Ventilation distribution during histamine provocation

Verbanck, S., D. Schuermans, A. Van Muylem, M. Paiva, M. Noppen, and W. Vincken. Ventilation distribution during histamine provocation. J. Appl. Physiol. 83(6):1907-1916, 1997.We investigated ventilation inhomogeneity duringprovocation with inhaled histamine in 20 asymptomatic nonsmokingsubjects. We used N₂multiple-breath washout (MBW) to deriveparameters S_condand S_acin as ameasurement of ventilation inhomogeneity in conductive and acinar zonesof the lungs, respectively. A 20% decrease of forced expiratory volume in 1 s (FEV₁) was used todistinguish responders from nonresponders. In the responder group,average FEV₁ decreased by 26%,whereas S_condincreased by 390% with no significant change inS_acin. In thenonresponder group, FEV₁ decreasedby 11%, whereasS_cond increased by 198% with no significantS_acin change.Despite the absence of change inS_acin duringprovocation, baselineS_acin wassignificantly larger in the responder vs. the nonresponder group. Themain findings of our study are that during provocation largeventilation inhomogeneities occur, that the small airways affected bythe provocation process are situated proximal to the acinar zone wherethe diffusion front stands, and that, in addition to overall decreasein airway caliber, there is inhomogeneous narrowing of parallelairways.

     

In vitro bronchial responsiveness in two highly inbred rat strains

Wang, C. G., J. J. Almirall, C. S. Dolman, R. J. Dandurand,and D. H. Eidelman. In vitro bronchial responsiveness in twohighly inbred rat strains. J. Appl.Physiol. 82(5): 1445-1452, 1997.We investigatedmethacholine (MCh)-induced bronchoconstriction in explanted airwaysfrom Fischer and Lewis rats. Lung explants, 0.5- to 1.0-mm thick, wereprepared from agarose-inflated lungs of anesthetized 8- to 12-wk-oldmale rats. After overnight culture, videomicroscopy was used to recordbaseline images of the individual airways. Dose-response curves to MChwere then constructed by repeated administration of MCh; airways werereimaged 10 min after each MCh administration. Airway internal luminalarea(A_i)was measured at successive MCh concentrations from10⁹ to10¹ M. Inaddition to the effective concentration leading to 50% of the achievedmaximal response, we also determined the effective concentrationleading to a 40% reduction inA_i.Both the effective concentration leading to 50% of the achievedmaximal response and the concentration leading to a 40% reduction inA_iwere significantly lower among Fischer rat airways(P < 0.05). Airway closure was morecommon among Fischer rat airways (17%) than among those of Lewis rats(7.5%). Responsiveness of Fischer rat airways was more heterogeneousthan among Lewis airways; a larger number of Fischer rat airwaysexhibited high sensitivity to MCh. There was no relationship betweenresponsiveness and baselineA_iin either strain. In a second experiment, we measured the rate ofcontraction of explanted airways from lungs inflated to 50, 75, and100% of total lung capacity. The average rate of contraction in thefirst 15 s was higher in Fischer rat airways at each inflation volume.These data indicate that the hyperresponsiveness of the Fischer rat reflects the responsiveness of individual airways throughout the airwaytree and are consistent with the notion that in this model hyperresponsiveness is an intrinsic property of airway smooth muscle.

     

Interaction between airway edema and lung inflation on responsiveness of individual airways in vivo

Brown, Robert H., Wayne Mitzner, and Elizabeth M. Wagner.Interaction between airway edema and lung inflation onresponsiveness of individual airways in vivo. J. Appl.Physiol. 83(2): 366-370, 1997.Inflammatorychanges and airway wall thickening are suggested to cause increasedairway responsiveness in patients with asthma. In fivesheep, the dose-response relationships of individual airways weremeasured at different lung volumes to methacholine (MCh) before andafter wall thickening caused by the inflammatory mediator bradykininvia the bronchial artery. At 4 cmH₂O transpulmonary pressure(Ptp), 5 µg/ml MCh constricted the airways to a maximum of 18 ± 3%. At 30 cmH₂O Ptp, MCh resultedin less constriction (to 31 ± 5%). Bradykinin increased airwaywall area at 4 and 30 cmH₂O Ptp(159 ± 6 and 152 ± 4%, respectively;P < 0.0001). At 4 cmH₂O Ptp, bradykinin decreasedairway luminal area (13 ± 2%; P < 0.01), and the dose-response curve was significantly lower (P = 0.02). At 30 cmH₂O, postbradykinin, the maximalairway narrowing was not significantly different (26 ± 5%;P = 0.76). Bradykinin produced substantial airway wall thickening and slight potentiation ofthe MCh-induced airway constriction at low lung volume. At high lung volume, bradykinin increased wall thickness but had no effecton the MCh-induced airway constriction. We conclude that inflammatoryfluid leakage in the airways cannot be a primary cause of airwayhyperresponsiveness.

