Relationship between heterogeneous changes in airway morphometry and lung resistance and elastance

Lutchen, Kenneth R., and Heather Gillis. Relationshipbetween heterogeneous changes in airway morphometry and lung resistanceand elastance. J. Appl. Physiol.83(4): 1192-1201, 1997.We present a dog lung model to predictthe relation between inhomogeneous changes in airway morphometry andlung resistance (RL) andelastance (EL) for frequenciessurrounding typical breathing rates. TheRL andEL were sensitive in distinctways to two forms of peripheral constriction. First, when there is alarge and homogeneous constriction, theRL increases uniformly over thefrequency range. The EL israther unaffected below 1 Hz but then increases with frequencies up to5 Hz. This increase is caused by central airway wallshunting. Second, the RL andEL are extremely sensitive to mild inhomogeneous constriction in which a few highly constricted ornearly closed airways occur randomly throughout theperiphery. This results in extreme increases in the levelsand frequency dependence of RLand EL but predominantly attypical breathing rates (<1 Hz). Conversely, theRL andEL are insensitive to highly inhomogeneous airway constriction that does not produce any nearly closed airways. Similarly, alterations in theRL andEL due to central airway wallshunting are not likely until the preponderance of the peripheryconstricts substantially. The RLand EL spectra are far moresensitive to these two forms of peripheral constriction than toconstriction conditions known to occur in the central airways. On thebasis of these simulations, we derived a set of qualitative criteria toinfer airway constriction conditions from RL andEL spectra.

     

Lung resistance and elastance in spontaneously breathing preterm infants: effects of breathing pattern and demographics

Reported values of lung resistance(RL) and elastance (EL) in spontaneouslybreathing preterm neonates vary widely. We hypothesized that thisvariability in lung properties can be largely explained by both inter-and intrasubject variability in breathing pattern and demographics.Thirty-three neonates receiving nasal continuous positive airwaypressure [weight 606-1,792 g, gestational age (GA) of25-33 wk, 2-49 days old] were studied. Transpulmonary pressure was measured by esophageal manometry and airway flow by facemask pneumotachography. Breath-to-breath changes in RL andEL in each infant were estimated by Fourier analysis ofimpedance (Z) and by multiple linear regression (MLR).RL_MLR (RL_MLR = 0.85 × RL_Z 0.43; r² = 0.95) and EL_MLR(EL_MLR = 0.97 × EL_Z + 8.4; r² = 0.98) werehighly correlated to RL_Z andEL_Z, respectively. Both RL(mean ± SD; RL_Z = 70 ± 38, RL_MLR = 59 ± 36 cmH₂O · s · l¹)and EL (EL_Z = 434 ± 212, EL_MLR = 436 ± 210 cmH₂O/l)exhibited wide intra- and intersubject variability.Regardless of computation method, RL was found to decreaseas a function of weight, age, respiratory rate (RR), and tidal volume(VT) whereas it increased as a function ofRR · VT and inspiratory-to-expiratorytime ratio (TI/TE). EL decreasedwith increasing weight, age, VT and female gender andincreased as RR and TI/TE increased. Weconclude that accounting for the effects of breathing patternvariability and demographic parameters on estimates of RLand EL is essential if they are to be of clinical value.Multivariate statistical models of RL and ELmay facilitate the interpretation of lung mechanics measurements inspontaneously breathing infants.

     

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.

     

Changes in respiratory control during and after 48h of isocapnic and poikilocapnic hypoxia in humans

Ventilatory acclimatization tohypoxia is associated with an increase in ventilation under conditionsof acute hyperoxia(E_hyperoxia) and an increase in acute hypoxic ventilatory response (AHVR). Thisstudy compares 48-h exposures to isocapnic hypoxia( protocol I) with 48-hexposures to poikilocapnic hypoxia ( protocolP) in 10 subjects to assess the importance ofhypocapnic alkalosis in generating the changes observed in ventilatoryacclimatization to hypoxia. During both hypoxic exposures,end-tidal PO₂ was maintained at60 Torr, with end-tidal PCO₂ held at the subject's prehypoxic level( protocol I) or uncontrolled( protocol P).E_hyperoxiaand AHVR were assessed regularly throughout the exposures.E_hyperoxia(P < 0.001, ANOVA) and AHVR(P < 0.001) increased during thehypoxic exposures, with no significant differences betweenprotocols I andP. The increase inE_hyperoxiawas associated with an increase in slope of theventilation-end-tidal PCO₂ response(P < 0.001) with no significantchange in intercept. These results suggest that changes in respiratorycontrol early in ventilatory acclimatization to hypoxiaresult from the effects of hypoxia per se and not the alkalosisnormally accompanying hypoxia.

