Role of tachykinins in ozone-induced airway hyperresponsiveness to cigarette smoke in guinea pigs

Wu, Zhong-Xin, Robert F. Morton, and Lu-Yuan Lee. Roleof tachykinins in ozone-induced airway hyperresponsiveness to cigarettesmoke in guinea pigs. J. Appl.Physiol. 83(3): 958-965, 1997.Acute exposure to ozone(O₃) induces airwayhyperresponsiveness to various inhaled bronchoactive substances.Inhalation of cigarette smoke, a common inhaled irritant in humans, isknown to evoke a transient bronchoconstrictive effect. To examinewhether O₃ increases airwayresponsiveness to cigarette smoke, effects of smoke inhalationchallenge on total pulmonary resistance(RL) and dynamic lungcompliance (Cdyn) were compared before and after exposure toO₃ (1.5 ppm, 1 h) in anesthetizedguinea pigs. Before O₃ exposure,inhalation of two breaths of cigarette smoke (7 ml) at a lowconcentration (33%) induced a mild and reproduciblebronchoconstriction that slowly developed and reached its peak(RL = 67 ± 19%, Cdyn = 29 ± 6%) after a delay of >1 min. After exposure toO₃ the same cigarette smokeinhalation challenge evoked an intense bronchoconstriction thatoccurred more rapidly, reaching its peak(RL = 620 ± 224%, Cdyn = 35 ± 7%) within 20 s, and was sustained for >2min. By contrast, sham exposure to room air did not alter thebronchomotor response to cigarette smoke challenge. Pretreatment withCP-99994 and SR-48968, the selective antagonists of neurokinin type 1 and 2 receptors, respectively, completely blocked the enhancedresponses of RL and Cdyn tocigarette smoke challenge induced byO₃. These results show thatO₃ exposure induces airwayhyperresponsiveness to inhaled cigarette smoke and that the enhancedresponses result primarily from the bronchoconstrictive effect ofendogenous tachykinins.

     

Association of chest wall motion and tidal volume responses during CO2 rebreathing

Yan, Sheng, Pawel Sliwinski, and Peter T. Macklem.Association of chest wall motion and tidal volume responses during CO₂ rebreathing.J. Appl. Physiol. 81(4):1528-1534, 1996.The purpose of this study is to investigate theeffect of chest wall configuration at end expiration on tidal volume(VT) response duringCO₂ rebreathing. In a group of 11 healthy male subjects, the changes in end-expiratory andend-inspiratory volume of the rib cage (Vrc,E andVrc,I, respectively) and abdomen (Vab,E and Vab,I, respectively) measured by linearizedmagnetometers were expressed as a function of end-tidalPCO₂(PET_CO2). The changes inend-expiratory and end-inspiratory volumes of the chest wall(Vcw,E and Vcw,I,respectively) were calculated as the sum of the respectiverib cage and abdominal volumes. The magnetometer coils were placed atthe level of the nipples and 1-2 cm above the umbilicus andcalibrated during quiet breathing against theVT measured from apneumotachograph. TheVrc,E/PET_CO2 slope was quite variable among subjects. It was significantly positive (P < 0.05) in fivesubjects, significantly negative in four subjects(P < 0.05), and not different fromzero in the remaining two subjects. TheVab,E/PET_CO2slope was significantly negative in all subjects(P < 0.05) with a much smallerintersubject variation, probably suggesting a relatively more uniformrecruitment of abdominal expiratory muscles and a variable recruitmentof rib cage muscles during CO₂rebreathing in different subjects. As a group, the meanVrc,E/PET_CO2,Vab,E/PET_CO2, andVcw,E/PET_CO2slopes were 0.010 ± 0.034, 0.030 ± 0.007, and0.020 ± 0.032 l / Torr, respectively;only theVab,E/PET_CO2 slope was significantly different from zero. More interestingly, theindividualVT/PET_CO2slope was negatively associated with theVrc,E/PET_CO2(r = 0.68,P = 0.021) and Vcw,E/PET_CO2slopes (r = 0.63,P = 0.037) but was not associated withtheVab,E/PET_CO2slope (r = 0.40, P = 0.223). There was no correlation oftheVrc,E/PET_CO2 andVcw,E/PET_CO2slopes with age, body size, forced expiratory volume in 1 s, orexpiratory time. The groupVab,I/PET_CO2 slope (0.004 ± 0.014 l / Torr) was not significantlydifferent from zero despite theVT nearly being tripled at theend of CO₂ rebreathing. Inconclusion, the individual VTresponse to CO₂, althoughindependent of Vab,E, is a function ofVrc,E to the extent that as theVrc,E/PET_CO2slope increases (more positive) among subjects, theVT response toCO₂ decreases. These results maybe explained on the basis of the respiratory muscle actions andinteractions on the rib cage.