     

Respiratory impedances and acinar gas transfer in a canine model for emphysema

Barnas, George M., Paul A. Delaney, Ileana Gheorghiu,Srinivas Mandava, Robert G. Russell, Renée Kahn, and Colin F. Mackenzie. Respiratory impedances and acinar gas transfer in acanine model for emphysema. J. Appl.Physiol. 83(1): 179-188, 1997.We examined howthe changes in the acini caused by emphysema affected gas transfer outof the acinus (T_aci) and lungand chest wall mechanical properties. Measurements were taken from fivedogs before and 3 mo after induction of severe bilateral emphysema byexposure to papain aerosol (170-350 mg/dose) for 4 consecutive wk.With the dogs anesthetized, paralyzed, and mechanically ventilated at0.2 Hz and 20 ml/kg, we measuredT_aci by the rate of washout of¹³³Xe from an area of the lungwith occluded blood flow. Measurements were repeated at positiveend-expiratory pressures (PEEP) of 10, 5, 15, 0, and 20 cmH₂O. We also measured dynamicelastances and resistances of the lungs(EL andRL, respectively) and chest wall at the different PEEP and during sinusoidal forcing in the normal rangeof breathing frequency and tidal volume. After final measurements, tissue sections from five randomly selected areas of the lung eachshowed indications of emphysema.T_aci during emphysema was similarto that in control dogs. ELdecreased by ~50% during emphysema (P < 0.05) but did not change itsdependence on frequency or tidal volume.RL did not change(P > 0.05) at the lowest frequencystudied (0.2 Hz), but in some dogs it increased compared with control at the higher frequencies. Chest wall properties were not changed byemphysema (P > 0.05). We suggestthat although large changes in acinar structure andEL occur during uncomplicatedbilateral emphysema, secondary complications must be present to causeseveral of the characteristic dysfunctions seen in patients withemphysema.

     

When does the lung die? Kfc, cell viability, and adenine nucleotide changes in the circulation-arrested rat lung

Jones, David R., Randy M. Becker, Steve C. Hoffmann, John J. Lemasters, and Thomas M. Egan. When does the lungdie? K_fc, cellviability, and adenine nucleotide changes in the circulation-arrested rat lung. J. Appl. Physiol. 83(1):247-252, 1997.Lungs harvested from cadavericcirculation-arrested donors may increase the donor pool for lungtransplantation. To determine the degree and time course ofischemia-reperfusion injury, we evaluated the effect ofO₂ ventilation on capillarypermeability [capillary filtration coefficient(K_fc)],cell viability, and total adenine nucleotide (TAN) levels in in situcirculation-arrested rat lungs.K_fc increased with increasing postmortem ischemic time(r = 0.88). Lungs ventilated withO₂ 1 h postmortem had similarK_fc andwet-to-dry ratios as controls. Nonventilated lungs had threefold(P < 0.05) and sevenfold (P < 0.0001) increases inK_fc at 30 and 60 min postmortem compared with controls. Cell viability decreased inall groups except for 30-min postmortemO₂-ventilated lungs. TAN levelsdecreased with increasing ischemic time, particularly in nonventilatedlungs. Loss of adenine nucleotides correlated with increasingK_fc values (r = 0.76). This study indicates thatlungs retrieved 1 h postmortem may have normalK_fc withpreharvest O₂ ventilation. Therelationship betweenK_fc and TANsuggests that vascular permeability may be related to lung TAN levels.

