bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperthermia stimulates nitric oxide formation: electron paramagnetic resonance detection of .NO-heme in blood
Authors: Hall D. M. , Buettner G. R. , Matthes R. D. , Gisolfi C. V.
Published: December 2017

Previous experiments from our laboratory have demonstrated that severe hyperthermia results in a selective loss of splanchnic vasoconstriction. Using electron paramagnetic resonance spectroscopy to scan whole blood samples collected in vivo from the portal vein and femoral artery of conscious unrestrained rats, we observed an increase in the concentration of spectroscopy-detectable species in portal venous blood of all heat-stressed animals. These spectra consisted of at least three distinct species: one with a broad feature having an effective g factor for the unpaired electron (g) of 2.06 assigned to the copper-binding acute phase protein ceruloplasmin, and two with narrower features that evolved at core temperatures > 39 degrees C representing a semiquinone radical and .NO-heme. This heat-induced signal displays the classic nitrogen triplet hyperfine structure (nitrogen hyperfine splitting constant = 17.5 gauss, centered at g = 2.012) that is consistent with a five-coordinate heme complex and is characteristic of an unpaired electron coupled to nitrogen in the ferrous .NO-heme adduct [(alpha 2+NO) beta 3+]2. The intensity of this signal increased approximately twofold as core temperature rose to > 39 degrees C, peaking 1 h post-heat exposure at greater than threefold basal concentration. This species was not seen in corresponding arterial blood samples. This is the first demonstration that whole body hyperthermia produces increased concentrations of radicals and metal binding proteins in the venous blood of the rat and suggests that severe hyperthermia stimulates an enhanced local release of .NO within the splanchnic circulation.
Regional lung hematocrit variation and assessment of acute lung injury
Authors: Kanazawa M. , Hasegawa N. , Urano T. , Sayama K. , Tasaka S. , Sakamaki F. , Nakamura H. , Waki Y. , Terashima T. , Fujishima S. , et al.
Published: December 2017

Estimating blood content in the lung remains a key step in calculating lung water volume and microvascular permeability. We studied the effect of regional lung hematocrit (Hct) variation on assessment of acute lung injury. Escherichia coli endotoxin was administered in guinea pigs intravenously. Lung injury was evaluated by measuring the wet-to-dry weight ratio (W/D) and transvascular 125I-labeled albumin leakage for 3 h [tissue-to-plasma 125I-albumin ratio (T/P)] in five tissue samples from each animal. Residual blood content was corrected using either 51Cr-red blood cells as a blood cell marker, 99mTc-albumin as a plasma marker, or both, injected 10 min before the guinea pigs were killed. Lung Hct, estimated from the marker counts of lung and peripheral blood samples, was lower than peripheral blood Hct; intraindividual variation, represented by the standard deviation in each subject, was 0.024 +/- 0.015 for the control group (coefficient of variation 8.0 +/- 5.1%) and 0.026 +/- 0.013 for the endotoxin group (coefficient of variation 8.5 +/- 4.1%). Uncorrected W/D for residual blood content was greater than the corrected W/D. 99mTc-albumin correction gave values closer to the W/D corrected by both markers. T/P corrected by 99mTc-albumin showed smaller data variations than the values obtained with 51Cr-red blood cell correction, which was affected by variations in lung Hct. We recommend using a plasma marker to correct for blood content in assessing acute lung injury by W/D and T/P.
Impact of parallel heterogeneity on a continuum model of the pulmonary arterial tree
Authors: Krenz G. S. , Lin J. , Dawson C. A. , Linehan J. H.
Published: December 2017

Model arterial trees were constructed following rules consistent with morphometric data, Nj = (Dj/Da)-beta 1 and Lj = La(Dj/Da)beta 2, where Nj, Dj, and Lj are number, diameter, and length, respectively, of vessels in the jth level; Da and La are diameter and length, respectively, of the inlet artery, and -beta 1 and beta 2 are power law slopes relating vessel number and length, respectively, to vessel diameter. Simulated heterogeneous trees approximating these rules were constructed by assigning vessel diameters Dm = Da[2/(m + 1)]1/beta 1, such that m-1 vessels were larger than Dm (vessel length proportional to diameter). Vessels were connected, forming random bifurcating trees. Longitudinal intravascular pressure [P(Qcum)] with respect to cumulative vascular volume [Qcum] was computed for Poiseuille flow. Strahler-ordered tree morphometry yielded estimates of La, Da, beta 1, beta 2, and mean number ratio (B); B is defined by Nk + 1 = Bk, where k is total number of Strahler orders minus Strahler order number. The parameters were used in P(Qcum) = Pa [formula: see text] and the resulting P(Qcum) relationship was compared with that of the simulated tree, where Pa is total arterial pressure drop, Q is flow rate, Ra = (128 microLa)/(pi D4a (where mu is blood viscosity), and Qa (volume of inlet artery) = 1/4D2a pi La. Results indicate that the equation, originally developed for homogeneous trees (J. Appl. Physiol. 72: 2225–2237, 1992), provides a good approximation to the heterogeneous tree P(Qcum).
Modulation of respiratory rhythm by alpha 2-adrenoceptors in awake and anesthetized goats
Authors: Hedrick M. S. , Ryan M. L. , Pizarro J. , Bisgard G. E.
Published: December 2017