     

Temporal dynamics of acute isovolume bronchoconstriction in the rat

Bates, Jason H. T., Thomas F. Schuessler, Carrie Dolman, andDavid H. Eidelman. Temporal dynamics of acute isovolume bronchoconstriction in the rat. J. Appl.Physiol. 82(1): 55-62, 1997.The time course oflung impedance changes after intravenous injection of bronchial agonisthave produced significant insights into the mechanisms ofbronchoconstriction in the dog (J. H. T. Bates, A.-M. Lauzon, G. S. Dechman, G. N. Maksym, and T. F. Shuessler. J. Appl.Physiol. 76: 616-626, 1994). We studied the timecourse of acute induced bronchoconstriction in five anesthetizedparalyzed open-chest rats injected intravenously with a bolus ofmethacholine. For the 16 s immediately after injection, we held thelung volume constant while applying small-amplitude flow oscillationsat 1.48, 5.45, and 19.69 Hz simultaneously, which provided us withcontinuous estimates of lung resistance(RL) and elastance(EL) at eachfrequency. This procedure was repeated at initial lung inflationpressures of 0.2, 0.4, and 0.6 kPa. BothRL andEL increased progressively aftermethacholine administration; however, the rate of change ofEL increased dramatically asfrequency was increased, whereas RL remained relativelyindependent of frequency. We interpret these findings in terms of athree-compartment model of the rat lung, featuring two parallelalveolar compartments feeding into a central airway compartment. Modelsimulations support the notions that both central airway shunting andregional ventilation inhomogeneity developed to a significant degree inour constricted rats. We also found that the rates of increase in bothRL andEL were greatly enhanced as theinitial lung inflation pressure was reduced, in accord with the notionthat parenchymal tethering is an important mechanism limiting theextent to which airways can narrow when their smooth muscle isstimulated to contract.

     

Parallel airways inhomogeneity and lung tissue mechanics in transition to constricted state in rabbits

Toinvestigate whether changes of tissue resistance (Rti) duringmethacholine (MCh)-induced constriction correspond to an intrinsicmechanism or are an artifact of increased airways inhomogeneity, rabbits were studied after exposure to air(n = 7) or 1.5 parts/million O₃(n = 6). Animals were anesthetized andmechanically ventilated. Tracheal flow and pressure (Ptr) and fouralveolar capsule pressures (Pcap) were measured during 3 min afteradministration of an intrajugular bolus of 0.8 mg/ml MCh. By adjustmentof the equation of motion [P(t) = E · V(t) + R · dV(t)/dt + P₀] [whereP(t), V(t), and dV(t)/dt are pressure, volume, and flow as a function of time, respectively, Eis elastance, R is resistance, and P₀ is end-expiratorypressure] to Ptr, lung resistance(RL) and dynamic elastance(EL) were determined breath bybreath. Rti and airways resistance (Raw) were determined from Pcap in phase with rate of change of pulmonary expansion. Hysteresivity () was calculated. Parallel inhomogeneity wasestimated from the coefficients of variation (CV) of every Pcap at endinspiration and end expiration. Increase in CV significantly laggedRti, RL, and . A linearrelationship between EL and Rawwas observed. Our results suggest that changes in tissue mechanicsduring the transition to the constricted state are not artifactual.