     

Chest wall motion during tidal breathing

De Groote, A., M. Wantier, G. Cheron, M. Estenne, and M. Paiva. Chest wall motion during tidal breathing. J. Appl. Physiol. 83(5): 1531-1537, 1997.We have used an automaticmotion analyzer, the ELITE system, to study changes inchest wall configuration during resting breathing in five normal,seated subjects. Two television cameras were used to record thex-y-z displacements of 36 markers positioned circumferentiallyat the level of the third (S₁) and fifth(S₂) costal cartilage, corresponding to the lung-apposedrib cage; midway between the xyphoid process and thecostal margin (S₃), corresponding to the abdomen-apposedrib cage; and at the level of the umbilicus (S₄).Recordings of different subsets of markers were made by submitting thesubject to five successive rotations of 45-90°. Each recordinglasted 30 s, and three-dimensional displacements of markers wereanalyzed with the Matlab software. At spontaneous end expiration,sections S_1-3 were elliptical but S₄ wasmore circular. Tidal changes in chest wall dimensions were consistentamong subjects. For S_1-2, changes during inspirationoccurred primarily in the cranial and ventral directions and averaged3-5 mm; displacements in the lateral direction were smaller(1-2 mm). On the other hand, changes at the level ofS₄ occurred almost exclusively in the ventral direction. Inaddition, both compartments showed a ventral displacement of theirdorsal aspect that was not accounted for by flexion of the spine. Weconclude that, in normal subjects breathing at rest in the seatedposture, displacements of the rib cage during inspiration are in thecranial, lateral outward, and ventral directions but that expansion ofthe abdomen is confined to the ventral direction.

     

Effects of the combination of skin cooling and hyperpnea of frigid air in asthmatic and normal subjects

McDonald, James S., Joann Nelson, K. A. Lenner, Melissa L. McLane, and E. R. McFadden, Jr. Effects of the combination of skincooling and hyperpnea of frigid air in asthmatic and normal subjects.J. Appl. Physiol. 82(2): 453-459, 1997.To investigate whether reducing integumental temperatures influences pulmonary mechanics and interacts with inhaling cold air, 10 normal and 10 asthmatic subjects participated in a three-part trial in which coolingthe skin of the head and thorax and isocapnic hyperventilation offrigid air were undertaken as isolated challenges and then administeredin combination. Integumental cooling for 30 min caused airwayobstruction to develop in both populations [change in 1-s forcedexpiratory volume (FEV₁)asthmatic subjects = 10%; normal subjects = 6%)].Hyperventilation, however, only affected the asthmatic subjects(FEV₁ asthmatic subjects = 18%; normal subjects = 3%). In contrast to expectations, the combinedchallenge did not produce a summation effect(FEV₁ asthmatic subjects = 21%; normal subjects = 7%). These data demonstrate that the skin of the trunk and head is cold sensitive and when stimulated causes similardegrees of bronchial narrowing in both normal subjects and patientswith airway disease independent of any ventilatory effect. They alsoindicate that cooling of the skin does not add to the obstructiveconsequences of hyperpnea.

     

Abdominal muscle fatigue after maximal ventilation in humans

Kyroussis, Dimitris, Gary H. Mills, Michael I. Polkey,Carl-Hugo Hamnegard, Nicholaos Koulouris, Malcolm Green, and John Moxham. Abdominal muscle fatigue after maximal ventilation inhumans. J. Appl. Physiol. 81(4):1477-1483, 1996.Abdominal muscles are the principal muscles ofactive expiration. To investigate the possibility of abdominal musclelow-frequency fatigue after maximal ventilation in humans, westimulated the nerve roots supplying the abdominal muscles. We used amagnetic stimulator (Magstim 200) powering a 90-mm circular coil andstudied six normal subjects. To assess the optimum level of stimulationand posture, we stimulated at each intervertebral level betweenT₇ andL₁ in the prone, supine, andseated positions. At T₁₀, we usedincreasing power outputs to assess the pressure-power relationship.Care was taken to avoid muscle potentiation. Twitch gastric pressure(Pga) was recorded with a balloon-tipped catheter. Mean (±SD)baseline twitch Pga measured with the subjects in the prone position atT₁₀ was 23.5 ± 5.4 cmH₂O. Within-occasion mean twitchPga coefficient of variation was 4.6 ± 1.1%. Twitch Pga wasmeasured with the subjects in the prone position with stimulation overT₁₀ before and after 2 min ofmaximal isocapnic ventilation (MIV). Twenty minutes after MIV, meantwitch Pga fell by 17 ± 9.1%(P = 0.03) and remained low 90 minafter MIV. We conclude that after maximal ventilation in humans thereis a reduction of twitch Pga and, therefore, of low-frequency fatiguein abdominal muscles.

