bluuebunny/crossref_metadata_2025 huggingface dataset:
Protein metabolism in rat gastrocnemius muscle after stimulated chronic concentric exercise
Authors: Wong T. S. , Booth F. W.
Published: December 2017

Previous results by use of a model of resistance exercise consisting of nonvoluntary electrical contraction of rat skeletal muscle have shown that significant gastrocnemius muscle enlargement was produced after 16 wk of chronic concentric resistance training with progressively increased weights but not after the same training program without weights (J. Appl. Physiol. 65: 950-954, 1988). In the present study we examined whether this differential effect on muscle mass between high- and low-resistance exercise is mediated through differential actions on muscle protein synthesis rates. In addition, we determined whether accumulation of specific mRNA quantities had a primary role in the protein synthesis response to this type of exercise. The data revealed that as little as 8 min of total contractile duration increased gastrocnemius protein synthesis rates by nearly 50%. Contrary to our hypothesis, post-exercise protein synthesis rates do not appear to be differentially regulated by the resistance imposed on the muscle during exercise but rather by the number of repetitions performed during the acute bout. This observation, the failure of high-frequency chronic training to produce gastrocnemius enlargement, and the relatively minor effects on mRNA levels collectively suggest that translational and posttranslational mechanisms, including protein degradation, may be the principal processes by which gastrocnemius protein expression is regulated in this model of stimulated concentric exercise.
Nonadrenergic bronchodilation induced by high concentrations of sulfur dioxide
Authors: Thompson D. C. , Szarek J. L. , Altiere R. J. , Diamond L.
Published: December 2017

SO2 is an environmental pollutant known to elicit bronchospasm in susceptible subjects. We observed that brief exposure of artificially bronchoconstricted cats to high concentrations of SO2 induces a bronchodilator response. This study assessed the characteristics of this response and examined various mechanisms that might underlie it. Cats were anesthetized with diallylbarbital-urethan, and airway smooth muscle tone, measured by lung resistance and dynamic lung compliance, was elevated with a continuous infusion of 5-hydroxytryptamine. Administration of 10 breaths of SO2 via a tracheostomy induced concentration-dependent bronchodilation in the range 100-1,000 parts/million. Only infrequently was bronchoconstriction observed before bronchodilation. SO2-induced bronchodilator responses were unaffected by pretreatment with intravenous atropine or propranolol, establishing them as nonadrenergic noncholinergic (NANC) in origin. Neither the ganglionic blocking agent hexamethonium nor the nerve toxin tetrodotoxin influenced the SO2-induced bronchodilation, thus excluding a role for central or local autonomic reflexes in the response. Efforts to modulate the response by pretreatment with the cyclooxygenase inhibitor indomethacin or the mediator release inhibitor cromolyn sodium also were unsuccessful. Administration of acidic aerosols failed to mimic the SO2-induced bronchodilator response. Although the mechanism whereby SO2 induces bronchodilation under these experimental conditions remains unclear, release of a NANC inhibitory transmitter from a neural, epithelial, or other cellular source via a mechanism insensitive to both tetrodotoxin and cromolyn is a distinct possibility. An intrinsic NANC inhibitory system may exist in feline airways functioning as a local regulator of bronchomotor tone and possibly serving to override responses to strong, potentially asphyxial bronchoconstrictive stimuli.
Selective pulmonary vasodilation with ATP-MgCl2 during pulmonary hypertension in lambs
Authors: Fineman J. R. , Crowley M. R. , Soifer S. J.
Published: December 2017

We investigated the effects of infusions of ATP-MgCl2 on the circulation in 11 spontaneously breathing newborn lambs during pulmonary hypertension induced either by the infusion of U-46619, a thromboxane A2 mimetic, or by hypoxia. During pulmonary hypertension induced by U-46619, ATP-MgCl2 (0.01-1.0 mg.kg-1.min-1) caused a significant dose-dependent decrease in pulmonary arterial pressure (12.4-40.7%, P less than 0.05), while systemic arterial pressure decreased only at the highest doses (P less than 0.05). Left atrial infusions of ATP-MgCl2 caused systemic hypotension without decreasing pulmonary arterial pressure. During hypoxia-induced pulmonary hypertension, ATP-MgCl2 caused a similar significant dose-dependent decrease in pulmonary arterial pressure (12.0-41.1%, P less than 0.05), while systemic arterial pressure decreased only at high doses (P less than 0.05). Regression analysis showed selectivity of the vasodilating effects of ATP-MgCl2 for the pulmonary circulation during pulmonary hypertension induced either by U-46619 or hypoxia. ATP-MgCl2 is a potent vasodilator with a rapid metabolism that allows for selective vasodilation of the vascular bed first encountered (pulmonary or systemic). We conclude that infusions of ATP-MgCl2 may be clinically useful in the treatment of children with pulmonary hypertension.
Role of xanthine oxidase and neutrophils in ischemia-reperfusion injury in rabbit lung
Authors: Adkins W. K. , Taylor A. E.
Published: December 2017