     

Maturational changes in responses of tissue and airway resistance to histamine

Dreshaj, Ismail A., Musa A. Haxhiu, Charles F. Potter, FatonH. Agani, and Richard J. Martin. Maturational changes in responsesof tissue and airway resistance to histamine. J. Appl.Physiol. 81(4): 1785-1791, 1996.We determinedhow postnatal maturation affects the relative contributions of airwaysand lung parenchyma to pulmonary resistance(RL) and whether there are developmental differences in their respective responses to constrictive agents. We studied open-chest ventilated anesthetized piglets of threeages: 2-4 days, 2-3 wk, and 10 wk.RL was partitioned into tissue(Rti) and airway (Raw) resistance by means of alveolar capsules underbaseline conditions and after intravenous histamine. Postnatalmaturation was associated with a progressive decline inRL, Rti, and Raw and with anincrease in the contribution of Rti toRL from 38 ± 8% at 2-4days to 72 ± 2% at both 2-3 and 10 wk. Histamine causedRL to increase at all ages. Whenpartitioned into Rti and Raw, the percent increase in Rti significantlyexceeded that of Raw at both 2-4 days and 2-3 wk. Incontrast, the percent increase in Raw significantly exceeded that ofRti at 10 wk. Administration of atropine before histamine in pigletsaged 10 wk reduced the response of Rti and Raw to histamine.Histamine-induced responses ofRL were blocked by priorH₁-receptor blockade withpyrilamine (2 mg/kg). These results indicate that1) the contribution of Rti and Rawto RL changes during maturationand that 2) contractile responses toexogenous histamine are manifest predominantly in most distal airwaysand lung parenchyma during early postnatal life; with advancingmaturation there is greater contribution of airways to the increase inRL induced by histamine.

     

Lung tissue behavior in the mouse during constriction induced by methacholine and endothelin-1

Nagase, Takahide, Hirotoshi Matsui, Tomoko Aoki, YasuyoshiOuchi, and Yoshinosuke Fukuchi. Lung tissue behavior in the mouseduring constriction induced by methacholine and endothelin-1. J. Appl. Physiol. 81(6):2373-2378, 1996.Recently, mice have been extensively used toinvestigate the pathogenesis of pulmonary disease because appropriatemurine models, including transgenic mice, are being increasinglydeveloped. However, little information about the lung mechanics of miceis currently available. We questioned whether lung tissue behavior andthe coupling between dissipative and elastic processes, hysteresivity(), in mice would be different from those in the other species. Toaddress this question, we investigated whether tissue resistance (Rti)and  in mice would be affected by varying lung volume, constrictioninduced by methacholine (MCh) and endothelin-1 (ET-1), andhigh-lung-volume challenge during induced constriction. From measuredtracheal flow and tracheal and alveolar pressures in open-chest ICRmice during mechanical ventilation [tidal volume = 8 ml/kg,frequency (f) = 2.5 Hz], we calculated lung resistance(RL), Rti, airway resistance(Raw), lung elastance (EL),and  (=2fRti/EL). Underbaseline conditions, increasing levels of end-expiratory transpulmonarypressure decreased Raw and increased Rti. The administration ofaerosolized MCh and intravenous ET-1 increasedRL, Rti, Raw, andEL in a dose-dependent manner.Rti increased from 0.207 ± 0.010 to 0.570 ± 0.058 cmH₂O ^· ml^{1 ·} safter 10⁷ mol/kg ET-1(P < 0.01). After inducedconstriction, increasing end-expiratory transpulmonary pressuredecreased Raw. However,  was not affected by changing lung volume,constriction induced by MCh and ET-1, or high-lung-volume challengeduring induced constriction. These observations suggest that1)  is stable in mice regardlessof various conditions, 2) Rti is animportant fraction of RL andincreases after induced constriction, and3) mechanical interdependence mayaffect airway smooth muscle shortening in this species. In mammalianspecies, including mice, analysis of  may indicate that both Rti andEL essentially respond to asimilar degree.

