to training protocols in a way that is similar to force-velocity specificity of skeletal muscle training. IM training was accomplished in 15 normal subjects by use of three protocols: high inspiratory pressure-no flow (group A, n = 5), low inspiratory pressure-high flow (group B, n = 5), and intermediate inspiratory pressure and flow (group C, n = 5). A control group (n = 4) did no training. Before and after training, we measured esophageal pressure (Pes) and inspiratory flow (VI) during single maximal inspiratory efforts against a range of external resistances including an occluded airway. Efforts originated below relaxation volume (Vrel), and peak Pes and VI were measured at Vrel. Isovolume maximal Pes-VI plots were constructed to assess maximal inspiratory pressure-flow performance. Group A (pressure training) performed 30 maximal static inspiratory maneuvers at Vrel daily, group B (flow training) performed 30 sets of three maximal inspiratory maneuvers with no added external resistance daily, and group C (intermediate training) performed 30 maximal inspiratory efforts on a midrange external resistance (7 mm ID) daily. Subjects trained 5 days/wk for 6 wk. Data analysis included comparison of posttraining Pes-VI slopes among training groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Pulmonary gas exchange during exercise in athletes. I. Ventilation-perfusion mismatch and diffusion limitation
Authors: Hopkins S. R. , McKenzie D. C. , Schoene R. B. , Glenny R. W. , Robertson H. T.
Published: December 2017

To investigate pulmonary gas exchange during exercise in athletes, 10 high aerobic capacity athletes (maximal aerobic capacity = 5.15 +/- 0.52 l/min) underwent testing on a cycle ergometer at rest, 150 W, 300 W, and maximal exercise (372 +/- 22 W) while trace amounts of six inert gases were infused intravenously. Arterial blood samples, mixed expired gas samples, and metabolic data were obtained. Indexes of ventilation-perfusion (VA/Q) mismatch were calculated by the multiple inert gas elimination technique. The alveolar-arterial difference for O2 (AaDO2) was predicted from the inert gas model on the basis of the calculated VA/Q mismatch. VA/Q heterogeneity increased significantly with exercise and was predicted to increase the AaDO2 by > 17 Torr during heavy and maximal exercise. The observed AaDO2 increased significantly more than that predicted by the inert gas technique during maximal exercise (10 +/- 10 Torr). These data suggest that this population develops diffusion limitation during maximal exercise, but VA/Q mismatch is the most important contributor (> 60%) to the wide AaDO2 observed.