This study evaluated the effect of ischemia-reperfusion (I-R) on pulmonary capillary permeability in isolated rabbit lungs and the roles of xanthine oxidase (XO), aldehyde oxidase (AO), and neutrophils (PMN) in producing this lung injury. Effects of XO and AO were studied by inactivation with a tungsten-enriched diet (0.7 g/kg) and inhibition of XO by allopurinol (100 microM) or AO by menadione (3.5 microM). PMN effects were studied by preventing endothelial adhesion with the monoclonal antibody IB4 (10 microM). Vascular permeability was evaluated by determining the capillary filtration coefficient (Kf,c) measured before and after I-R in all experimental conditions. Reperfusion after 2 h of ischemia significantly increased pulmonary capillary permeability (Kf,c changed from 0.096 +/- 0.014 to 0.213 +/- 0.025 ml.min-1. cmH2O-1.100 g-1), and this increase was blocked by the addition of catalase (50,000 U) at reperfusion (baseline Kf,c was 0.125 +/- 0.023 and 0.116 +/- 0.014 ml.min-1.cmH2O-1.100 g-1). XO inactivation with the tungsten-supplemented diet and XO inhibition with allopurinol prevented the Kf,c increase observed after I-R (0.183 +/- 0.030 to 0.185 +/- 0.033 and 0.126 +/- 0.018 to 0.103 +/- 0.005 ml.min-1.cmH2O-1.100 g-1). Inhibition of AO had no effect on I-R injury (Kf,c 0.108 +/- 0.011 to 0.167 +/- 0.014 ml.min-1.cmH2O-1.100 g-1). Preventing PMN adhesion resulted in significant attenuation of the change in Kf,c associated with I-R (0.112 +/- 0.032 to 0.090 +/- 0.065 ml.min-1.cmH2O-1.100 g-1). We conclude that XO and PMN adherence, but not AO, are involved in the increased capillary permeability associated with I-R.
Beta-adrenergic effects on carbohydrate metabolism in the unweighted rat soleus muscle
Authors: Kirby C. R. , Tischler M. E.
Published: December 2017

The effects of insulin on carbohydrate metabolism in atrophied rat soleus muscle are increased after unweighting by tail-cast suspension. This work has been extended by testing the effect of unweighting on the response of carbohydrate metabolism to isoproterenol, a beta-adrenergic agonist. Isoproterenol promoted glycogen degradation more in the unweighted than in the weight-bearing soleus but showed no differences in the extensor digitorum longus, which is unresponsive to hindlimb unweighting. In soleus muscles depleted of glycogen, to avoid varied inhibitory effects of glycogen on glycogen synthesis, isoproterenol inhibited this process more in the unweighted muscle. Isoproterenol did not have a greater inhibitory effect on net uptake of 2-deoxy-D[1,2-3H]glucose by the unweighted muscle. Measurements of intracellular 2-deoxy-[3H]glucose 6-phosphate and 3-O-methyl-D-[1-3H]glucose, which cannot be phosphorylated, showed that isoproterenol inhibited glucose phosphorylation but not transport. This effect could be explained by an increase of glucose 6-phosphate, an inhibitor of hexokinase. At 100 microU insulin/ml but not at a lower amount (10 microU/ml), isoproterenol inhibited hexose phosphorylation more in the control than in the unweighted muscle. This result may be explained by greater insulin antagonism in the unweighted muscle owing to increased insulin sensitivity. However, insulin antagonism of isoproterenol stimulation of glycogenolysis or inhibition of glycogenesis was not altered by unweighting. Therefore, for some aspects of carbohydrate metabolism, the unweighted muscle has an increased response to beta-adrenergic activation, just as this muscle shows increased responses to insulin.
Mechanical role of expiratory muscles during breathing in prone anesthetized dogs
Authors: Farkas G. A. , Schroeder M. A.
Published: December 2017

The purpose of the present study was to assess the mechanical role of the expiratory muscles during spontaneous breathing in prone animals. The electromyographic (EMG) activity of the triangularis sterni, the rectus abdominis, the external oblique, and the transversus abdominis was studied in 10 dogs light anesthetized with pentobarbital sodium. EMGs were recorded during spontaneous steady-state breathing in supine and prone suspended animals both before and after cervical vagotomy. We also measured the end-expiratory lung volume [functional residual capacity (FRC)] in supine and prone positions to assess the mechanical role of expiratory muscle activation in prone dogs. Spontaneous breathing in the prone posture elicited a significant recruitment of the triangularis sterni, the external oblique, and the transversus abdominis (P less than 0.05). Bilateral cervical vagotomy eliminated the postural activation of the external oblique and the transversus abdominis but not the triangularis sterni. Changes in posture during control and after cervical vagotomy were associated with an increase in FRC. However, changes in FRC, on average, were 132.3 +/- 33.8 (SE) ml larger (P less than 0.01) postvagotomy. We conclude that spontaneous breathing in prone anesthetized dogs is associated with a marked phasic expiratory recruitment of rib cage and abdominal muscles. The present data also indicate that by relaxing at end expiration the expiratory muscles of the abdominal region are directly responsible for generating roughly 40% of the tidal volume.
A model approach to assess diaphragmatic volume displacement
Authors: Petroll W. M. , Knight H. , Rochester D. F.
Published: December 2017

Diaphragmatic volume displacement (Vdi) is calculated from two models using measurements obtained from anteroposterior fluoroscopic images of supine anesthetized dogs. In model 1, diaphragmatic descent was treated as if it were a "piston in a cylinder." In contrast, model 2 incorporated thoracic configuration as well as inspiratory changes in rib cage diameter and diaphragm shape. In one dog, a computerized tomography reconstruction of Vdi was compared with Vdi calculated using the models. Vdi calculated from model 2 lay within 11% of the computerized tomographic value, whereas Vdi based on model 1 was 30% larger. In seven animals, radiopaque markers were sewn to the right costal diaphragm. Digitized fluoroscopic images were used to measure intermarker distance, an index of muscle shortening. For four tidal breaths per dog, in model 2 Vdi averaged 49 +/- 18% of tidal volume and was weakly correlated with costal diaphragm muscle shortening (R = 0.74). It is concluded that Vdi can be estimated from linear dimensions in the coronal plane, provided that inspiratory changes in rib cage diameter and diaphragmatic shape change are taken into account.
Effects of selective hepatic vagotomy on running endurance in rats
Authors: Doiron B. , Cardin S. , Brisson G. R. , Lavoie J. M.
Published: December 2017