     

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.

     

Genome and Hormones: Gender Differences in Physiology: Selected Contribution: Estrogen receptor-alpha gene transfer inhibits proliferation and NF-kappa B activation in VSM cells from female rats

Epidemiological studies have demonstrated that hormonereplacement therapy with estrogen (E₂) or E₂plus progesterone in postmenopausal women decreases the age-associatedrisk of cardiovascular disease by 30-50%. Treatment of vascularsmooth muscle (VSM) cells with physiological concentrations ofE₂ has been shown to inhibit growth factor-stimulated cellproliferation. In this study, we tested the hypothesis thatE₂ inhibits the age-associated increase in VSM cellproliferation by inhibiting nuclear factor (NF)-B pathway. Weinvestigated the effects of E₂ treatment andadenovirus-mediated estrogen receptor (ER)- gene transfer on cellproliferation and NF-B activation using VSM cells cultured from3-mo-old and 24-mo-old Fischer 344 female rats. Our results demonstratethat VSM cell proliferation was significantly increased(P < 0.05) in aged compared with young adult femalerats. Treatment of VSM cells with physiological concentrations ofE₂ inhibited VSM cell proliferation, and this inhibitionwas significantly greater (P < 0.05) in cells from aged female rats compared with young adults. The inhibitory effects ofE₂ on cell proliferation in aged female rats weresignificantly potentiated by overexpression of the human ER- geneinto VSM cells. Constitutive and interleukin (IL)-1-stimulatedNF-B activation was significantly greater (P < 0.05) in VSM cells from aged compared with young female rats.E₂ treatment of VSM cells from aged female rats inhibitedboth constitutive and IL-1-stimulated NF-B activation. ER-gene transfer into VSM cells from aged female rats further augmentedthe inhibitory effects of E₂. In conclusion, our data demonstrate that constitutive and IL-1-stimulated NF-B activation is increased in VSM cells from aged female rats due to loss of E₂ and this can be restored back to normal levels by ER-gene transfer and E₂ treatment. In addition, increasedNF-B signaling may be responsible for increased incidence ofcardiovascular disease in postmenopausal females.

     

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.

     

Mechanical and metabolic determination of VO2 and fatigue during repetitive isometric contractions in situ

Repetitiveisometric tetanic contractions (1/s) of the caninegastrocnemius-plantaris muscle were studied either at optimal length(L_o) or shortlength (L_s;~0.9 · L_o),to determine the effects of initial length on mechanical and metabolicperformance in situ. Respective averages of mechanical and metabolicvariables were(L_o vs.L_s, allP < 0.05) passive tension (preload) = 55 vs. 6 g/g, maximal active tetanic tension(P_o) = 544 vs. 174 (0.38 · P_o)g/g, maximal blood flow () = 2.0 vs. 1.4 ml · min¹ · g¹,and maximal oxygen uptake(O₂) = 12 vs. 9 µmol · min¹ · g¹.Tension at L_odecreased to0.64 · P_o over20 min of repetitive contractions, demonstrating fatigue; there were nosignificant changes in tension atL_s. In separatemuscles contracting atL_o, was set to that measured atL_s (1.1 ml · min¹ · g¹),resulting in decreased O₂(7 µmol · min¹ · g¹),and rapid fatigue, to0.44 · P_o. Thesedata demonstrate that 1)muscles at L_ohave higher andO₂ values than those at L_s;2) fatigue occurs atL_o with highO₂, adjusting metabolic demand (tension output) to match supply; and3) the lack of fatigue atL_s with lowertension, , andO₂ suggestsadequate matching of metabolic demand, set low by shortmuscle length, with supply optimized by low preload. Thesedifferences in tension andO₂ betweenL_o andL_s groupsindicate that muscles contracting isometrically at initial lengthsshorter than L_oare working under submaximal conditions.

