Quantitative analysis of transpleural flux in the isolated lung

Li, M. H., J. Hildebrandt, and M. P. Hlastala.Quantitative analysis of transpleural flux in the isolated lung.J. Appl. Physiol. 82(2): 545-551, 1997.In this study, the loss of inert gas through the pleura of anisolated ventilated and perfused rabbit lung was assessed theoreticallyand experimentally. A mathematical model was used to represent an idealhomogeneous lung placed within a box with gas flow(box) surrounding the lung. Thealveoli are assumed to be ventilated with room air(A) andperfused at constant flow () containinginert gases (x) with various perfusate-air partition coefficients(_p,x).The ratio of transpleural flux of gas(pl_x)to its total delivery to the lung via pulmonary artery( ),representing fractional losses across the pleura, can be shown todepend on four dimensionless ratios:1)_p,x,2) the ratio of alveolar ventilation to perfusion(A/), 3) the ratioof the pleural diffusing capacity(Dpl_x) to the conductance ofthe alveolar ventilation (Dpl_x /A_g,where _g is the capacitancecoefficient of gas), and 4) theratio of extrapleural (box) ventilation to alveolar ventilation(box/A).Experiments were performed in isolated perfused and ventilated rabbitlungs. The perfusate was a buffer solution containing six dissolvedinert gases covering the entire 10⁵-fold range of_p,x usedin the multiple inert gas elimination technique. Steady-state inert gasconcentrations were measured in the pulmonary arterial perfusate,pulmonary venous effluent, exhaled gas, and box effluent gas. Theexperimental data could be described satisfactorily by thesingle-compartment model. It is concluded that a simple theoreticalmodel is a useful tool for predicting transpleural flux from isolatedlung preparations, with known ventilation and perfusion, for inertgases within a wide range of .

     

Non-cAMP-mediated bronchial arterial vasodilation in response to inhaled beta -agonists

Carvalho, Paula, Shane R. Johnson, Nirmal B. Charan.Non-cAMP-mediated bronchial arterial vasodilation in response toinhaled -agonists. J. Appl.Physiol. 84(1): 215-221, 1998.We studied thedose-dependent effects of inhaled isoetharine HCl, a -adrenergicbronchodilator (2.5, 5.0, 10.0, and 20.0 mg), on bronchial blood flow(br) in anesthetized sheep. Isoetharine resulted ina dose-dependent increase in br. With atotal dose of 17.5 mg, br increased from baselinevalues of 22 ± 3.4 (SE) to 60 ± 16 ml/min(P < 0.001), an effect independentof changes in cardiac output and systemic arterial pressure. To furtherstudy whether synthesis of endogenous nitric oxide (NO) affects-agonist-induced increases in br, weadministered isoetharine (20 mg) by inhalation before and after theNO-synthase inhibitorN-nitro-L-argininemethyl ester (L-NAME).Intravenous L-NAME (30 mg/kg) rapidly decreased br by ~80% of baseline,whereas L-NAME via inhalation(10 mg/kg) resulted in a delayed and smaller (~22%) decrease.Pretreatment with L-NAME viaboth routes of administration attenuated bronchial arterialvasodilation after subsequent challenge with isoetharine. We concludethat isoetharine via inhalation increases br in adose-dependent manner and that -agonist-induced relaxation ofvascular smooth muscle in the bronchial vasculature is partiallymediated via synthesis of NO.

     

Tumor necrosis factor-alpha in ischemia and reperfusion injury in rat lungs

The effects ofboth recombinant rat tumor necrosis factor- (TNF-) and ananti-TNF- antibody were studied in isolated buffer-perfused ratlungs subjected to either 45 min of nonventilated[ischemia-reperfusion (I/R)] or air-ventilated(/R) ischemia followed by 90 min of reperfusion and ventilation. In the I/R group, the vascularpermeability, as measured by the filtration coefficient(K_fc),increased three- and fivefold above baseline after 30 and 90 min ofreperfusion, respectively (P < 0.001). Over the same time intervals, theK_fc for the/R group increased five- and tenfold above baseline values, respectively (P < 0.001).TNF- measured in the perfusates of both ischemic modelssignificantly increased after 30 min of reperfusion. Recombinant ratTNF- (50,000 U), placed into perfusate after baseline measurements,produced no measurable change in microvascular permeability in controllungs perfused over the same time period (135 min), but I/R injury wassignificantly enhanced in the presence of TNF-. An anti-TNF-antibody (10 mg/rat) injected intraperitoneally into rats 2 h beforethe lung was isolated prevented the microvascular damage in lungsexposed to both I/R and /R (P < 0.001). These results indicatethat TNF- is an essential component at the cascade of events thatcause lung endothelial injury in short-term I/R and/R models of lung ischemia.