     

Development of ventilatory responsiveness to progressive hypoxia and hypercapnia in low-birth-weight lambs

Moss, T. J., M. G. Davey, G. J. McCrabb, and R. Harding.Development of ventilatory responsiveness to progressive hypoxia and hypercapnia in low-birth-weight lambs. J. Appl.Physiol. 81(4): 1555-1561, 1996.Our aim was todetermine the effects of low birth weight on ventilatory responses toprogressive hypoxia and hypercapnia during early postnatal life. Sevenlow-birth-weight (2.7 ± 0.3 kg) and five normal-birth-weight (4.8 ± 0.2 kg) lambs, all born at term, underwent weekly rebreathingtests during wakefulness while arterialPO₂,PCO₂, and pH were measured. Hypoxicventilatory responsiveness (HOVR; percent increase in ventilation whenarterial PO₂ fell to 60% of resting values) increased in normal lambs from 86.6 ± 7.1% atweek 1 to 227.4 ± 24.9% atweek 6. In low-birth-weight lambs,HOVR was not significantly different at week1 (60.1 ± 18.7%) from that of normal lambs but didnot increase with postnatal age (56.6 ± 19.3% atweek 6). HOVR of all lambs at 6 wkwas significantly correlated with birth weight(r² = 0.8).Hypercapnic ventilatory responsiveness (gradient of ventilation vs.arterial PCO₂) did not change withage and was not significantly different between groups [84.7 ± 7.5 (low-birth-weight lambs) vs. 89.4 ± 6.6 ml ^· min^{1 ·} kg^{1 ·} mmHg¹(normal lambs)]. We conclude that intrauterine conditions that impair fetal growth lead to the failure of HOVR to increase with age.

     

Effects of N2O narcosis on breathing and effort sensations during exercise and inspiratory resistive loading

Fothergill, D. M., and N. A. Carlson. Effects ofN₂O narcosis on breathing andeffort sensations during exercise and inspiratory resistive loading.J. Appl. Physiol. 81(4):1562-1571, 1996.The influence of nitrous oxide(N₂O) narcosis on the responses toexercise and inspiratory resistive loading was studied in thirteen maleUS Navy divers. Each diver performed an incremental bicycle exercisetest at 1 ATA to volitional exhaustion while breathing a 23%N₂O gas mixture and a nonnarcoticgas of the same PO₂, density, andviscosity. The same gas mixtures were used during four subsequent30-min steady-state submaximal exercise trials in which the subjectsbreathed the mixtures both with and without an inspiratory resistance(5.5 vs. 1.1 cmH₂O ^· s ^· l¹at 1 l/s). Throughout each test, subjective ratings of respiratory effort (RE), leg exertion, and narcosis were obtained with acategory-ratio scale. The level of narcosis was rated between slightand moderate for the N₂O mixturebut showed great individual variation. Perceived leg exertion and thetime to exhaustion were not significantly different with the twobreathing mixtures. Heart rate was unaffected by the gas mixture andinspiratory resistance at rest and during steady-state exercise but wassignificantly lower with the N₂O mixture during incremental exercise (P < 0.05). Despite significant increases in inspiratory occlusionpressure (13%; P < 0.05),esophageal pressure (12%; P < 0.001), expired minute ventilation (4%;P < 0.01), and the work rate ofbreathing (15%; P < 0.001) when the subjects breathed the N₂O mixture,RE during both steady-state and incremental exercise was 25% lowerwith the narcotic gas than with the nonnarcotic mixture(P < 0.05). We conclude that the narcotic-mediated changes in ventilation, heart rate, and RE induced by23% N₂O are not of sufficientmagnitude to influence exercise tolerance at surface pressure.Furthermore, the load-compensating respiratory reflexes responsible formaintaining ventilation during resistive breathing are not depressed byN₂O narcosis.