     

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.

     

Respiratory muscle work compromises leg blood flow during maximal exercise

Harms, Craig A., Mark A. Babcock, Steven R. McClaran, DavidF. Pegelow, Glenn A. Nickele, William B. Nelson, and Jerome A. Dempsey.Respiratory muscle work compromises leg blood flow during maximalexercise. J. Appl. Physiol.82(5): 1573-1583, 1997.We hypothesized that duringexercise at maximal O₂ consumption (O_{2 max}),high demand for respiratory muscle blood flow() would elicit locomotor muscle vasoconstrictionand compromise limb . Seven male cyclists(O_{2 max} 64 ± 6 ml · kg¹ · min¹)each completed 14 exercise bouts of 2.5-min duration atO_{2 max} on a cycleergometer during two testing sessions. Inspiratory muscle work waseither 1) reduced via aproportional-assist ventilator, 2)increased via graded resistive loads, or3) was not manipulated (control).Arterial (brachial) and venous (femoral) blood samples, arterial bloodpressure, leg (legs;thermodilution), esophageal pressure, andO₂ consumption(O₂) weremeasured. Within each subject and across all subjects, at constantmaximal work rate, significant correlations existed(r = 0.74-0.90;P < 0.05) between work of breathing(Wb) and legs (inverse), leg vascular resistance (LVR), and leg O₂(O_{2 legs};inverse), and between LVR and norepinephrine spillover. Mean arterialpressure did not change with changes in Wb nor did tidal volume orminute ventilation. For a ±50% change from control in Wb,legs changed 2 l/min or 11% of control, LVRchanged 13% of control, and O₂extraction did not change; thusO_{2 legs}changed 0.4 l/min or 10% of control. TotalO_{2 max} was unchangedwith loading but fell 9.3% with unloading; thusO_{2 legs}as a percentage of totalO_{2 max} was 81% incontrol, increased to 89% with respiratory muscle unloading, anddecreased to 71% with respiratory muscle loading. We conclude that Wbnormally incurred during maximal exercise causes vasoconstriction inlocomotor muscles and compromises locomotor muscle perfusion andO₂.

     

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.

     

PGE1, dexamethasone, U-74389G, or Bt2-cAMP as an additive to promote protection by UW solution in I/R injury