     

Role for anions in pulmonary endothelial permeability

Griffin, M. Pamela. Role for anions in pulmonaryendothelial permeability. J. Appl.Physiol. 83(2): 615-622, 1997.-Adrenergic stimulation reduces albumin permeation across pulmonary artery endothelial monolayers and induces changes in cell morphology that aremediated by Cl flux. Wetested the hypothesis that anion-mediated changes in endothelial cellsresult in changes in endothelial permeability. We measured permeationof radiolabeled albumin across bovine pulmonary arterial endothelialmonolayers when the extracellular anion was Cl,Br,I,F, acetate(Ac), gluconate(G), and propionate(Pr). Permeability toalbumin (P_albumin)was calculated before and after addition of 0.2 mM of thephosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), whichreduces permeability. InCl, theP_albumin was 3.05 ± 0.86 × 10⁶ cm/s andfell by 70% with the addition of IBMX. The initialP_albumin was lowest forPr andAc. InitialP_albumin was higher inBr,I,G, andF than inCl. A permeability ratiowas calculated to examine the IBMX effect. The greatest IBMX effect wasseen when Cl was theextracellular anion, and the order among halide anions wasCl > Br > I > F. Although the level ofextracellular Ca²⁺ concentration([Ca²⁺]_o)varied over a wide range in the anion solutions,[Ca²⁺]_odid not systematically affect endothelial permeability in this system.When Cl was theextracellular anion, varying[Ca²⁺]_ofrom 0.2 to 2.8 mM caused a change in initialP_albumin but no changein the IBMX effect. The anion channel blockers4-acetamido-4-isothiocyanotostilbene-2,2-disulfonic acid(0.25 mM) and anthracene-9-carboxylic acid (0.5 mM) significantly altered initialP_albumin and the IBMXeffect. The anion transport blockers bumetanide (0.2 mM) and furosemide(1 mM) had no such effects. We conclude that extracellular anionsinfluence bovine pulmonary arterial endothelial permeability and thatthe pharmacological profile fits better with the activity of anionchannels than with other anion transport processes.

     

Determination of production of nitric oxide by lower airways of humans---theory

Hyde, Richard W., Edgar J. Geigel, Albert J. Olszowka, JohnA. Krasney, Robert E. Forster II, Mark J. Utell, and Mark W. Frampton.Determination of production of nitric oxide by the lower airwaysof humanstheory. J. Appl. Physiol.82(4): 1290-1296, 1997.Exercise and inflammatory lung disorderssuch as asthma and acute lung injury increase exhaled nitric oxide(NO). This finding is interpreted as a rise in production of NO by thelungs (NO)but fails to take into account the diffusing capacity for NO(DNO) that carries NO into thepulmonary capillary blood. We have derived equations to measureNO from thefollowing rates, which determine NO tension in the lungs(PL) at any moment from 1) production(NO);2) diffusion, whereDNO(PL) = rate of removal by lung capillary blood; and3) ventilation, whereA(PL)/(PB  47) = the rate of NO removal by alveolar ventilation(A) and PB is barometric pressure. During open-circuit breathingwhen PL is not in equilibrium,d/dtPL[V_L/(PB  47)] (where V_L is volumeof NO in the lower airways) = NO  DNO(PL)  A(PL)/(PB  47). When PL reaches asteady state so that d/dt = 0 andA iseliminated by rebreathing or breath holding, then PL = NO/DNO.PL can be interpreted as NOproduction per unit of DNO. Thisequation predicts that diseases that diminishDNO but do not alterNO willincrease expired NO levels. These equations permit precise measurementsof NO thatcan be applied to determining factors controlling NO production by thelungs.