The liver, through the afferent ways of the vagus hepatic nerve, may influence metabolic adaptations during exercise. This study assesses the functional significance of this hepatic innervation by determining the effect of a selective hepatic vagotomy (HV) on running endurance time during submaximal activity in rats subjected to an overnight 50% food restriction. The time to exhaustion was similar for the groups of HV and sham-operated (SHM) rats [66 +/- 15 vs. 64 +/- 21 (SD) min]. The HV group was associated with higher resting levels (P less than 0.05) of hepatic glycogen and plasma glucose. No significant differences were observed between HV and SHM rats at rest and after exercise for muscle glycogen, free fatty acids, insulin, glucagon, and lactate concentrations. These data indicate that if hepatic glucoreceptors do exist and contribute to the metabolic regulation of exercise, their functional significance is secondary to more important regulatory mechanisms.
Local application of somatostatin in the rat ventrolateral brain medulla induces apnea
Authors: Chen Z. B. , Hedner T. , Hedner J.
Published: December 2017

Local injections of the tetradecapeptide somatostatin (SOM) into the brain stem region were performed in anesthetized and decerebrate rats. SOM administration (0.6-1.8 nmol) into the nucleus paragigantocellularis and the nucleus reticularis lateralis of the ventrolateral medulla oblongata induced ventilatory depression and apnea. The occurrence of apnea was dose dependent and attributed to the anesthetic depth, and it was seen within 60-240 s after injection. In anesthetized rats the apnea was seen as a termination or a continuous decrease in tidal volume while respiratory frequency remained unaltered. SOM-induced apnea was caused by depression of central inspiratory drive. SOM injections into the dorsal medulla were ineffective in eliciting apnea, although a ventilatory depression but no apnea was induced in the awake unanesthetized state. In addition to its effect on basal ventilation, SOM administration in the ventrolateral medulla resulted in a blunted ventilatory response to hypoxic and hypercapnic stimuli in anesthetized rats. We conclude that SOM has potent inhibitory effects on respiration that are specifically located in the nucleus paragigantocellularis and the nucleus reticularislateralis.
Effects of hydrostatic pressure and inert gases on platelet aggregation in vitro
Authors: Pickles D. M. , Ogston D. , Macdonald A. G.
Published: December 2017

A novel cuvette was used to subject citrated platelet-rich plasma (PRP) to high hydrostatic pressure with negligible contamination by He (used for compression of the apparatus). Aggregation was induced at pressure by ADP and quantified turbidimetrically. The maximum degree of aggregation (MDA) was reduced from a control level of 82.2 to 53.6% by exposure to 101 ATA. Because decompression bubbles did not form, aggregation was also measured immediately after a compression cycle. After exposure to 101 ATA hydrostatic pressure, platelets responded normally to ADP at 1 ATA. In a matching apparatus, PRP was equilibrated with high partial pressures of inert gases. Normal physiological plasma Po2 and pH were maintained during equilibration. N2O (5 ATA) reduced the MDA from 86.5 (control) to 58.1%. N2 (51 ATA) reduced the MDA from 74.7 (control) to 51.6%, and 101 ATA Pn2 reduced the MDA from 78.0 (control) to 32.3%. He (100 ATA) reduced the MDA from 83.6 to 38.6%. It was concluded that platelet aggregation was relatively sensitive to hydrostatic pressure and less sensitive to inert gases than predicted from their anesthetic potency ratios.
Monocyte kinetics in rabbits
Authors: Ohgami M. , Doerschuk C. M. , Gie R. P. , English D. , Hogg J. C.
Published: December 2017

Previous studies of monocytes isolated from peripheral blood have suggested that the lung sequesters these cells and has an important role in monocyte kinetics. However, the lung also provides the first capillary bed encountered by these cells after intravenous injection. A major criticism of the previous reports is that the behavior of monocytes in the lung may be altered as a result of the isolation procedure. The present study addresses this question by comparing the distribution of isolated monocytes (87% pure) in various organs 10 min after they were injected into either the central venous or the arterial circulation. The data show that the extraction of monocytes on the first passage through the lung after intravenous injection was 86.5 +/- 1.5%. After the monocytes had circulated for 10 min, the lungs contained 35.5 +/- 2.5% of the cells after intravenous injection and 29.7 +/- 2.2% after intra-arterial injection (P greater than 0.05). The lung-to-blood recovery ratio after either intravenous or intra-arterial injection showed that the lung contained a marginating pool of monocytes that was five to seven times the size of the circulating pool. The retention of monocytes in a region of the lung was proportional to the regional erythrocyte transit time. The half-life of the radiolabeled monocytes in the circulation was approximately 25 h. We conclude that the lung contains a marginating pool of monocytes and speculate that they concentrate there in preparation for migration into the interstitium and air space of the lung.
Effect of acute hypoxia on respiration and brain stem blood flow in the piglet
Authors: Darnall R. A. , Green G. , Pinto L. , Hart N.
Published: December 2017