     

Skeletal muscle chemoreflex and pHi in exercise ventilatory control

Oelberg, David A., Allison B. Evans, Mirko I. Hrovat, PaulP. Pappagianopoulos, Samuel Patz, and David M. Systrom. Skeletal muscle chemoreflex and pH_i inexercise ventilatory control. J. Appl.Physiol. 84(2): 676-682, 1998.To determinewhether skeletal muscle hydrogen ion mediates ventilatory drive inhumans during exercise, 12 healthy subjects performed three bouts ofisotonic submaximal quadriceps exercise on each of 2 days in a 1.5-Tmagnet for ³¹P-magnetic resonancespectroscopy(³¹P-MRS). Bilaterallower extremity positive pressure cuffs were inflated to 45 Torr duringexercise (BLPP_ex) or recovery(BLPP_rec) in a randomized orderto accentuate a muscle chemoreflex. Simultaneous measurements were madeof breath-by-breath expired gases and minute ventilation, arterializedvenous blood, and by ³¹P-MRS ofthe vastus medialis, acquired from the average of 12 radio-frequencypulses at a repetition time of 2.5 s. WithBLPP_ex, end-exercise minuteventilation was higher (53.3 ± 3.8 vs. 37.3 ± 2.2 l/min;P < 0.0001), arterializedPCO₂ lower (33 ± 1 vs. 36 ± 1 Torr; P = 0.0009), and quadricepsintracellular pH (pH_i) more acid (6.44 ± 0.07 vs. 6.62 ± 0.07; P = 0.004), compared withBLPP_rec. Bloodlactate was modestly increased withBLPP_ex but without a change inarterialized pH. For each subject, pH_i was linearly relatedto minute ventilation during exercise but not to arterialized pH. Thesedata suggest that skeletal muscle hydrogen ion contributes to theexercise ventilatory response.

     

Effect of Nomega -nitro-L-arginine on ventilatory response to hypercapnia in anesthetized cats

Teppema, Luc, Aad Berkenbosch, and Cees Olievier Effectof N-nitro-L-arginine onventilatory response to hypercapnia in anesthetized cats.J. Appl. Physiol. 82(1): 292-297, 1997.The effect of intravenous administration of 40 mg/kgN-nitro-L-arginine(L-NNA), an inhibitor of thesynthesis of nitric oxide (NO), on the ventilatory response toCO₂ was studied in anesthetizedcats. The ventilatory response toCO₂ was assessed during normoxiaby applying square-wave changes in end-tidalPCO₂ of ~1 kPa. EachCO₂ response was separated into afast peripheral and slow central component characterized by aCO₂ sensitivity (S_pand S_c, respectively), time constant, time delay, and anoffset (apneic threshold). L-NNAreduced S_p,S_c, and the apneic threshold significantly by ~30%. However, the ratioS_p/S_cwas not changed. It is argued that the reduction inS_p andS_c,S_p/S_cremaining constant, may be due to a potent inhibitory action ofL-NNA on the brain stemrespiratory-integrating centers and on the neuromechanical link betweenthese centers and respiratory movements. It is concluded that NO playsan important role in the control of breathing.

     

Water transport and the distribution of aquaporin-1 in pulmonary air spaces

Effros, R. M., C. Darin, E. R. Jacobs, R. A. Rogers, G. Krenz, and E. E. Schneeberger. Water transport and thedistribution of aquaporin-1 in pulmonary air spaces.J. Appl. Physiol. 83(3): 1002-1016, 1997.Recent evidence suggests that water transport between the pulmonary vasculature and air spaces can be inhibited byHgCl₂, an agent that inhibitswater channels (aquaporin-1 and -5) of cell membranes. In the presentstudy of isolated rat lungs, clearances of labeled(³HOH) and unlabeled water werecompared after instillation of hypotonic or hypertonic solutions intothe air spaces or injection of a hypotonic bolus into the pulmonaryartery. The clearance of ³HOHbetween the air spaces and perfusate after intratracheal instillation and from the vasculature to the tissues after pulmonary arterial injections was invariably greater than that of unlabeled water, indicating that osmotically driven transport of water is limited bypermeability of the tissue barriers rather than the rate of perfusion.Exposure to 0.5 mM HgCl₂ in theperfusate and air-space solution reduced the product of the filtrationcoefficient and surface area(P_fS)of water from the air spaces to the perfusate by 28% afterinstillation of water into the trachea. In contrast, perfusion of 0.5 mM HgCl₂ in air-filled lungs reducedP_fSof the endothelium by 86% after injections into the pulmonary artery, suggesting that much of the action of this inhibitor is on the endothelial surfaces. Confocal laser scanning microscopy demonstrated that aquaporin-1 is on mouse pulmonary endothelium. No aquaporin-1 wasfound on alveolar type I cells with immunogold transmission electronmicroscopy, but small amounts were present on some type II cells.