     

Nitric oxide response in exhaled air during an incremental exhaustive exercise

Chirpaz-Oddou, M. F., A. Favre-Juvin, P. Flore, J. Eterradossi, M. Delaire, F. Grimbert, and A. Therminarias. Nitric oxide response in exhaled air during an incremental exhaustive exercise. J. Appl. Physiol. 82(4):1311-1318, 1997.This study examines the response of the exhalednitric oxide (NO) concentration (CNO) and the exhaled NOoutput(NO)during incremental exercise and during recovery in six sedentary women,seven sedentary men, and eight trained men. The protocolconsisted of increasing the exercise intensity by 30 W every 3 minuntil exhaustion, followed by 5 min of recovery. Minute ventilation(E), oxygen consumption (O₂), carbon dioxideproduction, heart rate, CNO, andNOwere measured continuously. TheCNO in exhaled air decreasedsignificantly provided that the exercise intensity exceeded 65% of thepeak O₂. It reached similarvalues, at exhaustion, in all three groups. TheNO increasedproportionally with exercise intensity up to exhaustion and decreasedrapidly during recovery. At exhaustion, the mean values weresignificantly higher for trained men than for sedentary men andsedentary women. During exercise,NOcorrelates well with O₂,carbon dioxide production, E, and heartrate. For the same submaximal intensity, and thus a givenO₂ and probably a similarcardiac output,NO appearedto be similar in all three groups, even if theE was different. These results suggestthat, during exercise,NO is mainlyrelated to the magnitude of aerobic metabolism and that thisrelationship is not affected by gender differences or by noticeabledifferences in the level of physical training.

     

Muscle capillarization, O2 diffusion distance, and VO2 kinetics in old and young individuals

Chilibeck, P. D., D. H. Paterson, D. A. Cunningham, A. W. Taylor, and E. G. Noble. Muscle capillarization,O₂ diffusion distance, andO₂ kinetics in old andyoung individuals. J. Appl. Physiol.82(1): 63-69, 1997.The relationships between muscle capillarization, estimated O₂diffusion distance from capillary to mitochondria, andO₂ uptake(O₂) kineticswere studied in 11 young (mean age, 25.9 yr) and 9 old (mean age, 66.0 yr) adults. O₂kinetics were determined by calculating the time constants () forthe phase 2 O₂ adjustment to andrecovery from the average of 12 repeats of a 6-min, moderate-intensityplantar flexion exercise. Muscle capillarization was determined fromcross sections of biopsy material taken from lateral gastrocnemius.Young and old groups had similarO₂ kinetics(O₂-on = 44 vs. 48 s;O₂-off = 33 vs. 44 s, for young and old, respectively), muscle capillarization, andestimated O₂ diffusion distances.Muscle capillarization, expressed as capillary density or averagenumber of capillary contacts per fiber/average fiber area, and theestimates of diffusion distance were significantly correlated toO₂-off kinetics in theyoung (r = 0.68 to 0.83;P < 0.05). We conclude that1) capillarization andO₂ kinetics during exerciseof a muscle group accustomed to everyday activity (e.g., walking) arewell maintained in old individuals, and2) in the young, recovery of O₂ after exercise isfaster, with a greater capillary supply over a given muscle fiber areaor shorter O₂ diffusion distances.

     

Combined heart rate and activity improve estimates of oxygen consumption and carbon dioxide production rates

Moon, Jon K., and Nancy F. Butte. Combined heart rateand activity improve estimates of oxygen consumption and carbon dioxideproduction rates. J. Appl. Physiol.81(4): 1754-1761, 1996.Oxygen consumption(O₂) andcarbon dioxide production (CO₂) rates were measuredby electronically recording heart rate (HR) and physical activity (PA).Mean daily O₂ andCO₂ measurements by HR andPA were validated in adults (n = 10 women and 10 men) with room calorimeters. Thirteen linear and nonlinear functions of HR alone and HR combined with PA were tested as models of24-h O₂ andCO₂. Mean sleepO₂ andCO₂ were similar to basalmetabolic rates and were accurately estimated from HR alone[respective mean errors were 0.2 ± 0.8 (SD) and0.4 ± 0.6%]. The range of prediction errorsfor 24-h O₂ andCO₂ was smallestfor a model that used PA to assign HR for each minute to separateactive and inactive curves(O₂, 3.3 ± 3.5%; CO₂, 4.6 ± 3%). There were no significant correlations betweenO₂ orCO₂ errors and subject age,weight, fat mass, ratio of daily to basal energy expenditure rate, orfitness. O₂,CO₂, and energy expenditurerecorded for 3 free-living days were 5.6 ± 0.9 ml ^· min^{1 ·} kg¹,4.7 ± 0.8 ml ^· min^{1 ·} kg¹,and 7.8 ± 1.6 kJ/min, respectively. Combined HR and PA measured 24-h O₂ andCO₂ with a precisionsimilar to alternative methods.