The purpose of this study was to examine the effects of alpha 2-adrenoceptor agonists in the control of breathing with goats that were either awake (n = 7) or anesthetized and artificially ventilated (n = 11). Awake goats infused intravenously with either of the alpha 2-agonists clonidine (1.0–6.0 micrograms/kg) or guanabenz (15.0–63.0 micrograms/kg) exhibited two distinct ventilatory patterns. One pattern was characterized by tachypnea in which respiratory frequency and minute ventilation increased to approximately 50% above control values. A second ventilatory pattern consisted of slow breathing with reductions of respiratory frequency and minute ventilation and highly variable expiratory duration intervals. These two patterns were unaffected by bilateral carotid body denervation. In anesthetized goats, alpha 2-agonists also caused an arrhythmia in phrenic nerve activity that was similar to the slow breathing pattern seen in awake goats. Respiratory disturbances were abolished by the selective alpha 2-receptor antagonist SKF-86466 (100–500 micrograms/kg), indicating that the effects are mediated by alpha 2-receptors. The results suggest that stimulation of alpha 2-adrenoceptors generally has an inhibitory effect on breathing in goats. The disruption of ventilation with clonidine or guanabenz suggests that alpha 2-adrenoceptors may play an important role in the control of central respiratory rhythm.
Lung vascular protein permeability in preterm fetal and mature newborn sheep
Authors: Carlton D. P. , Cummings J. J. , Scheerer R. G. , Bland R. D.
Published: December 2017

The purpose of this study was to see whether there are developmental differences in the protein permeability of the pulmonary circulation that might contribute to the abnormal lung fluid balance seen in premature lambs with respiratory failure. In one series of experiments, we measured albumin turnover time, which reflects the escape rate of radiolabeled albumin from the pulmonary circulation, of five preterm fetal lambs (125 +/- 1 days gestation) and five newborn lambs (19 +/- 9 days old). Turnover time was not significantly different in fetuses (160 +/- 38 min) and newborns (141 +/- 54 min), implying a similar protein permeability of the pulmonary circulation. In additional experiments, we measured pulmonary hemodynamic and lung lymph flow responses to intravenous saline infusion in seven preterm fetal lambs (130 +/- 3 days gestation) and seven newborn lambs (14 +/- 3 days old). During saline infusion, calculated fluid filtration pressure increased by a similar amount in fetuses and newborns (3.4 +/- 0.8 and 2.8 +/- 0.9 Torr, respectively), resulting in a similar change in lung lymph flow in fetuses and newborns (0.59 +/- 0.27 and 0.55 +/- 0.25 ml.h-1.kg body wt-1, respectively). The results of these studies indicate that protein permeability of the pulmonary circulation does not change significantly during late fetal and early postnatal development.
Supernormal muscle fiber conduction velocity during intermittent isometric exercise in human muscle
Authors: Van der Hoeven J. H. , Lange F.
Published: December 2017

Muscle fiber conduction velocity (MFCV) and surface electromyographic parameters were studied in the brachial biceps muscle of healthy males during voluntary intermittent isometric contractions at 50% of maximum force. Recovery in the following 15 min was then observed. The measurements were performed during duty cycles of 33, 25, and 20%. The main finding was a supernormal MFCV during the exercise phase when the duty cycle was 25 and 20%. The level continued to increase during the recovery phase. During the exercise phase when the duty cycle was 33%, the MFCV decreased slightly (suggesting that the local anaerobic threshold had been surpassed) but increased during recovery to supernormal values. The ratio of median frequency to MFCV was constant during all experiments, indicating that the changes in median frequency reflect those in MFCV. We suggest that the supernormal MFCV was due to a combination of altered membrane properties, muscle fiber swelling, and temperature increase and hypothesize that the changes of electrical properties formed part of an adaptive mechanism of the muscle fiber membrane during exercise. In that respect, the increase of the MFCV could be a component of the well-known warm-up effect.
Effects of hyperinflation and CPAP on work of breathing and respiratory failure in dogs
Authors: Shade E. , Kawagoe Y. , Brower R. G. , Permutt S. , Fessler H. E.
Published: December 2017

Increased end-expiratory lung volume (EELV) and airway resistance are both characteristic features of obstructive lung disease. Increased EELV alone loads the respiratory muscles and may cause respiratory failure, changes that could be reversed by continuous positive airway pressure (CPAP). To study the effects of elevated EELV on respiration without increased airway resistance, we used a mechanical analogue of airway closure to increase EELV in six spontaneously breathing anesthetized dogs. Hyperinflation of 0.84 +/- 0.11 liter for 30 min decreased minute ventilation from 4.8 +/- 0.37 to 3.5 +/- 0.21 l/min and increased arterial PCO2 from 40.3 +/- 1.5 to 73.2 +/- 8.1 Torr (both P < 0.01). Inspiratory work per breath increased 3-fold, work per liter increased 3.7-fold, and work per minute increased 2.8-fold (all P < 0.01). CPAP at 15 cmH2O restored minute ventilation to 4.3 +/- 0.3 l/min and reduced arterial PCO2 to 54 +/- 6.6 Torr (NS vs. baseline). All measurements of inspiratory work were also restored to baseline, but cardiac output was reduced (baseline 3.09 +/- 0.36, hyperinflation 2.71 +/- 0.36, hyperinflation + CPAP 1.94 +/- 0.29 l/min; P < 0.05, baseline vs. hyperinflation + CPAP). We conclude that increases in EELV mimic important features of airway obstruction, increase inspiratory work, and can cause respiratory failure independent of increased airway resistance. This respiratory failure is reversed by CPAP at the potential expense of hemodynamic compromise.
Energy balance at high altitude of 6,542 m
Authors: Westerterp K. R. , Kayser B. , Wouters L. , Le Trong J. L. , Richalet J. P.
Published: December 2017