Changes in local brain stem perfusion that alter extracellular fluid Pco2 and/or [H+] near central chemoreceptors may contribute to the decrease in respiration observed during hypoxia after peripheral chemoreceptor denervation and to the delayed decrease observed during hypoxia in the newborn. In this study, we measured the changes in respiration and brain stem blood flow (BBF) during 2–4 min of hypoxic hypoxia in both intact and denervated piglets and calculated the changes in brain stem Pco2 and [H+] that would be expected to occur as a result of the changes in BBF. All animals were anesthetized, spontaneously breathing, and between 2 and 7 days of age. Respiratory and other variables were measured before and during hypoxia in all animals, and BBF (microspheres) was measured in a subgroup of intact and denervated animals at 0, 30, and 260 s and at 0 and 80 s, respectively. During hypoxia, minute ventilation increased and then decreased (biphasic response) in the intact animals but decreased only in the denervated animals. BBF increased in a near linear fashion, and calculated brain stem extracellular fluid Pco2 and [H+] decreased over the first 80 s both before and after denervation. We speculate that a rapid increase in BBF during acute hypoxia decreases brain stem extracellular fluid Pco2 and [H+], which, in turn, negatively modulate the increase in respiratory drive produced by peripheral chemoreceptor input to the central respiratory generator.
Analysis of responses to endothelins in the rabbit pulmonary and systemic vascular beds
Authors: Lippton H. L. , Ohlstein E. H. , Summer W. R. , Hyman A. L.
Published: December 2017

The effects of two isoforms of human endothelin (ET) on the pulmonary and systemic vascular beds were compared in the anesthetized intact-chest rabbit under conditions of constant pulmonary blood flow and left atrial pressure. Intralobar bolus injections of ET-1 (0.1–1 micrograms) and ET-3 (1–3 micrograms) produced modest vasoconstriction in the pulmonary vascular bed, whereas both peptides decreased systemic arterial pressure. The pulmonary vasoconstrictor response to ET-1 and ET-3 was inhibited by intralobar infusion of nitrendipine but was not altered by indomethacin. In contrast to the small effects of ET-1 and ET-3 on intact pulmonary resistance vessels, both peptides markedly contracted isolated pulmonary conductance vessels, with greater activity on venous than on arterial segments. Intravenous bolus injection of ET-1 (0.1–0.3 micrograms) or ET-3 (0.3–1 microgram) decreased systemic arterial pressure, increased cardiac output, and markedly decreased systemic vascular resistance. Higher doses of ET-1 produce a biphasic systemic vascular response with a prominent secondary pressor component. The present data suggest that the pulmonary vasoconstrictor activity of ET-1 is greater than that of ET-3 and their pressor activity depends on an extracellular source of calcium. The pulmonary and systemic hemodynamic effects of ET-1 and ET-3 in the rabbit do not depend on cyclooxygenase products. The systemic vasodilator response to ET-1 is not altered by first-pass lung transit. Furthermore the systemic vasodilator response to both peptides occurs independent of activation of muscarinic, beta 2-adrenergic, and platelet-activating factor receptors. Although ET-1 and ET-3 were initially reported as vasoconstrictor peptides, the present data suggest that, by having unique and potent systemic vasodilator activity, ET-1 and ET-3 act differently in the systemic and pulmonary vascular beds under resting conditions in the rabbit.
Persistent airway hyperresponsiveness after neonatal viral bronchiolitis in rats
Authors: Sorkness R. , Lemanske R. F. , Castleman W. L.
Published: December 2017

Viral bronchiolitis in human infants has been associated with permanent changes in small airways and gas exchange and an increased incidence of hyperresponsive airways later in life. Respiratory infection by Sendai virus in neonatal rats also has been reported to cause permanent changes in lung morphology and increased numbers of bronchiolar mast cells and eosinophils. We evaluated pulmonary mechanics, gas exchange, and airway responsiveness in rats at 7 and 13–16 wk after neonatal Sendai virus infection. Rats from the virus group had lower arterial PO2 and increased total lung resistance compared with controls. There were no significant differences between groups for arterial PCO2, dynamic lung compliance, quasi-static respiratory system compliance, or vital capacity. Rats from the infected group were significantly more sensitive to aerosolized methacholine than were controls, although both virus and control groups became less sensitive with age. We conclude that neonatal Sendai virus infection in rats results in persistent alterations in lung function and airway responsiveness. This phenomenon may be valuable for the study of the relationships among airway inflammation, lung morphology, and airway hyperresponsiveness, and it may be relevant to human airway disease.
Diaphragmatic force and substrate response to resistive loaded breathing in the piglet
Authors: Mayock D. E. , Standaert T. A. , Murphy T. D. , Woodrum D. E.
Published: December 2017

Inspiratory resistive loaded (IRL) breathing results in hypoventilation and diaphragmatic fatigue in the piglet. We studied the effects of 6 h of IRL on ten 1-mo-old piglets. The load was adjusted to increase spontaneously generated transdiaphragmatic pressure five to six times baseline. Six 1-mo-old piglets acted as controls and were identically instrumented but were not subjected to IRL. Measurements of ventilation, blood gases and pH, diaphragmatic electromyogram, force-frequency curve, blood flow, and end-expiratory lung volume were obtained hourly. Diaphragmatic muscle samples were obtained after 6 h for determination of ATP, phosphocreatine, lactate, and glycogen levels. No changes occurred in the control animals. IRL resulted in a significant decrease in ventilation, an increase in diaphragmatic EMG, onset of abdominal expiratory muscle activity, and a fall in end-expiratory lung volume by 1 h. The force-frequency curve adjusted for lung volume change fell by 20% at all frequencies of stimulation at 1 h and by 40% at 6 h. Blood flow to the costal and crural diaphragm increased by 51 and 141%, respectively. No differences were noted in ATP, phosphocreatine, lactate, or glycogen between control and IRL animals. It is concluded that submaximal spontaneous contractions of the piglet diaphragm over a 6-h period cause a substantial decrease in its maximal force-generating capacity that is not related to substrate depletion.
Contribution of large airway to the input impedance of the respiratory system
Authors: Teeter J. P. , Saidel G. M. , Fouke J. M.
Published: December 2017