     

Short-term 17{beta}-estradiol decreases glucose Ra but not whole body metabolism during endurance exercise

The female sexhormone 17-estradiol (E₂) has been shown to increaselipid and decrease carbohydrate utilization in animals. Weadministrated oral E₂ and placebo (randomized, doubleblind, crossover) to eight human male subjects for 8 days (~3 mg/day) and measured respiratory variables, plasma substrates, hormones (E₂, testosterone, leptin, cortisol, insulin, andcatecholamines), and substrate utilization during 90 min of enduranceexercise. [6,6-²H]glucose and[1,1,2,3,3-²H]glycerol tracers were used to calculatesubstrate flux. E₂ administration increased serumE₂ (0.22 to 2.44 nmol/l, P < 0.05) anddecreased serum testosterone (19.4 to 11.5 nmol/l, P < 0.05) concentrations, yet there were no treatment effects on any of theother hormones. Glucose rates of appearance (R_a) anddisappearance (R_d) were lower, and glycerolR_a-to-R_d ratio was not affected byE₂ administration. O₂ uptake, CO₂production, and respiratory exchange ratio were not affected byE₂; however, there was a decrease in heart rate (P < 0.05). Plasma lactate and glycerol wereunaffected by E₂; however, glucose was significantly higher(P < 0.05) during exercise after E₂administration. We concluded that short-term oral E₂ administration decreased glucose R_a and R_d,maintained plasma glucose homeostasis, but had no effect on substrateoxidation during exercise in men.

     

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.

     

Depressed ventilatory response to hypoxia in hypothermic newborn piglets: role of glutamate

To evaluatewhether changes in extracellular glutamate (Glu) levels in the centralnervous system could explain the depressed hypoxic ventilatory responsein hypothermic neonates, 12 anesthetized, paralyzed, and mechanicallyventilated piglets <7 days old were studied. The Glu levels in thenucleus tractus solitarius obtained by microdialysis, minute phrenicoutput (MPO), O₂ consumption, arterial blood pressure, heart rate, and arterial blood gases weremeasured in room air and during 15 min of isocapnic hypoxia (inspiredO₂ fraction = 0.10) at braintemperatures of 39.0 ± 0.5°C [normothermia (NT)]and 35.0 ± 0.5°C [hypothermia (HT)]. During NT, MPO increased significantly during hypoxia and remained above baseline. However, during HT, there was a marked decrease in MPOduring hypoxia (NT vs. HT, P < 0.03). Glu levels increased significantly in hypoxia during NT;however, this increase was eliminated during HT(P < 0.02). A significant linearcorrelation was observed between the changes in MPO and Glu levelsduring hypoxia (r = 0.61, P < 0.0001). Changes in pH, arterialPO₂, O₂ consumption, arterial bloodpressure, and heart rate during hypoxia were not different between theNT and HT groups. These results suggest that the depressed ventilatoryresponse to hypoxia observed during HT is centrally mediated and inpart related to a decrease in Glu concentration in the nucleus tractussolitarius.

     

Redistribution of pulmonary blood flow during unilateral hypoxia in prone and supine dogs

We usedfluorescent-labeled microspheres in pentobarbital-anesthetized dogs tostudy the effects of unilateral alveolar hypoxia on the pulmonary bloodflow distribution. The left lung was ventilated with inspiredO₂ fraction of 1.0, 0.09, or 0.03 in random order; the right lung was ventilated with inspiredO₂ fraction of 1.0. The lungs wereremoved, cleared of blood, dried at total lung capacity, then cubed toobtain ~1,500 small pieces of lung (~1.7 cm³). The coefficient ofvariation of flow increased (P < 0.001) in the hypoxic lung but was unchanged in the hyperoxic lung.Most (70-80%) variance in flow in the hyperoxic lung wasattributable to structure, in contrast to only 30-40% of thevariance in flow in the hypoxic lung(P < 0.001). When adjusted for thechange in total flow to each lung, 90-95% of the variance in thehyperoxic lung was attributable to structure compared with 70-80%in the hypoxic lung (P < 0.001). Thehilar-to-peripheral gradient, adjusted for change in total flow,decreased in the hypoxic lung (P = 0.005) but did not change in the hyperoxic lung. We conclude thathypoxic vasoconstriction alters the regional distribution of flow inthe hypoxic, but not in the hyperoxic, lung.