Weight loss due to malnutrition and possibly intestinal malabsorption is a well-known phenomenon in high-altitude climbers. Up to approximately 5,000 m, energy balance may be attained and intestinal energy digestibility remains normal. To see whether 1) energy balance may also be attained at 6,542 m and, if not, 2) whether decreased energy digestibility would play a significant role in the energy deficit, energy intake (EI), energy expenditure, body composition, and energy digestibility of 10 subjects (4 women, 6 men; 27–44 yr) were assessed during a 21-day sojourn on the summit of Mt. Sajama, Bolivia (6,542 m). EI was measured during two 3-day intervals: EI1 (days 7–9) and EI2 (days 17–19). Total fecal energy loss during EI1 was calculated from fecal energy measured by bomb calorimetry. Average daily metabolic rate (ADMR) at altitude was measured in six subjects (2 women, 4 men) using doubly labeled water over a 10-day interval (days 9–19). Basal metabolic rate was measured before and after the expedition by respiratory gas analysis. Body composition was estimated from skinfolds and body mass before and during the altitude sojourn. Subjects were in negative energy balance throughout the observation period (EI1-ADMR = -2.9 +/- 1.8 MJ/day and EI2-ADMR = -2.3 +/- 1.8 MJ/day based on a gross energy digestibility of 95%). The activity level, expressed as ADMR to basal metabolic rate, was 1.56–2.39. The loss of fat mass (3.7 +/- 1.5 kg) represented 74 +/- 15% of the loss of body mass.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of pentobarbital anesthesia on intercostal muscle activation and shortening
Authors: DiMarco A. F. , Supinski G. S. , Kowalski K. E. , Romaniuk J. R.
Published: December 2017

Although pentobarbital (PB) is a commonly used anesthetic in animal studies examining respiratory motor control, there are virtually no studies that have examined the differential effects of deepening anesthesia on the activation of the various intercostal muscles. In dogs, anesthetized initially with 25 mg/kg of PB, the effects of additional doses of PB (20 mg) provided every 15 min on intercostal electromyogram (EMG) were monitored. In each animal, peak external intercostal (EI) and levator costae (LC) activation progressively decreased with additional doses of PB and were eventually abolished, at which point peak parasternal (PA) EMG had increased to 127 +/- 13% (SE) of control values; peak diaphragm EMG was unaffected. The reductions in EI activation were associated with progressive reductions in EI muscle shortening that, in turn, were associated with progressive reductions in lateral rib cage expansion. PA shortening was not significantly affected. Similar results were obtained in animals breathing supplemental oxygen. These results indicate that 1) activation of EI and LC compared with PA have divergent responses, with EI and LC decreasing and PA increasing; 2) the fall in EI activation results in decrements in EI shortening and lateral rib cage motion; and 3) anesthetic depth is an important variable that must be controlled in studies assessing intercostal muscle activation.
Lung volumes and expiratory flow limitation during exercise in interstitial lung disease
Authors: Marciniuk D. D. , Sridhar G. , Clemens R. E. , Zintel T. A. , Gallagher C. G.
Published: December 2017

Lung volumes were measured at rest and during exercise by an open-circuit N2-washout technique in patients with interstitial lung disease (ILD). Exercise tidal flow-volume (F-V) curves were also compared with maximal F-V curves to investigate whether these patients demonstrated flow limitation. Seven patients underwent 4 min of constant work rate bicycle ergometer exercise at 40, 70, and 90% of their previously determined maximal work rates. End-expiratory lung volume and total lung capacity were measured at rest and near the end of each period of exercise. There was no significant change in end-expiratory lung volume or total lung capacity when resting measurements were compared with measurements at 40, 70, and 90% work rates. During exercise, expiratory flow limitation was evident in four patients who reported stopping exercise because of dyspnea. In the remaining patients who discontinued exercise because of leg fatigue, no flow limitation was evident. In all patients, the mean ratio of maximal minute ventilation to maximal ventilatory capacity (calculated from maximal F-V curves) was 67%. We conclude that lung volumes during exercise do not significantly differ from those at rest in this population and that patients with ILD may demonstrate expiratory flow limitation during exercise. Furthermore, because most patients with ILD are not breathing near their maximal ventilatory capacity at the end of exercise, we suggest that respiratory mechanics are not the primary cause of their exercise limitation.
Synthetic surfactant scavenges oxidants and protects against hyperoxic lung injury
Authors: Ghio A. J. , Fracica P. J. , Young S. L. , Piantadosi C. A.
Published: December 2017

Injury and mortality after exposure to 100% oxygen can be diminished by surfactants that may operate by mechanisms other than those responsible for surface tension effects. We tested the hypotheses that 1) synthetic surfactant and its components function as antioxidants in vitro and 2) decrements in hyperoxic injury after treatment with a surfactant and its components are associated with decreases in oxidative stress to the lung. A synthetic surfactant (Exosurf) and its non-surface-active components tyloxapol and cetyl alcohol were incubated in an iron-containing hydroxyl radical-generating system to determine their abilities to prevent oxidation of deoxyribose. Doses of tyloxapol, cetyl alcohol, and artificial surfactant diminished the absorbance of thiobarbituric acid-reactive products of deoxyribose. Similarly, tyloxapol, cetyl alcohol, and the surfactant decreased hydroxylated products of salicylate in the same system. Rats were instilled intratracheally with saline, tyloxapol, tyloxapol plus cetyl alcohol, or artificial surfactant and immediately exposed to air or 100% oxygen. After 61 h of oxygen exposure, pleural fluid volume and wet-to-dry lung weight ratios were decreased in animals treated with surfactant and/or its components. There were also decrements in thiobarbituric acid-reactive products of lung tissue. In separate experiments, mean survival of saline-treated rats exposed to 100% oxygen was 67.3 +/- 8.1 h and > 96 h for rats given the surfactant or its components. We conclude that tyloxapol, cetyl alcohol, and Exosurf can function as antioxidants in vitro and their in vivo instillation is associated with reduction in measures of hyperoxic injury, oxidized tissue products, and mortality.
Effects of ONO-5046, a specific neutrophil elastase inhibitor, on endotoxin-induced lung injury in sheep
Authors: Kubo K. , Kobayashi T. , Hayano T. , Koizumi T. , Honda T. , Sekiguchi M. , Sakai A.
Published: December 2017