To evaluate the contribution of the large airway to total respiratory impedance, we develop a one-dimensional model of pressure and flow in these airways by coupling conservation of mass and momentum equations with the geometric information obtained by the acoustic reflection technique. We use this model to calculate the impedance of the respiratory system distal to the carina from impedance data estimated at the airway opening by the forced oscillation technique. Simulations show that the real part of the impedance distal to the carina is uniformly decreased from the impedance at the airway opening, indicating a resistive loss, while the imaginary part is increased as a function of frequency. We estimate parameter values for a six-parameter two-compartment lung model and for a three-parameter reduction of this model before and after the application of the upper airway data to the impedance spectrum. Although compliance terms seem to be minimally affected by the manipulation of the data, resistance and inertance terms are influenced in a fashion that suggests that the resistive contribution of the upper airway to total respiratory impedance is significant. Furthermore it appears that the elastic nature of the walls of the upper airway also impact on estimates of total respiratory impedance at the airway opening.
Hyperoxia prevents hypoxia-induced bronchial hyperreactivity via a cyclooxygenase-independent mechanism
Authors: D'Brot J. , Ahmed T.
Published: December 2017

We tested the hypothesis that prior exposure to alveolar hyperoxia prevents the hypoxia-induced enhancement of bronchial reactivity, possibly via a cyclooxygenase-dependent mechanism. In 15 sheep, specific lung resistance (sRL) was measured before and after 30 min of exposure to either air or a hypoxic gas mixture (13% O2). The sheep then inhaled 50 breaths of aerosolized 5% histamine solution (n = 9) or 10 breaths of 2.5% carbachol solution (n = 9), and measurements of sRL were repeated. On subsequent days the above protocols were repeated after a 30-min exposure to hyperoxia (O2 greater than or equal to 95%), without or after pretreatment with indomethacin (2 mg/kg). After air-sham exposure, carbachol and histamine increased mean sRL to 370 +/- 40 (SE) and 309 +/- 65% of baseline, respectively. Exposure to the hypoxic gas mixture had no effect on baseline sRL but enhanced the airway responsiveness to carbachol and histamine; mean sRL increased to 740 +/- 104 and 544 +/- 76% of baseline, respectively (P less than 0.05). Prior 30-min exposure to hyperoxia prevented the hypoxia-induced enhancement of bronchial reactivity to carbachol (sRL = 416 +/- 66% of baseline) and histamine (sRL = 292 +/- 41% of baseline) without affecting the airway responsiveness to these agents after air. Pretreatment with indomethacin did not reverse the protective effects of hyperoxia or the hypoxia-induced enhancement of bronchial reactivity. We conclude that 1) prior exposure to alveolar hyperoxia prevents the hypoxia-induced enhancement of bronchial reactivity and 2) neither the protective effects of hyperoxia nor the hypoxia-induced enhancement of bronchial reactivity is mediated via a cyclooxygenase-dependent mechanism.
Attenuated carotid body hypoxic sensitivity after prolonged hypoxic exposure
Authors: Tatsumi K. , Pickett C. K. , Weil J. V.
Published: December 2017

Prolonged exposure to hypoxia is accompanied by decreased hypoxic ventilatory response (HVR), but the relative importance of peripheral and central mechanisms of this hypoxic desensitization remain unclear. To determine whether the hypoxic sensitivity of peripheral chemoreceptors decreases during chronic hypoxia, we measured ventilatory and carotid sinus nerve (CSN) responses to isocapnic hypoxia in five cats exposed to simulated altitude of 5,500 m (barometric pressure 375 Torr) for 3-4 wk. Exposure to 3-4 wk of hypobaric hypoxia produced a decrease in HVR, measured as the shape parameter A in cats both awake (from 53.9 +/- 10.1 to 14.8 +/- 1.8; P less than 0.05) and anesthetized (from 50.2 +/- 8.2 to 8.5 +/- 1.8; P less than 0.05). Sustained hypoxic exposure decreased end-tidal CO2 tension (PETCO2, 33.3 +/- 1.2 to 28.1 +/- 1.3 Torr) during room-air breathing in awake cats. To determine whether hypocapnia contributed to the observed depression in HVR, we also measured eucapnic HVR (PETCO2 33.3 +/- 0.9 Torr) and found that HVR after hypoxic exposure remained lower than preexposed value (A = 17.4 +/- 4.2 vs. 53.9 +/- 10.1 in awake cats; P less than 0.05). A control group (n = 5) was selected for hypoxic ventilatory response matched to the baseline measurements of the experimental group. The decreased HVR after hypoxic exposure was associated with a parallel decrease in the carotid body response to hypoxia (A = 20.6 +/- 4.8) compared with that of control cats (A = 46.9 +/- 6.3; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Substance P-induced contraction of rabbit airways: mechanism of action
Authors: Armour C. L. , Johnson P. R. , Alouan L. A. , Black J. L.
Published: December 2017