     

V/Q distribution and correlation to atelectasis in anesthetized paralyzed humans

Tokics, Leif, Göran Hedenstierna, Leif Svensson, BoBrismar, Torsten Cederlund, Hans Lundquist, and ÅkeStrandberg. / distributionand correlation to atelectasis in anesthetized paralyzed humans.J. Appl. Physiol. 81(4):1822-1833, 1996.Regional ventilation and perfusion were studiedin 10 anesthetized paralyzed supine patients by single-photon emissioncomputerized tomography. Atelectasis was estimated from twotransaxial computerized tomography scans. The ventilation-perfusion(/) distribution was alsoevaluated by multiple inert gas elimination. While the patients wereawake, inert gas / ratio wasnormal, and shunt did not exceed 1% in any patient. Computerizedtomography showed no atelectasis. During anesthesia, shunt ranged from0.4 to 12.2%. Nine patients displayed atelectasis (0.6-7.2% ofthe intrathoracic area), and shunt correlated with the atelectasis(r = 0.91, P < 0.001). Shunt was located independent lung regions corresponding to the atelectatic area. There wasconsiderable / mismatch, withventilation mainly of ventral lung regions and perfusion of dorsalregions. Little perfusion was seen in the most ventral parts (zone 1)of caudal (diaphragmatic) lung regions. In summary, shunt during anesthesia is due to atelectasis in dependent lung regions. The / distributions differ fromthose shown earlier in awake subjects.

     

Protein kinase C modulation of ventilatory response to hypoxia in nucleus tractus solitarii of conscious rats

This study aimedto determine the role of protein kinase C (PKC) in signal transductionmechanisms underlying ventilatory regulation in the nucleus tractussolitarii (NTS). Microinjection of phorbol 12-myristate 13-acetate intothe commissural NTS of nine chronically instrumented, unrestrained ratselicited significant cardiorespiratory enhancements that lasted for atleast 4 h, whereas administration of vehicle(n = 15) or the inactive phorbol ester 4-phorbol 12,13-didecanoate (n = 7)did not elicit minute ventilation (E)changes. Peak hypoxic Eresponses (10% O₂-balanceN₂) were measured in 19 additional animals after NTS microinjection of bisindolylmaleimide(BIM) I, a selective PKC inhibitor (n = 12), BIM V (inactive analog; n = 7),or vehicle (Con; n = 19). In Con,E increased from 139 ± 9 to 285 ± 26 ml/min in room air and hypoxia, respectively, and similarresponses occurred after BIM V. BIM I did not affect room airE but markedly attenuated hypoxia-induced E increases (128 ± 12 to 167 ± 18 ml/min; P < 0.02 vs. Con and BIM V). When BIM I was microinjected into the cerebellum(n = 4), cortex(n = 4), or spinal cord(n = 4),E responses were similar to Con.Western blots of subcellular fractions of dorsocaudal brain stemlysates revealed translocation of PKC, , , , , and  isoenzymes during acute hypoxia, and enhanced overall PKC activity wasconfirmed in the particulate fraction of dorsocaudal brain stem lysatesharvested after acute hypoxia. These studies suggest that, in the adultrat, PKC activation in the NTS mediates essential components of theacute hypoxic ventilatory response.

     

NO does not mediate inhibitory neural responses in sheep airway and bronchial vascular smooth muscle