The purpose of the present study was to assess the role of polymorphonuclear leukocyte (neutrophil) elastase in endotoxin-induced acute lung injury in sheep with lung lymph fistula. We studied the effects of ONO-5046, a specific inhibitor of neutrophil elastase, on the lung dysfunction induced by the intravenous infusion of 1 microgram/kg of Escherichia coli endotoxin. Endotoxin alone produced a biphasic response as previously reported. Early (0.5–1 h) after endotoxin, pulmonary arterial pressure increased from 19.5 +/- 0.9 cmH2O at baseline to a peak of 46.8 +/- 2.4 cmH2O (P > 0.05). Pulmonary vascular resistance increased from 3.03 +/- 0.17 cmH2O.l–1.min at baseline to a peak of 9.77 +/- 0.70 cmH2O.l–1.min (P < 0.05). Circulating neutrophils decreased from 7,355 +/- 434/mm3 at baseline to a nadir of 1,762 +/- 32/mm3 (P < 0.05). Thromboxane B2 and 6-ketoprostaglandin F1 alpha concentrations in plasma and lung lymph were significantly increased. Late (3–5 h) after endotoxin, pulmonary arterial pressure and pulmonary vascular resistance returned to baseline levels, but lung lymph flow remained increased from 4.2 +/- 0.3 ml/0.5 h at baseline to 7.3 +/- 0.7 ml/0.5 h (P < 0.05), with a slight increase in lung lymph-to-plasma protein concentration ratio, suggesting increased pulmonary vascular permeability. The histopathological features of the lungs during the early period in sheep treated with endotoxin alone revealed a large increase in neutrophils per 100 alveoli and changes of pulmonary edema such as thickening of the interstitium of the lung and alveolar flooding.(ABSTRACT TRUNCATED AT 250 WORDS)
Arm muscle sympathetic nerve activity during preparation for and initiation of leg-cycling exercise in humans
Authors: Callister R. , Ng A. V. , Seals D. R.
Published: December 2017

We tested the hypothesis that sympathetic vasoconstrictor nerve activity to nonactive skeletal muscle (MSNA) decreases immediately before and remains suppressed during initiation of conventional large muscle upright dynamic exercise in humans. In 11 healthy young subjects, adequate recordings of MSNA from the radial nerve in the arm were obtained during upright seated rest (control) and throughout 1 min of leg-cycling exercise at one or more submaximal workloads (range 33–266 W; approximately 10–80% of peak power output). MSNA was analyzed during four consecutive time intervals; control, preparation for cycling (end of control to onset of pedal movement), initiation of cycling (onset of pedal movement to attainment of target power output), and the initial 60 s of cycling at target power output. MSNA decreased (P < 0.05) abruptly and markedly in all subjects [to 19 +/- 4% (SE) of control levels] during the preparation period before the 33-W load and remained suppressed throughout the period of initiation of cycling in 8 of 11 subjects; MSNA increased during the initiation period in three subjects in whom diastolic arterial pressure fell below control levels. This general pattern was observed at all loads. MSNA remained at or below control levels throughout the 1 min of cycling exercise at 33–166 W. MSNA increased above control levels during the latter portion of the 1 min of cycling only at loads > or = 60% of peak power output.(ABSTRACT TRUNCATED AT 250 WORDS)
Entrainment of respiration to rocking in premature infants: coherence analysis
Authors: Sammon M. P. , Darnall R. A.
Published: December 2017

Vestibular influences on breathing pattern were investigated in 18 premature infants in the neonatal intensive care nursery. Respiratory abdominal movements were recorded while the babies were manually rocked at varying rates between 30 and 60 cycles/min (cpm). Coherence spectra were estimated between the respiratory and rocker signals, and their magnitudes were evaluated at the rocking frequency, with coherence spectra > 0.85 indicative of strong entrainment to rocking. At least one incident of entrainment was seen in 15 of 18 infants, with 2:1 ratios (2 breaths/rocker cycle) occurring at rocking frequencies of 30–40 cpm (8 of 18 subjects) and 1:1 entrainment at rates of 42–50 cpm (5 of 18 subjects). More complex synchronization was observed in three infants, with patterns consisting of alternans between 2:1 and 3:2 ratios (5:3 entrainment). Infants > 35 wk postconceptional age exhibited greater coherence to rocking than infants < 35 wk (P < 0.01), indicating a maturational change in the reflex may occur. Results show that the natural stimulation of rocking a newborn provides a phasic input to its respiratory pattern generator that is capable of resetting the system's oscillation and entraining its rhythm.
Measurement of high lung volumes by nitrogen washout method
Authors: Sivan Y. , Hammer J. , Newth C. J.
Published: December 2017