The mechanism by which substance P induces contraction of airway smooth muscle has been the subject of numerous reports. It has been suggested that in rabbit airways the action of substance P is indirect, via the release of endogenous acetylcholine, whereas this is not so in other species. The present detailed study investigated whether substance P-induced contraction in rabbit isolated bronchus and trachea is due to the release of endogenous acetylcholine or in bronchus is due to histamine release and whether substance P is metabolized by the enzymes enkephalinase and acetylcholinesterase. Isometric contraction to cumulative addition of substance P was measured in the presence of 10(-6) and 10(-4) M atropine, 10(-6) M pyrilamine, 10(-5) M phosphoramidon, or 3 x 10(-7) M neostigmine. Neither atropine nor pyrilamine had any effect on the substance P responses. Phosphoramidon, however, produced a 12-fold shift to the left in the response curve with a decrease in the 50% effective concentration from 7.0 x 10(-8) to 6.1 x 10(-9) M (n = 4 control and 5 treated; P less than 0.05). In contrast, neostigmine at a concentration that produced a sixfold shift to the left in the acetylcholine response curve had no effect on substance P responses. We conclude that, in rabbit airways in vitro, substance P-induced contraction is not mediated by release of endogenous acetylcholine or histamine. In addition, endogenous enkephalinase but not acetylcholinesterase may be involved in the degradation of substance P. Our results show that, in contrast to previous studies in rabbits, the mechanism of action of substance P may resemble that described in humans.
Oxygen uptake dynamics during high-intensity exercise in children and adults
Authors: Armon Y. , Cooper D. M. , Flores R. , Zanconato S. , Barstow T. J.
Published: December 2017

We hypothesized that the O2 uptake (Vo2) response to high-intensity exercise would be different in children than in adults. To test this hypothesis, 22 children (6-12 yr old) and 7 adults (27-40 yr old) performed 6 min of constant-work-rate cycle-ergometer exercise. Sixteen children performed a single test above their anaerobic threshold (AT). In a separate protocol, six children and all adults exercised at low and high intensity. Low-intensity exercise corresponded to the work rate at 80% of each subject's AT. High-intensity exercise (above the AT) was determined first by calculating the difference in work rate between the AT and the maximal Vo2 (delta). Twenty-five, 50, and 75% of this difference were added to the work rate at the subject's AT, and these work rates were referred to as 25% delta, 50% delta, and 75% delta. For exercise at 50% delta and 75% delta, Vo2 increased throughout exercise (O2 drift, linear regression slope of Vo2 as a function of time from 3 to 6 min) in all the adults, and the magnitude of the drift was correlated with increasing work rates in the above-AT range (r = 0.91, P less than 0.0001). In contrast, no O2 drift was observed in over half of the children during above-AT exercise. The O2 drifts were much higher in adults (1.76 +/- 0.63 ml O2.kg-1.min-2 at 75% delta) than in children (0.20 +/- 0.42, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of alveolar and pleural pressures on interstitial pressures in isolated dog lungs
Authors: Glucksberg M. R. , Bhattacharya J.
Published: December 2017

We report the first direct measurements of perialveolar interstitial pressures in lungs inflated with negative pleural pressure. In eight experiments, we varied surrounding (pleural) pressure in a dog lung lobe to maintain constant inflation with either positive alveolar and ambient atmospheric pleural pressures (positive inflation) or ambient atmospheric alveolar and negative pleural pressures (negative inflation). Throughout, vascular pressure was approximately 4 cmH2O above pleural pressure. By the micropuncture servo-null technique we recorded interstitial pressures at alveolar junctions (Pjct) and in the perimicrovascular adventitia (Padv). At transpulmonary pressure of 7 cmH2O (n = 4), the difference of Pjct and Pady from pleural pressure of 0.9 +/- 0.4 and -1.1 +/- 0.2 cmH2O, respectively, during positive inflation did not significantly change (P less than 0.05) after negative inflation. After increase of transpulmonary pressure from 7 to 15 cmH2O (n = 4), the decrease of Pjct by 3.3 +/- 0.3 cmH2O and Pady by 2.0 +/- 0.4 cmH2O during positive inflation did not change during negative inflation. The Pjct-Pady gradient was not affected by the mode of inflation. Our measurements indicate that, in lung, when all pressures are referred to pleural or alveolar pressure, the mode of inflation does not affect perialveolar interstitial pressures.
Spectral vs. compartmental averaging of VA/Q distributions: confidence limits
Authors: Wang X. H. , Poon C. S.
Published: December 2017

We have investigated the method of statistical averaging as a nonparametric approach to obtain a representative ventilation-perfusion (VA/Q) distribution that exemplifies the family of compatible solutions for multiple inert gas elimination data. The variability of the compatible solutions was examined by determining the standard deviation of the statistical average. For six inert gases, it can be predicted that a distribution with up to seven contiguous nonzero VA/Q compartments can be uniquely recovered, whereas the compatible family becomes more diverse, the broader the distribution. For a given compatible family consisting of multimodal distributions with various phase relationships, the average distribution was found to display an uncharacteristically unimodal shape as a result of modal smoothing. To avoid this possible artifact, an alternative approach was adopted in which statistical averaging was performed in the frequency domain. For both deterministic and empirical data, the energy spectra of all feasible VA/Q distributions displayed a well-defined low-frequency band that was invariant within the compatible family and with a bandwidth that approximated the predicted sampling cutoff frequency. The nonuniqueness of the result was ascribable to a variable high-frequency band that was due to an aliasing effect. For a wide range of clinical data, the representative distributions resulting from compartmental and spectral averaging were indistinguishable from each other and had little variability both in the VA/Q and frequency domains. For these cases, therefore, the resolving power of the recovery algorithm was not critical. Finally, an efficient method of finding the average distribution was proposed.
Erythrocyte deformability and lung segmental vascular resistance: effect of hematocrit
Authors: Raj J. U. , Anderson J.
Published: December 2017