Chiang, Chi-Huei, Kang Hsu, Horng-Chin Yan, Horng-Jyh Harn,and Deh-Ming Chang.PGE₁, dexamethasone,U-74389G, or Bt₂-cAMP as anadditive to promote protection by UW solution in I/R injury. J. Appl. Physiol. 83(2): 583-590, 1997.A method to reduce ischemia-reperfusion (I/R) injury can be animportant criterion to improve the preservation solution. AlthoughUniversity of Wisconsin solution (UW) works as a lung preservationsolution, its attenuation effect on I/R injury has not beeninvestigated. We attempted to determine whether, by adding variousprotective agents, modified UW solutions will enhance the I/Rattenuation by UW. We examined the I/R injury in an isolated rat lungmodel. Various solutions, e.g., physiological salt solution (PSS), UW,and modified UW solutions containing various protective agents such asprostaglandin E₁, dexamethasone, U-74389G, or dibutyryl adenosine 3,5-cyclic monophosphatewere perfused individually to evaluate the I/R injury. Isolated rat lung experiments, with ischemia for 45 min, then reperfusion for 60 min, were conducted in a closed circulating system.Hemodynamic changes, lung weight gain (LWG), capillary filtrationcoefficient (K_fc), proteincontent of lavage fluid, concentration of cytokines, and lunghistopathology were analyzed. Results showed that the acute I/R lunginjury with immediate permeability pulmonary edema was associated withan increase in tumor necrosis factor- (TNF-) production. A significant correlation existed betweenTNF- and K_fc(r = 0.8, P < 0.0001) and TNF- and LWG(r = 0.9, P < 0.0001), indicatingthat TNF- is an important cytokine modulating early I/R injury.Significantly lower levels ofK_fc, LWG,TNF-, and protein concentration of lung lavage(P < 0.05) were found in theUW-perfused group than in the control group perfused with PSS. ModifiedUW promoted the protective effect of UW to further decreaseK_fc, LWG, andTNF- (P < 0.05).Histopathological observations also substantiated this evidence. In theUW+U-74389G group, bronchial alveolar lavage fluid contained lowestprotein concentration. We conclude that the UW solution attenuates I/Rinjury of rat lung and that the modified UW solutions further enhancethe effect of UW in reducing I/R injury. Among modified solutions,UW+U-74389G is the best. Further investigation of the improved effectsof the modified UW solutions would be beneficial in lungtransplantation.

     

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 .

     

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.

     

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.

     

Changes in maximum oxygen uptake during prolonged training, overtraining, and detraining in horses

Tyler, Catherine M., Lorraine C. Golland, David L. Evans,David R. Hodgson, and Reuben J. Rose. Changes in maximum oxygenuptake during prolonged training, overtraining, and detraining inhorses. J. Appl. Physiol. 81(5):2244-2249, 1996.Thirteen standardbred horses were trained asfollows: phase 1 (endurance training, 7 wk),phase 2 (high-intensity training, 9 wk),phase 3 (overload training, 18 wk), andphase 4 (detraining, 12 wk). Inphase 3, the horses were divided intotwo groups: overload training (OLT) and control (C). The OLT groupexercised at greater intensities, frequencies, and durations than groupC. Overtraining occurred after 31 wk of training and was defined as asignificant decrease in treadmill run time in response to astandardized exercise test. In the OLT group, there was a significantdecrease in body weight (P < 0.05).From pretraining values of 117 ± 2 (SE)ml ^· kg^{1 ·} min¹,maximal O₂ uptake(O_{2 max}) increased by15% at the end of phase 1, and when signs of overtraining werefirst seen in the OLT group,O_{2 max} was 29%higher (151 ± 2 ml ^· kg^{1 ·} min¹in both C and OLT groups) than pretraining values. There was nosignificant reduction inO_{2 max} until after 6 wk detraining whenO_{2 max} was 137 ± 2 ml ^· kg^{1 ·} min¹.By 12 wk detraining, meanO_{2 max} was134 ± 2 ml ^· kg^{1 ·} min¹,still 15% above pretraining values. When overtraining developed, O_{2 max} was notdifferent between C and OLT groups, but maximal values forCO₂ production (147 vs. 159 ml ^· kg^{1 ·} min¹)and respiratory exchange ratio (1.04 vs. 1.11) were lower in the OLTgroup. Overtraining was not associated with a decrease inO_{2 max} and, afterprolonged training, decreases inO_{2 max} occurredslowly during detraining.

     