Studies on human infants suggested that thoracic gas volume (TGV) measured at end exhalation may not depict the true TGV and may differ from TGV measured from a series of higher lung volumes and corrected for the volume added. This was explained by gas trapping. If true, we should expect the discrepancy to be more pronounced when functional residual capacity (FRC) and higher lung volumes are measured by gas dilution techniques. We studied lung volumes above FRC by the nitrogen washout technique in 12 spontaneously breathing rhesus monkeys (5.0–11.3 kg wt; 42 compared measurements). Lung volumes directly measured were compared with preset lung volumes achieved by artificial inflation of the lungs above FRC with known volumes of air (100–260 ml). Measured lung volume strongly correlated with and was not significantly different from present lung volume (P = 0.05; r = 0.996). The difference between measured and preset lung volume was 0–5% in 41 of 42 cases [1 +/- 0.4% (SE)]. The direction of the difference was unpredictable; in 22 of 42 cases the measured volume was larger than the preset volume, but in 17 of 42 cases it was smaller. The difference was not affected by the volume of gas artificially inflated into the lungs. We conclude that, overall, lung volumes above FRC can be reliably measured by the nitrogen washout technique and that FRC measurements by this method reasonably reflect true FRC.
Decrease in ventricular stroke volume at apnea termination is independent of oxygen desaturation
Authors: Garpestad E. , Parker J. A. , Katayama H. , Lilly J. , Yasuda T. , Ringler J. , Strauss H. W. , Weiss J. W.
Published: December 2017

Patients with obstructive sleep apnea experience nocturnal hemodynamic oscillations in association with repetitive respiratory events. Apnea termination (recovery) is accompanied by the nadir of arterial O2 saturation (SaO2), changes in intrathoracic pressure, and arousal from sleep. To investigate separately the contributions of hypoxemia and of arousal from sleep to changes in cardiac function, we continuously measured left ventricular stroke volume (LVSV) and mean arterial pressure (MAP) in eight subjects with severe obstructive sleep apnea (apnea-hypopnea index > 30 events/h associated with SaO2 < or = 82%) during two experimental conditions: 1) subjects slept without intervention for 1–2 h and then supplemental O2 was administered to maintain SaO2 > or = 90% (mean SaO2 nadir 92.7%) throughout the apnea-recovery cycle and 2) upper airway obstructions were abolished using nasal continuous positive airway pressure and subjects were aroused from sleep by an auditory signal. Recovery was associated with an increase in MAP and a decrease in LVSV both with and without supplemental O2. Arousal from sleep on nasal continuous positive airway pressure reproduced the postapneic elevation of MAP but not a decrease in cardiac function of the magnitude that occurred at apnea termination. We conclude that elevation of blood pressure and reduction of LVSV that occurred at apnea termination may be due to different physiological mechanisms.
NMDA receptors in caudal ventrolateral medulla mediate reflex airway dilation arising from the hindlimb
Authors: Solomon I. C. , Motekaitis A. M. , Wong M. K. , Kaufman M. P.
Published: December 2017

The caudal ventrolateral medulla (CVLM) has been shown to participate in the reflex airway dilation evoked by stimulation of thin fiber afferents innervating the hindlimb of anesthetized dogs. Nevertheless, the pharmacological mechanism in the CVLM by which hindlimb afferents evoke this reflex airway dilation is not known. Therefore, we examined the role played by excitatory amino acid receptors in the CVLM in the reflex airway dilation arising from the hindlimb. Using chloralose-anesthetized dogs, we found that bilateral microinjections into the CVLM of either (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (25 mM, 50 nl) or (+/-)-2-amino-5-phosphonovaleric acid (50 mM, 50 nl), both of which block N-methyl-D-aspartate (NMDA) receptors, reversibly attenuated the decrease in total lung resistance that was evoked by either electrical stimulation of C-fibers in the sciatic nerve or by static contraction of both gastrocnemius muscles. In contrast, bilateral microinjection into the CVLM of 6-cyano-7-nitroquinoxaline-2,3-dione (39 microM, 50 nl), which blocks non-NMDA receptors, augmented the reflex decrease in total lung resistance that was evoked by either sciatic nerve stimulation or contraction of the gastrocnemius muscles. Bilateral microinjections of xanthurenic acid (100 mM, 50 nl) into the CVLM had no effect on the decrease in total lung resistance that was evoked by sciatic nerve stimulation. We conclude that NMDA, but not non-NMDA, receptors in the CVLM play an important role in the reflex arc that dilates the airways when hindlimb afferents are stimulated by either muscular contraction or electrical stimulation.
Use of twitch pressures to assess diaphragmatic function and central drive
Authors: Ferguson G. T.
Published: December 2017

Transdiaphragmatic pressures generated by phrenic nerve twitches have been proposed as a means to assess diaphragmatic function and central drive, but their validity and reliability have not been determined. We evaluated diaphragmatic twitch and twitch occlusion measurements in a rabbit model of diaphragmatic contractile dysfunction and diaphragmatic fatigue to determine whether 1) diaphragmatic twitch pressures accurately assess changes in low- and high-frequency diaphragm trains during the development of, and recovery from, contractile fatigue; 2) twitch occlusion measurements accurately quantify the intensity of central drive to the diaphragm; and 3) twitch measurements are affected by thoracoabdominal binding or twitch potentiation. Single-twitch and 20-Hz double- and triple-twitch pressures accurately reflected changes in low-frequency diaphragm train pressures, whereas only 80-Hz triple-twitch pressures accurately reflected changes in high-frequency trains. Twitch occlusion measurements of central drive closely mirrored central drive as reflected by phrenic nerve recordings and only slightly underestimated the absolute intensity of central drive. Thoracoabdominal binding increased twitch and train pressures, and repetitive electrical stimulations further potentiated twitch pressure. However, twitch potentiation and a lack of thoracoabdominal binding had no effect on twitch measurements of diaphragmatic function during the induction and recovery from fatigue or on twitch occlusion measurements of intensity of central drive. Thus, twitch measurements can be used to accurately assess diaphragmatic low- and high-frequency fatigue and to quantify the intensity of central drive to the diaphragm.
Erythrocyte and polymorphonuclear cell transit time and concentration in human pulmonary capillaries
Authors: Hogg J. C. , Coxson H. O. , Brumwell M. L. , Beyers N. , Doerschuk C. M. , MacNee W. , Wiggs B. R.
Published: December 2017