We have investigated the role of erythrocyte (RBC) deformability and perfusate viscosity on lung segmental vascular resistance in 12 isolated perfused lungs of 3- to 5-wk-old rabbits. Each lung was perfused alternately with control and formaldehyde-fixed rabbit RBCs at a flow rate of 80 ml.kg-1.min-1, left atrial and airway pressures being 8 and 6 cmH2O, respectively (zone 3). Perfusate RBC concentration was kept constant at 3.2 x 10(6)/mm3 for group I lungs (n = 6) and 7.2 x 10(6)/mm3 for group II lungs (n = 6). In all lungs, we measured pressures in the pulmonary artery and in 20- to 50-microns-diam arterioles and venules with the micropipette servo-null method during both perfusion periods. Compared with control, fixed cells had a 60% decrease in deformability index (i.e., the volume of a dilute solution of RBCs filtered through a 5-microns Nuclepore filter in 1 min). In groups I and II, perfusate viscosity of fixed cells was 15 and 55% greater, respectively, than that of control cells. We found that perfusion with fixed cells in group I lungs did not alter total or segmental vascular pressure drops. However, in group II lungs, perfusion with fixed cells at twice the cell concentration resulted in an increase in total vascular pressure drop, mainly due to an increase in pressure drop in veins (50% of total) and arteries (33%). The relatively small (17%) increase in pressure drop in microvessels was probably due to distension and/or recruitment of capillaries resulting from increased venular pressures.(ABSTRACT TRUNCATED AT 250 WORDS)
Antioxidants attenuate endotoxin-induced microvascular leakage of macromolecules in vivo
Authors: Matsuda T. , Eccleston C. A. , Rubinstein I. , Rennard S. I. , Joyner W. L.
Published: December 2017

The purpose of this study was to examine whether antioxidants attenuate endotoxin-induced microvascular hyper-permeability for macromolecules in the hamster cheek pouch. Twenty-two adult male Syrian hamsters were anesthetized, and a removable plastic chamber was placed in the cheek pouch to observe and collect suffusate from the microvasculature. Fluorescent-labeled dextran (FITC-D; mol wt 150,000) was injected intravenously, and changes in the number of microvascular leaky sites and microvascular clearance of FITC-D were measured in five groups: saline control (group 1, n = 4), endotoxin (0.1 mg/ml) suffusion for 120 min (group 2, n = 6), endotoxin plus dimethyl sulfoxide (1.0 g/kg iv; group 3, n = 4), endotoxin plus allopurinol (30 mg/kg ip; group 4, n = 4), and endotoxin plus dimethyl sulfoxide and allopurinol (group 5, n = 4). The number of leaky sites and the FITC-D clearance were significantly higher in group 2 [45 +/- 18 (SD) sites/cm2 and 20 +/- 6 X 10(-6) ml/min, respectively; P less than 0.01] than in group 1 (7 +/- 6 sites/cm2 and 7 +/- 5 X 10(-6) ml/min), group 3 (9 +/- 5 sites/cm2 and 8 +/- 2 X 10(-6) ml/min), group 4 (11 +/- 7 sites/cm2 and 9 +/- 4 X 10(-6) ml/min), and group 5 (11 +/- 6 sites/cm2 and 7 +/- 1 x 10(-6) ml/min). The leaky sites appeared predominantly in postcapillary venules. There was a positive and significant correlation between the number of leaky sites and FITC-D clearance.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of changing venoarterial pH difference on in vivo arterial pH
Authors: Takahashi E. , Phillipson E. A.
Published: December 2017

Plasma pH has been postulated to change slowly in blood leaving the pulmonary capillaries because of the uncatalyzed dehydration of CO2. If so, there could be a difference between in vivo and in vitro arterial pH, the magnitude of which would be dependent on the venoarterial pH difference (v-aDpH). We tested this hypothesis in anesthetized dogs by changing v-aDpH by airway CO2 loading and by comparing arterial pH measured in vivo by a rapidly responding intravascular pH electrode with that measured in vitro by a conventional glass electrode. Using a multiple regression analysis, we found a small but significant contribution of venous pH to in vivo arterial pH, with a regression coefficient of 0.0718 (P less than 0.0001), suggesting a postcapillary increase of in vivo arterial pH. When carbonic anhydrase was inhibited by the administration of acetazolamide, the effect of venous pH on arterial pH was abolished, and a unique relationship between in vivo and in vitro arterial pH was established (regression coefficient 1.02; P greater than 0.05, comparison with unity). These results could be accounted for in a computer simulation of gas exchange among alveolus, plasma, and erythrocyte. We conclude that there exists a small but measurable postcapillary increase in arterial pH.
Theophylline, fatigue, and diaphragm contractility: cellular levels of 45Ca and cAMP
Authors: Kolbeck R. C. , Speir W. A.
Published: December 2017