     

Curtailed respiration by repeated vs. isolated hypoxia in maturing piglets is unrelated to NTS ME or SP levels

Waters, Karen A., André Laferrière, JuliePaquette, Cynthia Goodyer, and Immanuela R. Moss. Curtailedrespiration by repeated vs. isolated hypoxia in maturing piglets isunrelated to NTS ME or SP levels. J. Appl.Physiol. 83(2): 522-529, 1997.In earlydevelopment, respiratory disorders can produce recurring hypoxicepisodes during sleep. To examine possible effects of daily repeatedvs. isolated hypoxic hypoxia, cardiorespiratory functions and central,respiratory-related neuromodulator levels in 21- to 32-day-old,chronically instrumented, unsedated piglets were compared between afifth sequential daily hypoxia and an isolated hypoxia (10%O₂-90%N₂ for 30 min). Diaphragmaticelectromyographic activity, heart rate and arterial pressure, and pHand gas tensions were measured. In vivo microdialysis, via chronicallyimplanted guides, served to sample interstitial substance P (SP) andmethionine-enkephalin (ME) at the level of the respiratory-relatednucleus tractus solitarii (NTS). Compared with an isolated hypoxia,repeated hypoxia resulted in 1)lower respiratory frequency (f), ventilation equivalent, and arterialpH, higher arterial PO₂during hypoxia, and lower f in recovery from hypoxia; and2) increased SP concentrations butno change in ME concentrations. We conclude that, in these maturingswine, repeated vs. isolated hypoxic exposure curtails respiratoryresponses to hypoxia by a mechanism(s) unrelated to SP or ME levels atthe NTS.

     

Gender differences in airway resistance during sleep

Trinder, John, Amanda Kay, Jan Kleiman, and Judith Dunai.Gender differences in airway resistance during sleep.J. Appl. Physiol. 83(6):1986-1997, 1997.At the onset of non-rapid-eye-movement (NREM)sleep there is a fall in ventilation and an increase in upper airwayresistance (UAR). In healthy men there is a progressive increase in UARas NREM sleep deepens. This study compared the pattern of change in UARand ventilation in 14 men and 14 women (aged 18-25 yr) both duringsleep onset and over the NREM phase of a sleep cycle (from wakefulnessto slow-wave sleep). During sleep onset, fluctuations betweenelectroencephalographic alpha and theta activity were associated withmean alterations in inspiratory minute ventilation and UAR of between 1 and 4.5 l/min and between 0.70 and 5.0 cmH₂O · l¹ · s,respectively, with no significant effect of gender on either change(P > 0.05). During NREM sleep,however, the increment in UAR was larger in men than in women(P < 0.01), such that the meanlevels of UAR at peak flow reached during slow-wave sleep were ~25and 10 cmH₂O · l¹ · sin men and women, respectively. We speculate that the greater increasein UAR in healthy young men may represent a gender-related susceptibility to sleep-disordered breathing that, in conjunction withother predisposing factors, may contribute to the development ofobstructive sleep apnea.

     

Conservation of bronchiolar wall area during constriction and dilation of human airways

Mitchell, R. W., E. Rühlmann, H. Magnussen, N. M. Muñoz, A. R. Leff, and K. F. Rabe. Conservation ofbronchiolar wall area during constriction and dilation of humanairways. J. Appl. Physiol. 82(3):954-958, 1997.We assessed the effect of smooth musclecontraction and relaxation on airway lumen subtended by the internalperimeter(A_i)and total cross-sectional area (A_o)of human bronchial explants in the absence of the potential lungtethering forces of alveolar tissue to test the hypothesis thatbronchoconstriction results in a comparable change ofA_i andA_o.Luminal area (i.e.,A_i) andA_owere measured by using computerized videomicrometry, and bronchial wallarea was calculated accordingly. Images on videotape were captured;areas were outlined, and data were expressed as internal pixel numberby using imaging software. Bronchial rings were dissected in 1.0- to1.5-mm sections from macroscopically unaffected areas of lungs frompatients undergoing resection for carcinoma, placed in microplate wellscontaining buffered saline, and allowed to equilibrate for 1 h.Baseline, A_o[5.21 ± 0.354 (SE)mm²], andA_i(0.604 ± 0.057 mm²) weremeasured before contraction of the airway smooth muscle (ASM) withcarbachol. MeanA_inarrowed by 0.257 ± 0.052 mm²in response to 10 µM carbachol (P = 0.001 vs. baseline). Similarly, A_onarrowed by 0.272 ± 0.110 mm²in response to carbachol (P = 0.038 vs. baseline; P = 0.849 vs. change inA_i).Similar parallel changes in cross-sectional area forA_iandA_owere observed for relaxation of ASM from inherent tone of otherbronchial rings in response to 10 µM isoproterenol. We demonstrate aunique characteristic of human ASM; i.e., both luminal and totalcross-sectional area of human airways change similarly on contractionand relaxation in vitro, resulting in a conservation of bronchiolarwall area with bronchoconstriction and dilation.