     

Effects of carotid body hypocapnia during ventilatory acclimatization to hypoxia

Dwinell, M. R., P. L. Janssen, J. Pizarro, and G. E. Bisgard. Effects of carotid body hypocapnia during ventilatory acclimatization to hypoxia. J. Appl.Physiol. 82(1): 118-124, 1997.Hypoxicventilatory sensitivity is increased during ventilatory acclimatizationto hypoxia (VAH) in awake goats, resulting in a time-dependent increasein expired ventilation (E). Theobjectives of this study were to determine whether the increasedcarotid body (CB) hypoxic sensitivity is dependent on the level of CB CO₂ and whether the CBCO₂ gain is changed during VAH.Studies were carried out in adult goats with CB blood gases controlled by an extracorporeal circuit while systemic (central nervous system) blood gases were regulated independently by the level of inhaled gases. Acute E responsesto CB hypoxia (CB PO₂ 40 Torr) and CBhypercapnia (CB PCO₂ 50 and 60 Torr)were measured while systemic normoxia and isocapnia were maintained. CBPO₂ was then lowered to 40 Torr for 4 h while the systemic blood gases were kept normoxic and normocapnic.During the 4-h CB hypoxia, E increasedin a time-dependent manner. Thirty minutes after return to normoxia,the ventilatory response to CB hypoxia was significantly increasedcompared with the initial response. The slope of the CBCO₂ response was also elevatedafter VAH. An additional group of goats(n = 7) was studied with asimilar protocol, except that CB PCO₂was lowered throughout the 4-h hypoxic exposure to prevent reflexhyperventilation. CB PCO₂ wasprogressively lowered throughout the 4-h CB hypoxic period to maintainE at the control level. After the 4-hCB hypoxic exposure, the ventilatory response to hypoxia was alsosignificantly elevated. However, the slope of the CBCO₂ response was not elevatedafter the 4-h hypoxic exposure. These results suggest that CBsensitivity to both O₂ andCO₂ is increased after 4 h of CBhypoxia with systemic isocapnia. The increase in CB hypoxic sensitivityis not dependent on the level of CBCO₂ maintained during the 4-hhypoxic period.

     

Antioxidants protect rat diaphragmatic muscle function under hypoxic conditions

In hypoxia, mitochondrial respiration isdecreased, thereby leading to a buildup of reducing equivalents thatcannot be transferred to O₂ at thecytochrome oxidase. This condition, called reductive stress, canparadoxically lead to enhanced formation of reactive O₂ species, or a decrease in theability of the cell to defend against an oxidative stress. Wehypothesized that antioxidants would protect tissues under conditionsof hypoxia. Rat diaphragm strips were incubated in tissue bathscontaining one of four antioxidants: N-acetyl-L-cysteine,dimethyl sulfoxide, superoxide dismutase, or Tiron. The strips weredirectly stimulated in an electrical field. Force-frequencyrelationships were studied under baseline oxygenation (95%O₂-5%CO₂), after 30 min of hypoxia(95% N₂-5% CO₂), and 30 min afterreoxygenation. In all tissues, antioxidants markedly attenuated theloss of contractile function during hypoxia (P < 0.01) and alsosignificantly improved recovery on reoxygenation (P < 0.05). We conclude that bothintracellular and extracellular antioxidants improve skeletal musclecontractile function in hypoxia and facilitate recovery duringreoxygenation in an in vitro system. The strong influence ofantioxidants during hypoxic exposure suggests that they can be aseffective in protecting cell function in a reducing environment as theyhave been in oxidizing environments.

     

Effect of prior O2 breathing on ventilatory response to sustained isocapnic hypoxia in adult humans

Honda, Y., H. Tani, A. Masuda, T. Kobayashi, T. Nishino, H. Kimura, S. Masuyama, and T. Kuriyama. Effect of priorO₂ breathing on ventilatoryresponse to sustained isocapnic hypoxia in adult humans.J. Appl. Physiol. 81(4):1627-1632, 1996.Sixteen healthy volunteers breathed 100%O₂ or room air for 10 min in random order, then their ventilatory response to sustained normocapnic hypoxia (80% arterial O₂saturation, as measured with a pulse oximeter) was studied for 20 min.In addition, to detect agents possibly responsible for the respiratorychanges, blood plasma of 10 of the 16 subjects was chemically analyzed.1) Preliminary O₂ breathing uniformly andsubstantially augmented hypoxic ventilatory responses.2) However, the profile ofventilatory response in terms of relative magnitude, i.e., biphasichypoxic ventilatory depression, remained nearly unchanged.3) Augmented ventilatory incrementby prior O₂ breathing wassignificantly correlated with increment in the plasma glutamine level.We conclude that preliminary O₂administration enhances hypoxic ventilatory response without affectingthe biphasic response pattern and speculate that the excitatory aminoacid neurotransmitter glutamate, possibly derived from augmentedglutamine, may, at least in part, play a role in this ventilatoryenhancement.