Oxygen transport in conscious newborn dogs during hypoxic hypometabolism

We questioned whether the decrease inO₂ consumption(O₂) during hypoxia innewborns is a regulated response or reflects a limitation inO₂ availability. Experiments wereconducted on previously instrumented conscious newborn dogs.O₂ was measured at a warmambient temperature (30°C, n = 7)or in the cold (20°C, n = 6),while the animals breathed air or were sequentially exposed to 15 minof fractional inspired O₂(FI_O2): 21, 18, 15, 12, 10, 8, and 6%. In normoxia,O₂ averaged 15 ± 1 (SE)and 25 ± 1 ml · kg¹ · min¹in warm and cold conditions, respectively. In the warmcondition, hypometabolism (i.e., hypoxicO₂ < normoxicO₂) occurred at FI_O2 10%, whereas in thecold condition, hypometabolism occurred atFI_O2 12%. The sameresults were obtained in a separate group(n = 14) of noninstrumented puppies.For all levels of FI_O2 withhypometabolism, the relationships between measures ofO₂ availability (arterialO₂ saturation or content, venousPO₂ or saturation,x-axis) vs.O₂(y-axis) had lower slopes in warm than in coldconditions. Hence, O₂ during hypometabolism in the warm condition was not the maximal attainable for the level of oxygenation. The results do not support thepossibility that the hypoxic drop inO₂ in the newborn reflects a limitation in O₂availability. The results are compatible with the ideathat the phenomenon is one of "regulated conformism" tohypoxia.

     

Faster adjustment of O2 delivery does not affect VO2 on-kinetics in isolated in situ canine muscle

The mechanism(s)limiting muscle O₂ uptake(O₂) kinetics wasinvestigated in isolated canine gastrocnemius muscles(n = 7) during transitions from restto 3 min of electrically stimulated isometric tetanic contractions(200-ms trains, 50 Hz; 1 contraction/2 s; 60-70% of peakO₂). Two conditions weremainly compared: 1) spontaneousadjustment of blood flow () [control, spontaneous (C Spont)]; and2) pump-perfused, adjusted ~15 s before contractions at aconstant level corresponding to the steady-state value duringcontractions in C Spont [faster adjustment ofO₂ delivery (FastO₂ Delivery)]. During FastO₂ Delivery, 1-2 ml/min of10² M adenosine wereinfused intra-arterially to prevent inordinate pressure increases withthe elevated . The purpose of the study was todetermine whether a faster adjustment ofO₂ delivery would affectO₂ kinetics. was measured continuously; arterial(Ca_O2) and popliteal venous(Cv_O2)O₂ contents were determined atrest and at 5- to 7-s intervals during contractions;O₂ delivery was calculated as · Ca_O2,and O₂ was calculated as · arteriovenous O₂ content difference. Times toreach 63% of the difference between baseline and steady-stateO₂ during contractions were23.8 ± 2.0 (SE) s in C Spont and 21.8 ± 0.9 s in FastO₂ Delivery (not significant). Inthe present experimental model, elimination of any delay inO₂ delivery during therest-to-contraction transition did not affect muscleO₂ kinetics, which suggeststhat this kinetics was mainly set by an intrinsic inertia of oxidativemetabolism.

     

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.

     

Effects of respiratory muscle work on cardiac output and its distribution during maximal exercise

We have recently demonstrated that changes inthe work of breathing during maximal exercise affect leg blood flow andleg vascular conductance (C. A. Harms, M. A. Babcock, S. R. McClaran, D. F. Pegelow, G. A. Nickele, W. B. Nelson, and J. A. Dempsey. J. Appl. Physiol. 82: 1573-1583,1997). Our present study examined the effects of changesin the work of breathing on cardiac output (CO) during maximalexercise. Eight male cyclists [maximalO₂ consumption(O_{2 max}):62 ± 5 ml · kg¹ · min¹]performed repeated 2.5-min bouts of cycle exercise atO_{2 max}. Inspiratorymuscle work was either 1) at controllevels [inspiratory esophageal pressure (Pes): 27.8 ± 0.6 cmH₂O],2) reduced via a proportional-assistventilator (Pes: 16.3 ± 0.5 cmH₂O), or 3) increased via resistive loads(Pes: 35.6 ± 0.8 cmH₂O).O₂ contents measured in arterialand mixed venous blood were used to calculate CO via the direct Fickmethod. Stroke volume, CO, and pulmonaryO₂ consumption(O₂) were not different(P > 0.05) between control andloaded trials atO_{2 max} but were lower(8, 9, and 7%, respectively) than control withinspiratory muscle unloading atO_{2 max}. Thearterial-mixed venous O₂difference was unchanged with unloading or loading. We combined thesefindings with our recent study to show that the respiratory muscle work normally expended during maximal exercise has two significant effectson the cardiovascular system: 1) upto 14-16% of the CO is directed to the respiratory muscles; and2) local reflex vasoconstriction significantly compromises blood flow to leg locomotor muscles.