Pulmonary capillary transit times were examined in patients who required lung resection by use of 99mTc-labeled macroaggregates (99Tc-MAA) and chromium-labeled erythrocytes (51Cr-RBC) to measure regional blood flow and volume in the resected lung. Cell flow (cells.ml-1.s-1) to each resected lung sample was determined by multiplying the number of polymorphonuclear leukocytes (PMN) per milliliter of circulating blood by the blood flow to that sample. Capillary blood volume was obtained by multiplying the morphometrically determined fraction of pulmonary blood in capillaries by the total 51Cr-RBC volume in each sample. Cell concentrations (cells/ml) in capillary blood were calculated morphometrically, and capillary transit times were obtained by dividing cell concentration by cell flow. The results show that PMN transit times were 60–100 times longer than the RBC transit times, with a 22% overlap between their distributions. We conclude that PMN are concentrated with respect to RBC in pulmonary capillary blood because of differences in their transit times and that these long transit times provide an opportunity for PMN-endothelial interactions.
Relationship between blood pressure and airway obstruction during sleep in the dog
Authors: O'Donnell C. P. , King E. D. , Schwartz A. R. , Robotham J. L. , Smith P. L.
Published: December 2017

The relationship between airway obstruction during sleep and changes in mean arterial pressure (MAP) was investigated in four chronically instrumented tracheostomized dogs during 12-h nocturnal experiments. The MAP response was determined 1) during experimental airway obstruction whenever sleep occurred, 2) over each 12-h experiment, and 3) during a 2-h recovery period at the end of each experiment. The effects of 24 h of sleep deprivation and changes in plasma levels of renin and atrial natriuretic peptide were assessed. In non-rapid-eye-movement sleep, a period of airway obstruction caused MAP to increase (P < 0.002) from 95 +/- 3 (SE) mmHg to 112 +/- 3 mmHg, and this difference was enhanced (P < 0.04) by sleep deprivation. There was an increase of 12 +/- 2 mmHg in the overall MAP over time (P < 0.001) in non-rapid-eye-movement sleep that was sustained in the 2-h recovery period. Plasma levels of renin and atrial natriuretic peptide were constant and unrelated to changes in MAP. We conclude that in the sleeping dog airway obstruction causes an increase in MAP that can be accentuated by prior sleep deprivation and that repetitive airway obstruction will cause an increase in MAP over time that is sustained for > or = 2 h when normal airway patency is restored.
Acute lung injury isolated to an in situ lung preparation causes sustained reflex cardiovascular depression in dogs
Authors: Allen D. A. , Schertel E. R. , Weisbrode S. E. , Myerowitz P. D.
Published: December 2017

We tested the hypothesis that acute lung injury (ALI) isolated to a perfused in situ left lung preparation results in sustained reflex cardiovascular depression. Phorbol myristate acetate (PMA), an agent that activates neutrophils, administered into the isolated lung preparation of chloralose-anesthetized dogs resulted in ALI, as assessed by wet-to-dry weight ratios and histopathology, and significant decreases in heart rate (43%), mean arterial pressure (27%), aortic blood flow (29%) and maximum rate of change in left ventricular pressure (30%). Significant reflex effects occurred by 20 min after PMA administration and were sustained for 40 min (n = 7). Hemodynamic variables recovered when the left lung was denervated 60 min after PMA administration. Indomethacin administered into the isolated circulation before PMA (n = 5) did not significantly influence the ALI or reflex effects. Systemic atropinization (n = 6) prevented only the bradycardia. Left lung denervation before ALI (n = 3) prevented all reflex effects. We conclude that PMA administration into an isolated in situ lung preparation results in ALI and sustained reflex cardiovascular depression that is most likely elicited by pulmonary C-fiber stimulation and mediated by withdrawal of sympathetic efferent nerve activity.
Adverse effect of hyperinflation on parasternal intercostals
Authors: Ninane V. , Gorini M.
Published: December 2017

The force-generating ability of the parasternal intercostals is maintained during acute hyperinflation in the dog (Jiang et al. Am. Rev. Respir. Dis. 139: 522–528, 1989). In the present studies, we assessed whether the ability of these muscles to expand the rib cage and inflate the lungs is really maintained. We thus measured the electromyogram and the changes in length of these muscles, the axial motion of the sternum and the ribs, and the changes in pleural pressure and tidal volume in anesthetized vagotomized phrenicotomized dogs during selective parasternal stimulation and during spontaneous breathing at different lung volumes corresponding to 0, 5, 10, and 15 cmH2O positive airway pressure. Compared with functional residual capacity, parasternal stimulation at 15 cmH2O positive airway pressure caused a mild decrease in muscle shortening, a large reduction in cranial rib motion, and a large reduction in pleural pressure fall. The caudal displacement of the sternum, however, was increased. Similar alterations in rib and sternal motions and in muscle shortening were seen during spontaneous breathing; tidal volume was markedly reduced as well. These observations thus indicate that hyperinflation affects the action of the parasternal intercostals on the rib cage; their rib-elevating action is decreased, whereas their action on the sternum is increased. As a result, their ability to inflate the lung is reduced. Thus, the inflationary actions of both the diaphragm and parasternal intercostals are reduced by hyperinflation.
Hypoxic and hypercapnic ventilatory responses in Prader-Willi syndrome
Authors: Arens R. , Gozal D. , Omlin K. J. , Livingston F. R. , Liu J. , Keens T. G. , Ward S. L.
Published: December 2017