     

Hypertonic perfusion inhibits intracellular Na and Ca accumulation in hypoxic myocardium

Muchevidence supports the view that hypoxic/ischemic injury is largely dueto increased intracellular Ca concentration([Ca]_i) resulting from 1) decreasedintracellular pH (pH_i), 2) stimulated Na/H exchangethat increases Na uptake and thus intracellular Na (Na_i),and 3) decreased Na gradient that decreases or reverses net Catransport via Na/Ca exchange. The Na/H exchanger (NHE) is alsostimulated by hypertonic solutions; however, hypertonic media mayinhibit NHE's response to changes in pH_i (Cala PM and Maldonado HM. J Gen Physiol 103: 1035-1054, 1994). Thus wetested the hypothesis that hypertonic perfusion attenuates acid-induced increases in Na_i in myocardium and, thereby, decreasesCa_i accumulation during hypoxia. Rabbit hearts wereLangendorff perfused with HEPES-buffered Krebs-Henseleit solutionequilibrated with 100% O₂ or 100% N₂. Hypertonic perfusion began 5 min before hypoxia or normoxicacidification (NH₄Cl washout). Na_i,[Ca]_i, pH_i, and high-energyphosphates were measured by NMR. Control solutions were 295 mosM, andhypertonic solutions were adjusted to 305, 325, or 345 mosM by additionof NaCl or sucrose. During 60 min of hypoxia (295 mosM),Na_i rose from 22 ± 1 to 100 ± 10 meq/kg dry wt while[Ca]_i rose from 347 ± 11 to 1,306 ± 89 nM.During hypertonic hypoxic perfusion (325 mosM), increases inNa_i and [Ca]_i were reduced by 65 and 60%, respectively (P < 0.05). Hypertonicperfusion also diminished Na uptake after normoxic acidification by87% (P < 0.05). The data are consistent with the hypothesisthat mild hypertonic perfusion diminishes acid-induced Na accumulationand, thereby, decreases Na/Ca exchange-mediated Ca_iaccumulation during hypoxia.

     

Physiological and Genomic Consequences of Intermittent Hypoxia: Selected Contribution: Variation in acute hypoxic ventilatory response is linked to mouse chromosome 9

Genetic determinants confervariation among inbred mouse strains with respect to the magnitude andpattern of breathing during acute hypoxic challenge. Specifically,inheritance patterns derived from C3H/HeJ (C3) and C57BL/6J (B6)parental strains suggest that differences in hypoxic ventilatoryresponse (HVR) are controlled by as few as two genes. The present studydemonstrates that at least one genetic determinant is located on mousechromosome 9. This genotype-phenotype association was established byphenotyping 52 B6C3F₂ (F₂) offspring for HVRcharacteristics. A genome-wide screen was performed usingmicrosatellite DNA markers (n = 176) polymorphicbetween C3 and B6 mice. By computing log-likelihood values (LODscores), linkage analysis compared marker genotypes with minuteventilation (E), tidal volume (VT), andmean inspiratory flow (VT/TI, whereTI is inspiratory time) during acute hypoxic challenge(inspired O₂ fraction = 0.10, inspired CO₂fraction = 0.03 in N₂). A putative quantitative traitlocus (QTL) positioned in the vicinity of D9Mit207 wassignificantly associated with hypoxic E (LOD = 4.5), VT (LOD = 4.0), andVT/TI (LOD = 5.1). For each of the threeHVR characteristics, the putative QTL explained more than 30% of thephenotypic variation among F₂ offspring. In conclusion,this genetic model of differential HVR characteristics demonstratesthat a locus ~33 centimorgans from the centromere on mouse chromosome9 confers a substantial proportion of the variance inE, VT, and VT/TIduring acute hypoxic challenge.