     

Scaling of submaximal oxygen uptake with body mass and combined mass during uphill treadmill bicycling

This study examined the scaling relationships ofnet O₂ uptake [O_2(net) = O₂  restingO₂] to body mass(M_B) andcombined mass (M_C = M_B + bicycle)during uphill treadmill bicycling. It was hypothesized thatO_2(net)(l/min) would scale proportionally withM_C [i.e.,O_2(net)  M^1.0_C] and less than proportionally withM_B [i.e.,O_2(net)  M_B].Twenty-five competitive cyclists [73.9 ± 8.8 and 85.0 ± 9.0 (SD) kg forM_B andM_C,respectively] rode their bicycles on a treadmill at 3.46 m/s andgrades of 1.7, 3.5, 5.2, and 7.0% whileO₂ was measured. Multiplelog-linear regression procedures were applied to the pooledO_2(net)data to determine the exponents forM_C andM_B afterstatistically controlling for differences in treadmill grade anddynamic friction. The regression models were highly significant (R² = 0.95, P < 0.001). Exponents forM_C (0.99, 95%confidence interval = 0.80-1.18) andM_B (0.89, 95%confidence interval = 0.72-1.07) did not differ significantly fromeach other or 1.0. It was concluded that the 0.99 M_C exponent wasdue to gravitational resistance, whereas theM_B exponent was<1.0 because the bicycles were relatively lighter for heaviercyclists.

     

Urethan anesthesia protects rats against lethal endotoxemia and reduces TNF-alpha release

Kotanidou, Anastasia, Augustine M. K. Choi, Richard A. Winchurch, Leo Otterbein, and Henry E. Fessler. Urethan anesthesia protects rats against lethal endotoxemia and reduces TNF- release. J. Appl. Physiol. 81(5):2304-2311, 1996.Urethan is a commonly used animalanesthetic for nonrecovery laboratory surgery. However, urethan hasdiverse biological effects that may complicate the interpretation ofexperimental findings. This study examined the effect of urethan on theresponse to an intravenous bolus of lipopolysaccharide (LPS; 30 mg/kg)in rats. In instrumented rats, urethan (1.2 gm/kg ip) completelyprevented the fall in arterial pressure immediately after LPSadministration but did not prevent late cardiovascular collapse. Inuninstrumented rats, urethan also attenuated indexes of organ injurymeasured 4 h after LPS administration, including mural bowelhemorrhage, hemoconcentration, hypoglycemia, metabolic acidosis, andlung myeloperoxidase activity, a measure of neutrophil sequestration.The peak increase in tumor necrosis factor- (TNF-) 90 min afterLPS administration was reduced 88% by urethan (2,060 ± 316 vs.16,934 ± 847 pg/ml; P < 0.001).In uninstrumented animals, urethan at 1.2 gm/kg reduced the 90%mortality rate of a lethal dose of LPS to 0-10% whengiven up to 24 h before LPS administration but did not reduce mortalitywhen given 2 h after LPS. Urethan neither directly bound LPS byLimulus assay nor inhibitedLPS-stimulated TNF- mRNA expression in cultured mouse peritonealmacrophages, but TNF- mRNA expression was suppressed by serum from aurethan-treated rat. Moreover, rauwolscine, which shares₂-adrenoceptor-blocking activity with urethan, also prevented death from a subsequent 90% lethal dose LPS bolus. We conclude that urethan or its metabolites protect against LPS, in part, by reducing TNF- release andspeculate that this may be mediated by₂-adrenoceptors. These actionsof urethan make it an undesirable anesthetic agent for in vivo studies of sepsis or LPS.