Endogenous nitric oxide (NO) influences acetylcholine-inducedbronchovascular dilation in sheep and is a mediator of the airway smooth muscle inhibitory nonadrenergic, noncholinergic neural responsein several species. This study was designed to determine the importanceof NO as a neurally derived modulator of ovine airway and bronchialvascular smooth muscle. We measured the response of pulmonaryresistance (RL) and bronchialblood flow (br) to vagal stimulationin 14 anesthetized, ventilated, open-chest sheep duringthe following conditions: 1)control; 2) infusion of the -agonist phenylephrine to reduce baseline br bythe same amount as would be produced by infusion ofN-nitro-L-arginine(L-NNA), a NO synthaseinhibitor; 3) infusion ofL-NNA(10² M); and4) after administration of atropine(1.5 mg/kg). The results showed that vagal stimulation produced anincrease in RL andbr in periods 1, 2, and 3 (P < 0.01) that was not affected byL-NNA. Afteratropine was administered, there was no increase inbr or RL. Invitro experiments on trachealis smooth muscle contracted with carbachol showed no effect ofL-NNA on neural relaxation butshowed a complete blockade with propranolol(P < 0.01). In conclusion, thevagally induced airway smooth muscle contraction and bronchial vasculardilation are not influenced by NO, and the sheep's trachealis muscle,unlike that in several other species, does not have inhibitorynonadrenergic, noncholinergic innervation.

     

Interferon-gamma has immunomodulatory effects with minor endocrine and metabolic effects in humans

To evaluatewhether interferon- (IFN-) is involved in the interaction betweenthe immune and endocrine systems in vivo, we studied six healthysubjects twice in a placebo-controlled trial: once after administrationof recombinant human IFN- and, on another occasion, afteradministration of saline. The rate of appearance of glucose wasdetermined by infusion of[6,6-²H₂]glucoseand resting energy expenditure by indirect calorimetry. Human leukocyteantigen-DR gene expression on monocytes and serum neopterin increased after administration of IFN-(P < 0.05 vs. control). IFN-increased serum interleukin-6 levels significantly. Levels of tumornecrosis factor- remained below detection limits. IFN- increasedplasma concentrations of ACTH and cortisol(P < 0.05 vs. control), IFN- didnot alter concentrations of growth hormone,(nor)epinephrine, insulin, C peptide, glucagon, or insulin-like growthfactor I. IFN- did not alter plasma concentrations of glucose andfree fatty acids nor the rate of appearance of glucose. IFN-increased resting energy expenditure significantly. We conclude thatIFN- is a minor stimulator of the endocrine and metabolic pathways.Therefore, IFN- by itself is probably not a major mediator in theinteraction between the immune and the endocrine and metabolic systems.     

Influence of muscle fiber type and pedal frequency on oxygen uptake kinetics of heavy exercise

Barstow, Thomas J., Andrew M. Jones, Paul H. Nguyen, andRichard Casaburi. Influence of muscle fiber type and pedal frequency on oxygen uptake kinetics of heavy exercise.J. Appl. Physiol. 81(4):1642-1650, 1996.We tested the hypothesis that the amplitude ofthe additional slow component ofO₂ uptake(O₂) during heavy exerciseis correlated with the percentage of type II (fast-twitch) fibers inthe contracting muscles. Ten subjects performed transitions to a workrate calculated to require aO₂ equal to 50% betweenthe estimated lactate (Lac) threshold and maximalO₂ (50%).Nine subjects consented to a muscle biopsy of the vastus lateralis. Toenhance the influence of differences in fiber type among subjects,transitions were made while subjects were pedaling at 45, 60, 75, and90 rpm in different trials. Baseline O₂ was designed to besimilar at the different pedal rates by adjusting baseline work ratewhile the absolute increase in work rate above the baseline was thesame. The O₂ response after the onset of exercise was described by a three-exponential model. Therelative magnitude of the slow component at the end of 8-min exercisewas significantly negatively correlated with %type I fibers at everypedal rate (r = 0.64 to 0.83, P < 0.05-0.01). Furthermore,the gain of the fast component forO₂ (asml ^· min^{1 ·} W¹)was positively correlated with the %type I fibers across pedal rates(r = 0.69-0.83). Increase inpedal rate was associated with decreased relative stress of theexercise but did not affect the relationships between%fiber type and O₂parameters. The relative contribution of the slow component was alsosignificantly negatively correlated with maximalO₂(r = 0.65), whereas the gainfor the fast component was positively associated(r = 0.68-0.71 across rpm). Theamplitude of the slow component was significantly correlated with netend-exercise Lac at all four pedal rates(r = 0.64-0.84), but Lac was notcorrelated with %type I (P > 0.05).We conclude that fiber type distribution significantly affects both thefast and slow components ofO₂ during heavy exerciseand that fiber type and fitness may have both codependent andindependent influences on the metabolic and gas-exchange responses toheavy exercise.