Abnormalities of ventilatory control may play a significant role in the pathophysiology of sleep-disordered breathing in patients with the Prader-Willi syndrome (PWS). We measured rebreathing hypercapnic and hypoxic ventilatory responses (HCVR and HPVR, respectively) during wakefulness in 8 nonobese PWS (NOB-PWS) and 9 obese PWS (OB-PWS) patients and compared their results with those from 24 healthy nonobese control (NOB-CON) and 10 obese control (OB-CON) subjects. The slope of HCVR was similar in NOB-PWS patients and NOB-CON subjects (NS). However, HCVR was significantly lower in OB-PWS patients than in OB-CON subjects (P < 0.02). In PWS patients, the mean point of origin of the positive slope of HCVR occurred at a significantly higher end-tidal PCO2 than in either control group. During isocapnic hypoxic challenges, six PWS patients had no significant HPVR. In the remainder, mean slopes of HPVR were -0.80 +/- 0.06 l.min-1.%arterial O2 saturation-1 in five NOB-PWS patients and -0.68 +/- 0.15 l.min-1.%arterial O2 saturation-1 in six OB-PWS patients. These responses were significantly decreased compared with those in the control groups (P < 0.006). We conclude that NOB-PWS patients have normal HCVR, which is blunted in OB-PWS patients. Furthermore, isocapnic HPVR is either absent or markedly reduced in PWS patients. The severity of abnormality of the HPVR is independent of the degree of obesity. We postulate that the primary abnormality of ventilatory control in PWS affects peripheral chemoreceptor pathways.
Running-induced muscle injury and myocellular enzyme release in rats
Authors: Komulainen J. , Kytola J. , Vihko V.
Published: December 2017

The relationships and time course of exercise-induced muscle damage, estimated by beta-glucuronidase activity and microscopy, to muscle swelling, estimated by muscle water content and microscopy, and to the serum activity of creatine kinase (CK) and the concentration of carbonic anhydrase III were studied in rats 2, 12, 48, and 96 h after 90 min of intermittent running uphill (+13.5 degrees) or downhill (-13.5 degrees) at a speed of 17 m/min. The injury was more pronounced in soleus after uphill running and in the red parts of quadriceps femoris and in the white part of vastus lateralis after downhill running, whereas triceps brachii was not damaged. Increase in muscle water content preceded the increase of beta-glucuronidase activity. Both running protocols similarly increased serum CK 2 h postexercise. After downhill running a second peak in serum CK was observed 48 h later. The CK changes were not in concert with the changes in muscle water content or beta-glucuronidase activity, suggesting that these responses may not be mechanistically (or causally) related.
Stroma-free hemoglobin increases blood pressure and GFR in the hypotensive rat: role of nitric oxide
Authors: Thompson A. , McGarry A. E. , Valeri C. R. , Lieberthal W.
Published: December 2017

The short-term systemic and renal hemodynamic effects of two stroma-free hemoglobin (SFH) solutions, one unmodified and the other modified by cross-linking, were examined in anesthetized rats after hemorrhagic hypotension. Both forms of SFH increased mean arterial pressure (MAP) and glomerular filtration rate (GFR) to baseline (prehemorrhage) values. The increase in MAP induced by unmodified SFH was greater than the increase in MAP caused by an albumin solution isoncotic to the unmodified SFH solution. Similarly, the increase in MAP caused by the modified SFH was also substantially greater than that induced by an albumin solution of comparable oncotic pressure to the modified SFH solution. Both unmodified and modified SFH increased GFR. As with MAP, the increase in GFR induced by both SFH solutions was greater than that associated with the oncotically matched albumin solutions. In separate experiments, the effects of nitric oxide (NO) inhibition with N omega-nitro-L-arginine methyl ester (L-NAME) on MAP after hemorrhagic hypotension and subsequent infusion of unmodified SFH or albumin were also examined. In the albumin-infused rats, L-NAME increased MAP. In marked contrast, NO inhibition with L-NAME had no further effect on MAP when infused after SFH. We conclude that both unmodified and modified SFH solutions acutely improve MAP and GFR by the combined effects of intravascular volume expansion resulting from the colloid effect of the protein and by inactivation of NO.
Sympathetic and blood pressure responses to voluntary apnea are augmented by hypoxemia
Authors: Hardy J. C. , Gray K. , Whisler S. , Leuenberger U.
Published: December 2017

Oscillations of arterial pressure during sleep are the hemodynamic hallmark of the sleep apnea syndrome. The mechanism of these transient pressure elevations is incompletely understood. To investigate the role of the arterial chemoreflex in the neurocirculatory responses to apnea, we measured mean arterial pressure (MAP; Finapres) and muscle sympathetic nerve activity (MSNA; peroneal microneurography) during voluntary end-expiratory apnea during exposure to room air, 10.5% O2 in N2 (hypoxemia), and 100% O2 (hyperoxia) in 11 healthy men. While the men breathed spontaneously, MSNA (in bursts/min) rose during hypoxemia and decreased during hyperoxia and MAP remained unchanged. During room air exposure, apnea led to a rise of 94 +/- 54% in MSNA total amplitude and a rise of 6.5 +/- 2.1 mmHg in MAP. MSNA and MAP increased by 616 +/- 158% and 10.8 +/- 2.4 mmHg, respectively, during hypoxemic apnea of equal duration (time-matched responses) and by 98 +/- 41% and 4.9 +/- 2.0 mmHg, respectively, during hyperoxic apnea (P < 0.05 for hypoxemic vs. hyperoxic apnea for both). Thus, in awake healthy humans, activation of the arterial chemoreflex by hypoxemia appears to contribute importantly to the sympathetic and blood pressure responses to apnea.
Free fatty acid metabolism in aerobically fit individuals
Authors: Calles-Escandon J. , Driscoll P.
Published: December 2017