     

Effect of different levels of hyperoxia on breathing in healthy subjects

Becker, Heinrich F., Olli Polo, Stephen G. McNamara, MichaelBerthon-Jones, and Colin E. Sullivan. Effect of different levelsof hyperoxia on breathing in healthy subjects. J. Appl. Physiol. 81(4): 1683-1690, 1996.Wehave recently shown that breathing 50%O₂ markedly stimulates ventilationin healthy subjects if end-tidal PCO₂(PET_CO2) ismaintained. The aim of this study was to investigate apossible dose-dependent stimulation of ventilation byO₂ and to examine possiblemechanisms of hyperoxic hyperventilation. In eight normalsubjects ventilation was measured while they were breathing 30 and 75%O₂ for 30 min, withPET_CO2 being held constant.Acute hypercapnic ventilatory responses were also tested in thesesubjects. The 75% O₂ experimentwas repeated without controllingPET_CO2 in 14 subjects, andin 6 subjects arterial blood gases were taken at baseline and at theend of the hyperoxia period. Minute ventilation(I) increased by 21 and 115% with 30 and 75% isocapnic hyperoxia, respectively. The 75%O₂ without any control onPET_CO2 led toa 16% increase inI, butPET_CO2 decreased by3.6 Torr (9%). There was a linear correlation(r = 0.83) between the hypercapnic and the hyperoxic ventilatory response. In conclusion, isocapnic hyperoxia stimulates ventilation in a dose-dependent way, withI more than doubling after 30 min of75% O₂. If isocapnia is notmaintained, hyperventilation is attenuated by a decrease in arterialPCO₂. There is a correlation betweenhyperoxic and hypercapnic ventilatory responses. On the basis of datafrom the literature, we concluded that the Haldane effect seems to bethe major cause of hyperventilation duringboth isocapnic and poikilocapnichyperoxia.

     

Hyperpnea-induced bronchoconstriction is dependent on tachykinin-induced cysteinyl leukotriene synthesis

Yang, X. X., W. S. Powell, M. Hojo, and J. G. Martin.Hyperpnea-induced bronchoconstriction is dependent ontachykinin-induced cysteinyl leukotriene synthesis. J. Appl. Physiol. 82(2): 538-544, 1997.The purposeof the study was to test the hypothesis that tachykinins mediatehyperpnea-induced bronchoconstriction indirectly by triggeringcysteinyl leukotriene (LT) synthesis in the airways. Guinea pigs(350-600 g) were anesthetized with xylazine and pentobarbital sodium and received hyperpnea challenge (tidal volume 3.5-4.0 ml,frequency 150 breaths/min) with either humidified isocapnic gas(n = 6) or dry gas(n = 7). Dry gas challenge wasperformed on animals that received MK-571(LTD₄ antagonist; 2 mg/kg iv; n = 5), capsaicin(n = 4), neurokinin (NK) antagonists[NK₁ (CP-99994) + NK₂ (SR-48968) (1 mg/kg iv);n = 6], or theH₁ antihistamine pyrilamine (2 mg/kg iv; n = 5). We measured thetracheal pressure and collected bile for 1 h before and 2 h afterhyperpnea challenge. We examined the biliary excretion of cysteinylLTs; the recovery of radioactivity in bile after instillation of 1 µCi [³H]LTC₄intratracheally averaged 24% within 4 h(n = 2). The major cysteinyl LTidentified was LTD₄ (32% recoveryof radioactivity). Cysteinyl LTs were purified from bile of animalsundergoing hyperpnea challenge by using reverse-phase high-pressureliquid chromatography and quantified by radioimmunoassay. There was asignificant increase in the peak value of tracheal pressure afterchallenge, indicating bronchoconstriction in dry gas-challenged animalsbut not after humidified gas challenge. MK-571, capsaicin, and NKantagonists prevented the bronchoconstriction; pyrilamine didnot. Cysteinyl LT levels in the bile after challenge weresignificantly increased from baseline in dry gas-challenged animals(P < 0.05) and were higher than inthe animals challenged with humidified gas or dry gas-challengedanimals treated with capsaicin or NK antagonists (P < 0.01). The results indicatethat isocapnic dry gas hyperpnea-induced bronchoconstriction is LTmediated and the role of tachykinins in the response is indirectthrough release of LTs. Endogenous histamine does not contribute to theresponse.