     

Dissociation between hysteresivity and tension in constricted tracheal and parenchymal strips

The object of this study was to investigatehow changes in the contractile state of smooth muscle would modifyoscillatory mechanics of tracheal muscle and lung parenchyma duringagonist challenge. Guinea pig tracheal and parenchymal lung strips were suspended in an organ bath. Measurements of length(L) and tension (T) were recordedduring sinusoidal oscillations under baseline conditions and afterchallenge with 1 mM ACh. Measurements were also obtained in stripspretreated with the calmodulin inhibitor calmidazolium (Cmz) orstaurosporine (Stauro), a protein kinase C inhibitor. Elastance (E) andresistance (R) were calculated by fitting changes in T,L, andL/tto the equation of motion. Hysteresivity () was obtained from thefollowing equation: = (R/E)2f,where f is frequency. Finally, maximalunloaded shortening velocity during electrical field stimulation wasmeasured in Cmz-pretreated and control tracheal strips. In trachealstrips, pretreatment with Cmz caused a significant decrease in the  response to ACh challenge and in maximal unloaded shortening velocitymeasured during electrical field stimulation; Stauro decreased the T,E, and R response to ACh. In parenchymal strips, Cmz decreased the  response, whereas Stauro had no effect. These results suggest thatmodifications in the contractile state of the smooth muscle arereflected in changes in the hysteretic behavior and that T and  maybe controlled independently. Second, inasmuch as changes in  weresimilar in parenchymal and tracheal strips, the contractile element isimplicated as the structure responsible for constriction-induced changes in the mechanical behavior of the lung periphery.

     

Vascular tree structure affects lung blood flow heterogeneity simulated in three dimensions

Parker, James C., Chris B. Cave, Jeffrey L. Ardell, CharlesR. Hamm, and Susan G. Williams. Vascular treestructure affects lung blood flow heterogeneity simulated in threedimensions. J. Appl. Physiol. 83(4):1370-1382, 1997.Pulmonary arterial tree structures related toblood flow heterogeneity were simulated by using a symmetrical,bifurcating model in three-dimensional space. The branch angle (),daughter-parent length ratio(r_L), branchrotation angle (), and branch fraction of parent flow () for asingle bifurcation were defined and repeated sequentially through 11 generations. With  fixed at 90°, tree structures were generatedwith  between 60 and 90°,r_L between 0.65 and 0.85, and an initial segment length of 5.6 cm and sectioned into1-cm³ samples for analysis. Bloodflow relative dispersions (RD%) between 52 and 42% and fractaldimensions (D_s)between 1.20 and 1.15 in 1-cm³samples were observed even with equal branch flows. When  0.5, RD% increased, butD_s eitherdecreased with gravity bias of higher branch flows or increased withrandom assignment of higher flows. Blood flow gradients along gravityand centripetal vectors increased with biased flow assignment of higherflows, and blood flows correlated negatively with distance only when   0.5. Thus a recursive branching vascular tree structuresimulated D_s andRD% values for blood flow heterogeneity similar to those observedexperimentally in the pulmonary circulation due to differences in thenumber of terminal arterioles per1-cm³ sample, but blood flowgradients and a negative correlation of flows with distance requiredunequal partitioning of blood flows at branchpoints.

     

Human ventilatory response to 8h of euoxic hypercapnia

Tansley, John G., Michala E. F. Pedersen, Christine Clar,and Peter A. Robbins. Human ventilatory response to 8 h of euoxic hypercapnia. J. Appl.Physiol. 84(2): 431-434, 1998.Ventilation (E) risesthroughout 40 min of constant elevated end-tidalPCO₂ without reaching steady state(S. Khamnei and P. A. Robbins. Respir. Physiol. 81: 117-134, 1990). The present studyinvestigates 8 h of euoxic hypercapnia to determine whetherE reachessteady state within this time. Two protocols were employed:1) 8-h euoxic hypercapnia (end-tidalPCO₂ = 6.5 Torr above prestudy value,end-tidal PO₂ = 100 Torr) followed by 8-h poikilocapnic euoxia; and2) control, where the inspired gaswas air. Ewas measured over a 5-min period before the experiment and then hourly over a 16-h period. In the hypercapnia protocol,E had notreached a steady state by the first hour(P < 0.001, analysis of variance), but there were no further significant differences inEover hours 2-8 (analysis ofvariance). Efell promptly on return to eucapnic conditions. We conclude that,whereas there is a component of theE responseto hypercapnia that is slow, there is no progressive rise inE throughoutthe 8-h period.