     

Variations with Age in Net Assimilation Rate and other Growth Attributes of Sugar-beet, Potato, and Barley in a Controlled Environment: With two Figures in the Text

Sugar-beet, potato, and barley plants were grown in a controlledenvironment, for periods of up to 10 weeks from sowing, witha light intensity of 1,8oo f.c. (4·9 cal./cm.²/hr.) anda temperature of 20° C. during the 18-hour photoperiod and15° C. during the dark period, to test whether net assimilationrate varied with age and differed between the three species. Net assimilation rate of all species based on leaf area (E_A)fell approximately linearly with time. During 5 weeks E_A ofsugar-beet decreased by only about 20 per cent. and E_A of potatodecreased by 50 per cent. E_A of barley remained approximatelyconstant for 4 weeks after sowing and was halved during thesubsequent 4 weeks. The average value of E_A for all times wasgreatest for sugarbeet and least for barley. Net assimilation rates based on leaf weight (E_W) and leaf N(E_N) decreased at about 15 per cent. of the initial value perweek for all species; this was similar to the mean rate of decreaseof E_A of potato and barley, but greater than that of E_A of sugar-beet.Mean values of E_W or E_N for potato and barley were similar andless than for sugar-beet. Relative growth rate (R_W), relative leaf growth-rate (R_A), andleaf-area ratio (F) fell with time at similar rates for allspecies. Average values of R_W decreased and of F increased inthe order sugar-beet, potato, barley. R_A was greatest for potatoand least for barley.     

Human ventilatory response to CO2 after 8h of isocapnic or poikilocapnic hypoxia

Duringventilatory acclimatization to hypoxia (VAH), the relationship betweenventilation (E) and end-tidalPCO₂ (PET_CO2) changes.This study was designed to determine 1) whether these changes can be seenearly in VAH and 2) if these changesare present, whether the responses differ between isocapnic andpoikilocapnic exposures. Ten healthy volunteers were studied by usingthree 8-h exposures: 1) isocapnichypoxia (IH), end-tidal PO₂(PET_O2) = 55 Torr andPET_CO2 held at thesubject's normal prehypoxic value;2) poikilocapnic hypoxia (PH),PET_O2 = 55 Torr; and3) control (C), air breathing. TheE-PET_CO2relationship was determined in hyperoxia (PET_O2 = 200 Torr) beforeand after the exposures. We found a significant increase in theslopes ofE-PET_CO2 relationship after both hypoxic exposures compared with control (IH vs.C, P < 0.01; PH vs. C,P < 0.001; analysis of covariance with pairwise comparisons). This increase was not significantly different between protocols IH andPH. No significant changes in theintercept were detected. We conclude that 8 h of hypoxia, whetherisocapnic or poikilocapnic, increases the sensitivity of the hyperoxicchemoreflex response to CO₂.

     

Thermogenesis in newborn rats after prenatal or postnatal hypoxia

Oxygenconsumption (O₂)was measured in normoxia as ambient temperature(T_a) was lowered from 40 to15°C, at the rate of 0.5°C/min (thermoneutrality ~33°C).In 2-day-old rats born in hypoxia after hypoxic gestation, theT_a-O₂relationship was as in controls; their interscapular brown adiposetissue (IBAT) was hypoplastic (less proteins and DNA), with lowerconcentration of the mitochondrial uncoupling proteinthermogenin. In 8-day-old rats exposed to hypoxiapostnatally (day 2 today 8), at anyT_a below thermoneutralityO₂ was higher than incontrols; also, in this group IBAT was hypoplastic with decreasedthermogenin. Additional measurements under variousexperimental conditions indicated that the increased thermogeniccapacity was not explained by the smaller body mass and increased bloodoxygen content or by the eventuality of intermittent cold stimuliduring the chronic hypoxia. On the other hand, chronic hypercapnia (3%CO₂ in normoxia, fromday 2 to day8) also resulted in increased normoxic thermogenesis. We conclude that chronic hypoxia in the perinatal period1) reduces IBAT mass andthermogenin concentration and2) can increase the newborn's thermogenic capacity because of stress-related mechanisms not specific to hypoxia.