The impact of aerobic fitness level on the production and disposal of serum free fatty acids was investigated in 26 normal young volunteers. The fitness level was ascertained by history and confirmed by determination of maximal aerobic capacity. Energy expenditure and substrate oxidation at rest were measured with indirect calorimetry. Free fatty acid turnover was measured with an infusion of [14C]palmitic acid. All tests were done > or = 48 h after the last bout of exercise. The sedentary (SED) volunteers had higher rates of systemic delivery of fatty acids than aerobically fit (FIT) individuals (532 +/- 53.4 vs. 353 +/- 62.3 mumol/min; P = 0.05). This difference was accentuated when the values were normalized to fat-free mass (9.2 +/- 0.8 and 5.9 +/- 0.98 mumol.kg-1.min-1 for SED and FIT, respectively). Fatty acid oxidation was similar between FIT and SED volunteers in absolute numbers (209 +/- 25 vs. 202 +/- 21 mumol/min, respectively; NS) as well as when normalized to fat-free mass (3.8 +/- 0.9 vs. 3.6 +/- 1.4 mumol.kg-1.min-1, respectively; NS). In contrast, the nonoxidative disposal of serum fatty acids was higher in SED (330 +/- 46.1 mumol/min) than in FIT individuals (144 +/- 52 mumol/min; P = 0.026). Thus, the ratio of nonoxidative to oxidative disposal rates of fatty acids was higher in SED than in FIT individuals (1.65 +/- 0.29 vs. 0.75 +/- 0.17; P = 0.021). The data support the hypothesis that high aerobic fitness level is associated with a low rate of systemic delivery of fatty acids at rest. Nevertheless, subjects with high aerobic fitness levels have fat oxidation at the same rate as unfit individuals.
Initial fall in skeletal muscle force development during ischemia is related to oxygen availability
Authors: Hogan M. C. , Richardson R. S. , Kurdak S. S.
Published: December 2017

We examined the hypothesis that the initial decline (first 1–2 min) in force development that occurs in working muscle when blood flow is halted is caused by O2 availability and not another factor related to blood flow. This was tested by reducing O2 delivery (muscle blood flow X arterial O2 content) to working muscle by either stopping blood flow [ischemia (I)] or maintaining blood flow with low arterial O2 content [hypoxemia (H)]. If initial decline in force development were similar between these two methods of reducing O2 delivery, it would suggest O2 availability as the common pathway. Isolated dog gastrocnemius muscle was stimulated at approximately 60–70% of maximal O2 uptake (1 isometric tetanic contraction every 2 s) until steady-state conditions of muscle blood flow and developed force were attained (approximately 3 min). Two conditions were then sequentially imposed on the working muscle: I, induced by shutting off pump controlling arterial perfusion of the muscle and clamping venous outflow, and H, induced by perfusing the muscle with deoxygenated blood (collected before testing while animal breathed N2) at steady-state blood flow level. Rates of the fall in force production in 17 matched conditions of H and I (approximately 40 s for each condition) were compared in 6 muscles tested. The blood perfusing the muscle during H had arterial PO2 = 8 +/- 1 (SE) Torr, arterial PCO2 = 37 +/- 1 Torr, and arterial pH = 7.39 +/- 0.03. The rate of decline in developed force was not significantly different (P = 0.46) between the 17 matched conditions of H (0.66 +/- 0.10 g force.g mass-1.s-1) and I (0.79 +/- 0.15 g force.g mass-1.s-1). These findings suggest that the initial fall in developed force in working skeletal muscle that occurs with ischemia is related to O2 availability.
Effects of N-acetylcysteine on in vitro diaphragm function are temperature dependent
Authors: Diaz P. T. , Brownstein E. , Clanton T. L.
Published: December 2017

Recent evidence has shown that systemic administration of N-acetylcysteine (NAC), a compound structurally similar to the intracellular antioxidant glutathione, inhibits skeletal muscle fatigue. To further elucidate the actions of NAC, we studied its effects on in vitro rat diaphragm contractile function. Rat diaphragm strips were incubated in tissue baths containing physiological salt solution (n = 29) or physiological salt solution containing 4 mg/ml of NAC (n = 29). Strips were stimulated by either indirect or direct means. After determination of baseline contractile characteristics, strips were fatigued for 4 min at 20 Hz (1 train/s, 0.33 ms train duration). Force-frequency relationships were then studied over a 60-min recovery period. We found that 1) NAC had significant effects on the baseline force-frequency relationship; treated strips had increased peak tension but diminished twitch tension and accelerated twitch kinetics; 2) NAC had significant fatigue-sparing effects that were magnified at 37 degrees C; and 3) NAC treatment did not improve postfatigue recovery. The effects of NAC were generally independent of the stimulation method. We conclude that NAC has direct temperature-dependent effects on diaphragm function. These effects are consistent with the properties of NAC as an antioxidant and suggest important but complex effects of oxidant stress on skeletal muscle.