     

Mitochondrial redox state as a potential detector of liver dysoxia in vivo

Dysoxia canbe defined as ATP flux decreasing in proportion toO₂ availability with preserved ATPdemand. Hepatic venous -hydroxybutyrate-to-acetoacetate ratio(-OHB/AcAc) estimates liver mitochondrial NADH/NAD and may detectthe onset of dysoxia. During partial dysoxia (as opposed to anoxia),however, flow may be adequate in some liver regions, diluting effluentfrom dysoxic regions, thereby rendering venous -OHB/AcAc unreliable.To address this concern, we estimated tissue ATP whilegradually reducing liver blood flow of swine to zero in a nuclearmagnetic resonance spectrometer. ATP flux decreasing withO₂ availability was taken asO₂ uptake(O₂) decreasing inproportion to O₂ delivery(O₂);and preserved ATP demand was taken as increasingP_i/ATP.O₂, tissueP_i/ATP, and venous -OHB/AcAcwere plotted againstO₂to identify critical inflection points. Tissue dysoxia required meanO₂for the group to be critical for bothO₂ and forP_i/ATP. CriticalO₂values for O₂ andP_i/ATP of 4.07 ± 1.07 and 2.39 ± 1.18 (SE) ml · 100 g¹ · min¹,respectively, were not statistically significantly different but notclearly the same, suggesting the possibility that dysoxia might havecommenced after O₂ begandecreasing, i.e., that there could have been"O₂ conformity." CriticalO₂for venous -OHB/AcAc was 2.44 ± 0.46 ml · 100 g¹ · min¹(P = NS), nearly the same as that forP_i/ATP, supporting venous -OHB/AcAc as a detector of dysoxia. All issues considered, tissue mitochondrial redox state seems to be an appropriate detector ofdysoxia in liver.

     

Gas exchange and cardiovascular kinetics with different exercise protocols in heart transplant recipients

Grassi, Bruno, Claudio Marconi, Michael Meyer, Michel Rieu,and Paolo Cerretelli. Gas exchange and cardiovascular kinetics with different exercise protocols in heart transplant recipients. J. Appl. Physiol. 82(6): 1952-1962, 1997.Metabolicand cardiovascular adjustments to various submaximal exercises wereevaluated in 82 heart transplant recipients (HTR) and in 35 controlsubjects (C). HTR were tested 21.5 ± 25.3 (SD) mo (range1.0-137.1 mo) posttransplantation. Three protocols were used:protocol A consisted of 5 min of rectangular 50-W load repeatedtwice, 5 min apart [5 min rest, 5 min 50 W (Ex 1), 5 minrecovery, 5 min 50 W (Ex 2)]; protocol B consistedof 5 min of rectangular load at 25, 50, or 75 W; protocol Cconsisted of 15 min of rectangular load at 25 W. Breath-by-breathpulmonary ventilation (E),O₂ uptake (O₂),and CO₂ output(CO₂) were determined.During protocol A, beat-by-beat cardiacoutput () was estimated by impedance cardiography. The half times (t_1/2) of the on- andoff-kinetics of the variables were calculated. In all protocols,t_1/2 values forO₂ on-,E on-, andCO₂ on-kinetics were higher(i.e., the kinetics were slower) in HTR than in C, independently ofworkload and of the time posttransplantation. Also,t_1/2 on- was higher in HTRthan in C. In protocol A, no significant difference of t_1/2 O₂on- was observed in HTR between Ex 1 (48 ± 9 s) and Ex2 (46 ± 8 s), whereas t_1/2 on- was higher during Ex 1 (55 ± 24 s)than during Ex 2 (47 ± 15 s). In all protocols and for all variables, the t_1/2 off-values were higher in HTRthan in C. In protocol C, no differences of steady-stateE,O₂, andCO₂ were observed in bothgroups between 5, 10, and 15 min of exercise. We conclude that1) in HTR, a "priming" exercise, while effective inspeeding up the adjustment of convective O₂ flow to muscle fibers during a second on-transition, did not affect theO₂ on-kinetics, suggestingthat the slower O₂ on- inHTR was attributable to peripheral (muscular) factors; 2) thedissociation between on- andO₂ on-kinetics in HTRindicates that an inertia of muscle metabolic machinery is the mainfactor dictating theO₂ on-kinetics; and 3) theO₂ off-kinetics was slowerin HTR than in C, indicating a greater alactic O₂ deficitin HTR and, therefore, a sluggish muscleO₂ adjustment.