     

Esophageal stimulation by hydrochloric acid causes neurogenic inflammation in the airways in guinea pigs

Hamamoto, Junji, Hirotsugu Kohrogi, Osamu Kawano,Hajime Iwagoe, Kazuhiko Fujii, Nahomi Hirata, and Masayuki Ando.Esophageal stimulation by hydrochloric acid causes neurogenicinflammation in the airways in guinea pigs. J. Appl.Physiol. 82(3): 738-745, 1997.Toinvestigate whether tachykinins are released in the airways in responseto stimulation of the esophagus, we studied the airway plasmaextravasation induced by intraesophageal HCl in the presence or absenceof neutral endopeptidase inhibitor phosphoramidon and NK₁-receptor antagonist FK-888 inanesthetized guinea pigs. The airway plasma leakage wasevaluated by measuring extravasated Evans blue dye in the animalspretreated with propranolol and atropine. Infusion of 1 N HCl into theesophagus significantly increased plasma extravasation in the trachea.Phosphoramidon significantly potentiated plasma extravasation in thetrachea and main bronchi, whereas FK-888 significantly inhibited that extravasation in a dose-related manner. In the capsaicin-treated animals, airway plasma extravasation was completely inhibited even inthe presence of phosphoramidon. Tracheal plasma extravasation potentiated by phosphoramidon was significantly inhibited in the bilateral vagotomized animals. These results suggest that1) tachykinin-like substances arereleased to cause plasma extravasation in the airways as a result ofintraesophageal HCl stimulation and2) there are neural pathwayscommunicating between the esophagus and airways, including the vagusnerve.

     

Control of breathing during sleep assessed by proportional assist ventilation

Meza, S., E. Giannouli, and M. Younes. Control ofbreathing during sleep assessed by proportional assist ventilation. J. Appl. Physiol. 84(1): 3-12, 1998.We used proportional assist ventilation (PAV) to evaluate thesources of respiratory drive during sleep. PAV increases the slope ofthe relation between tidal volume(VT) andrespiratory muscle pressure output (Pmus). We reasoned that ifrespiratory drive is dominated by chemical factors, progressiveincrease of PAV gain should result in only a small increase inVT because Pmus would bedownregulated substantially as a result of small decreases inPCO₂. In the presence of substantialnonchemical sources of drive [believed to be the case inrapid-eye-movement (REM) sleep] PAV should result in a substantial increase in minute ventilation and reductionin PCO₂ as the output related to thechemically insensitive drive source is amplified severalfold. Twelvenormal subjects underwent polysomnography while connected to a PAVventilator. Continuous positive air pressure (5.2 ± 2.0 cmH₂O) was administered tostabilize the upper airway. PAV was increased in 2-min steps from 0 to20, 40, 60, 80, and 90% of the subject's elastance and resistance.VT, respiratory rate, minuteventilation, and end-tidal CO₂pressure were measured at the different levels, and Pmus wascalculated. Observations were obtained in stage 2 sleep (n = 12), slow-wave sleep(n = 11), and REM sleep(n = 7). In all cases, Pmus wassubstantially downregulated with increase in assist so that theincrease in VT, althoughsignificant (P < 0.05), was small(0.08 liter at the highest assist). There was no difference in responsebetween REM and non-REM sleep. We conclude that respiratory driveduring sleep is dominated by chemical control and that there is nofundamental difference between REM and non-REM sleep in this regard.REM sleep appears to simply add bidirectional noise to what isbasically a chemically controlled respiratory output.