The relationship between variations in diaphragmatic contractility and corresponding changes in total tissue levels of 45Ca and adenosine 3',5'-cyclic monophosphate (cAMP) was examined. The contractile performance of perfused contracting rat diaphragms was manipulated with theophylline (10(-4) M), induced fatigue, or both. The increased contractility associated with theophylline was related to significant increases in 45Ca levels without changes in cAMP levels. Fatigue-diminished contractility was associated with increases in both 45Ca and cAMP levels. The increased 45Ca and cAMP levels associated with fatigue persisted, even in the presence of theophylline. Calcium channel blockade with 10(-4) M verapamil blocked the positive inotropic influence of theophylline as well as the theophylline-associated increase in 45Ca levels. Verapamil had no effect on either the fatigue-associated decreases in contractility or the fatigue-enhanced 45Ca uptake. The results of this study strongly suggest that the enhanced contractility associated with theophylline is related to its influence on cellular calcium metabolism. The elevated level of isotopic calcium measured in fatigued muscle probably represents calcium sequestered in the sarcoplasmic reticulum, the result of cAMP-enhanced Ca-adenosine triphosphatase activity.
Capsaicin-induced release of tachykinins: effects of enzyme inhibitors
Authors: Martins M. A. , Shore S. A. , Drazen J. M.
Published: December 2017

We studied the effects of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) inhibition on the airway responses and the recovery of endogenously released substance P- and neurokinin A-like immunoreactivities (SP-LI and NKA-LI) after tracheal injection of capsaicin in isolated guinea pig lungs superfused through the trachea. Capsaicin in doses from 10(-10) to 10(-7) mol induced a dose-dependent increase in airway opening pressure and release of SP-LI and NKA-LI. Airway opening pressure changes and the recovery of SP-LI and NKA-LI were significantly greater in lungs superfused with the NEP inhibitor SCH 32615 than in control lungs. ACE inhibition with captopril did not increase the mechanical response or the recovery of SP-LI compared with lungs not receiving captopril. In lungs from guinea pigs pretreated with high doses of capsaicin 7-10 days before study, a regimen designed to deplete endogenous tachykinins, there was a significant decrease in the content and release of NKA-LI and SP-LI. There were no detectable airway effects of acute capsaicin infusion even after doses of 10(-5) mol. Because NEP is important in modulating the airway effects of endogenously released tachykinins after tracheal infusion of capsaicin, but ACE is not, it seems likely that tracheal administration of capsaicin releases tachykinins from epithelial rather than endothelial loci.
Molecular and cell biology of cystic fibrosis
Authors: Davis P. B.
Published: December 2017

The questions emerged in better focus: we need to know, definitively, what CFTR is and what it does. We need to know how mutant CFTR expression leads to the relentless lung disease that takes the lives of the patients. We need to know how the different mutations in CFTR behave functionally. Much more information is needed on the pathways for ion transport in the airways in order for us to consider therapeutic alternatives. Better information on CFTR expression, particularly in the lung, would greatly facilitate consideration of pathophysiology as well as gene therapy. Many of these questions can be attacked by imaginative use of the tools already in hand. The need is urgent. The wondrous scientific advancements of the last five years and the additional money being spent on CF research have bought no dramatic increase in life expectancy for the patients. Every day, three more succumb.
Modeling Pioneer: Fred S.Grodins (1915-1989)
Authors: Yamashiro S. M. , Poon C. S. , DiStefano JJ III.
Published: December 2017

In every scientific field, significant progress often comes about in two steps, coevolving in the building of scientific knowledge: the accumulation of critical data and their consolidation into working hypotheses or models.
Tracheal vascular and smooth muscle responses to air temperature and humidity in dogs
Authors: Salonen R. O. , Webber S. E. , Deffebach M. E. , Widdicombe J. G.
Published: December 2017

The effect of three chemically dissimilar cyclooxygenase inhibitors on ethchlorvynol-(ECV) induced acute lung injury was studied in isolated buffer-perfused rat and blood-perfused rabbit lungs. ECV caused the microvascular fluid filtration coefficient (Kf) to increase by greater than threefold in the rat lungs and twofold in the rabbit lungs. ECV caused increased pulmonary vascular resistance (PVR) and microvascular pressure measured by the double occlusion technique (Pdo) compared with the vehicle control group in the rat experiments. However, ECV had no effect on PVR or Pdo in the rabbit experiments. Pretreatment with the cyclooxygenase inhibitors indomethacin, ibuprofen, and meclofenamate prevented the increase in microvascular permeability in both the rat and rabbit lung preparations. The cyclooxygenase inhibitors also prevented the ECV-induced PVR and Pdo increases in the rat lungs but had no effect on PVR or Pdo in the rabbit lungs. These results indicate that cyclooxygenase products of arachidonate metabolism mediate the ECV-induced Kf increase in both isolated rat and rabbit lungs.
A new method to measure nasal impedance in spontaneously breathing adults
Authors: Tawfik B. , Sullivan K. J. , Chang H. K.
Published: December 2017

As an alternative to standard rhinomanometric methods, we applied forced oscillations at the mouth in five normal subjects and determined their nasal impedance with a novel method involving flow subtraction. Pressure oscillations of constant amplitude were applied at the mouth of a subject both when the nostrils were open and when they were closed with a noseclip. The airflows measured under the two conditions were subtracted to yield the oscillating nasal airflow at the imposed pressure. The resultant pressure-flow relation defined the nasal impedance of the subject. For frequencies between 3 and 15 Hz, the transnasal pressure-flow relation was well described by a linear lumped parameter model consisting of a resistive and inertial element. Nasal resistance obtained with flow subtraction did not differ significantly from control measurements obtained while the subjects performed the Valsalva maneuver. In contrast, nasal inertance obtained with flow subtraction was approximately twice that obtained with the Valsalva method. The difference between inertances may reflect structural changes in nasopharyngeal dimensions that occur with the Valsalva maneuver. We conclude that the mechanical impedance of the nasal passage may be determined during spontaneous breathing from the response to imposed forced oscillations at the mouth. The noninvasive nature of this method suggests that it may be simpler to implement than traditional rhinomanometric methods.