     

Effects of nitric oxide on blood flow distribution and O2 extraction capabilities during endotoxic shock

Zhang, Haibo, Peter Rogiers, Nadia Smail, Ana Cabral,Jean-Charles Preiser, Marie-Odile Peny, and Jean-Louis Vincent.Effects of nitric oxide on blood flow distribution andO₂ extraction capabilities duringendotoxic shock. J. Appl. Physiol.83(4): 1164-1173, 1997.The effects of the nitric oxide (NO)synthase inhibitorN^G-monomethyl-L-arginine(L-NMMA) and the NO donor3-morpholinosydnonimine (SIN-1) were tested in 18 endotoxic dogs. L-NMMA infusion(10 mg · kg¹ · h¹)increased arterial and pulmonary artery pressures and systemic andpulmonary vascular resistances but decreased cardiac index, leftventricular stroke work index, and blood flow to the hepatic, portal,mesenteric, and renal beds. SIN-1 infusion (2 µg · kg¹ · min¹)increased cardiac index; left ventricular stroke work index; andhepatic, portal, and mesenteric blood flow. It did not significantly influence arterial and pulmonary artery pressures but decreased renalblood flow. The critical O₂delivery was similar in the L-NMMA group and in the controlgroup (13.3 ± 1.6 vs. 12.8 ± 3.3 ml · kg¹ · min¹)but lower in the SIN-1 group (9.1 ± 1.8 ml · kg¹ · min¹,both P < 0.05). The criticalO₂ extraction ratio was alsohigher in the SIN-1 group than in the other groups (58.7 ± 10.6 vs.42.2 ± 7.6% in controls, P < 0.05; 43.0 ± 15.5% inL-NMMA group,P = not significant). We conclude thatNO is not implicated in the alterations inO₂ extraction capabilitiesobserved early after endotoxin administration.

     

Susceptibility to periodic breathing with assisted ventilation during sleep in normal subjects

Assisted ventilation with pressure support (PSV)or proportional assist (PAV) ventilation has the potential to produceperiodic breathing (PB) during sleep. We hypothesized that PB willdevelop when PSV level exceeds the product of spontaneous tidal volume (VT) and elastance(VT_sp · E)but that the actual level at which PB will develop[PSV(PB)] will be influenced by thePCO₂ (difference between eupneicPCO₂ andCO₂ apneic threshold) and by RR[response of respiratory rate (RR) to PSV]. We also wishedto determine the PAV level at which PB develops to assess inherentventilatory stability in normal subjects. Twelve normal subjectsunderwent polysomnography while connected to a PSV/PAV ventilatorprototype. Level of assist with either mode was increased in smallsteps (2-5 min each) until PB developed or the subject awakened.End-tidal PCO₂,VT, RR, and airway pressure (Paw) were continuously monitored, and the pressure generated byrespiratory muscle (Pmus) was calculated. The pressure amplification factor (PAF) at the highest PAV level was calculated from[(Paw + Pmus)/Pmus], where Paw is peak Paw  continuous positive airway pressure. PB with central apneas developedin 11 of 12 subjects on PSV. PCO₂ranged from 1.5 to 5.8 Torr. Changes in RR with PSV were small andbidirectional (+1.1 to 3.5min¹). With use ofstepwise regression, PSV(PB) was significantly correlated withVT_sp(P = 0.001), E(P = 0.00009),PCO₂ (P = 0.007), and RR(P = 0.006). The final regressionmodel was as follows: PSV(PB) = 11.1 VT_sp + 0.3E  0.4 PCO₂  0.34 RR  3.4 (r = 0.98). PBdeveloped in five subjects on PAV at amplification factors of1.5-3.4. It failed to occur in seven subjects, despite PAF of upto 7.6. We conclude that 1) aPCO₂ apneic threshold exists duringsleep at 1.5-5.8 Torr below eupneicPCO₂,2) the development of PB during PSVis entirely predictable during sleep, and3) the inherent susceptibility to PBvaries considerably among normal subjects.