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.

     

Physiological and Genomic Consequences of Intermittent Hypoxia: Selected Contribution: Chemoreflex responses to CO2 before and after an 8-h exposure to hypoxia in humans

The ventilatorysensitivity to CO₂, in hyperoxia, is increased after an 8-hexposure to hypoxia. The purpose of the present study was to determinewhether this increase arises through an increase in peripheral orcentral chemosensitivity. Ten healthy volunteers each underwent 8-hexposures to 1) isocapnic hypoxia, with end-tidalPO₂ (PET_O2) = 55 Torr and end-tidal PCO₂(PET_CO2) = eucapnia; 2)poikilocapnic hypoxia, with PET_O2 = 55 Torr and PET_CO2 = uncontrolled;and 3) air-breathing control. The ventilatory response toCO₂ was measured before and after each exposure with theuse of a multifrequency binary sequence with two levels of PET_CO2: 1.5 and 10 Torr above the normalresting value. PET_O2 was held at 250 Torr.The peripheral (Gp) and the central (Gc) sensitivities were calculatedby fitting the ventilatory data to a two-compartment model. There wereincreases in combined Gp + Gc (26%, P < 0.05),Gp (33%, P < 0.01), and Gc (23%, P = not significant) after exposure to hypoxia. There were no significant differences between isocapnic and poikilocapnic hypoxia. We conclude that sustained hypoxia induces a significant increase inchemosensitivity to CO₂ within the peripheral chemoreflex.

     

Differences between estimates and measured PaCO2 during rest and exercise in older subjects

Williams, J. S., and T. G. Babb. Differences betweenestimates and measured Pa_CO2 during restand exercise in older subjects. J. Appl.Physiol. 83(1): 312-316, 1997.ArterialPCO₂ (Pa_CO2) has been estimated duringexercise with good accuracy in younger individuals by using the Jonesequation(P_JCO₂)(J. Appl. Physiol. 47: 954-960,1979). The purpose of this project was to determine the utility ofestimating Pa_CO2 from end-tidal PCO₂(PET_CO2) orP_JCO₂at rest, ventilatory threshold (Th), and maximalexercise (Max) in older subjects. PET_CO2 was determined fromrespired gases simultaneously (MGA 1100) with arterial blood gases(radial arterial catheter) in 12 older and 11 younger subjects at restand during exercise. Mean differences were analyzed with pairedt-tests, and relationships between theestimated Pa_CO2 values and the actualvalues of Pa_CO2 were determined withcorrelation coefficients. In the older subjects, PET_CO2 was not significantlydifferent from Pa_CO2 at rest (1.2 ± 4.3 Torr), Th (0.4 ± 2.5), or Max(0.8 ± 2.7), and the two were significantly(P < 0.05) correlated atth (r = 0.84) andMax (r = 0.87) but not atrest (r = 0.47).P_JCO₂was similar to Pa_CO2 at rest (1.0 ± 3.9) and th (1.3 ± 2.3) but significantly lower at Max (3.0 ± 2.6), and the two weresignificantly correlated at th(r = 0.86) and Max(r = 0.80) but not at rest (r = 0.54).PET_CO2 was significantlyhigher than Pa_CO2 during exercise in theyounger subjects but similar to Pa_CO2 at rest.P_JCO₂was similar to Pa_CO2 at rest andth but significantly lower at Max in youngersubjects. In conclusion, our data demonstrate thatPa_CO2 during exercise is betterestimated by PET_CO2 than byP_JCO₂in older subjects, contrary to what is observed in younger subjects.This appears to be related to the finding thatPET_CO2 does not exceedPa_CO2 during exercise in older subjects,as occurs in the younger subjects. However,Pa_CO2 at rest is best estimated byP_JCO₂in both younger and older subjects.

     

Apneic threshold for CO2 in the anesthetized rat: fundamental properties under steady-state conditions

Experiments were performed to measure the apneicthreshold for CO₂ and itsfundamental properties in anesthetized rats under steady-stateconditions. Breathing was detected from diaphragmatic electromyogramactivity. Mechanical hyperventilation resulted in apnea once arterialPCO₂(Pa_CO2) had fallen farenough. Apnea was not a reflex response to lung inflationbecause it did not occur immediately, was not prevented by vagotomy,and was reversed by raising Pa_CO2without changing mechanical hyperventilation. The apneic threshold wasmeasured by hyperventilating rats mechanically withO₂ until apnea had occurred andthen raising Pa_CO2 at constant hyperventilation until breathing reappeared. The meanPa_CO2 level of the apneic threshold in42 rats was 32.8 ± 0.4 Torr. The level of thethreshold did not depend on the volume at which the lungs wereinflated. The level of the threshold, under steady-state conditions,was the same when approached from hypocapnia as from eupnea. The levelof the threshold could be raised by 9 Torr by chronic elevation of theeupneic Pa_CO2 level by 18 Torr.

     

Ventilatory response to exercise in subjects breathing CO2 or HeO2

Babb, T. G. Ventilatory response to exercise insubjects breathing CO₂ orHeO₂.J. Appl. Physiol. 82(3): 746-754, 1997.To investigate the effects of mechanical ventilatory limitationon the ventilatory response to exercise, eight older subjects with normal lung function were studied. Each subject performed graded cycleergometry to exhaustion once while breathing room air; once whilebreathing 3% CO₂-21%O₂-balanceN₂; and once while breathing HeO₂ (79% He and 21%O₂). Minute ventilation(E) and respiratory mechanics weremeasured continuously during each 1-min increment in work rate (10 or20 W). Data were analyzed at rest, at ventilatory threshold (VTh),and at maximal exercise. When the subjects were breathing 3%CO₂, there was an increase(P < 0.001) inE at rest and at VTh but not duringmaximal exercise. When the subjects were breathingHeO₂,E was increased(P < 0.05) only during maximalexercise (24 ± 11%). The ventilatory response to exercise belowVTh was greater only when the subjects were breathing 3% CO₂(P < 0.05). Above VTh, theventilatory response when the subjects were breathingHeO₂ was greater than whenbreathing 3% CO₂(P < 0.01). Flow limitation, aspercent of tidal volume, during maximal exercise was greater(P < 0.01) when the subjects werebreathing CO₂ (22 ± 12%) thanwhen breathing room air (12 ± 9%) or when breathingHeO₂ (10 ± 7%)(n = 7). End-expiratory lung volumeduring maximal exercise was lower when the subjects were breathingHeO₂ than when breathing room airor when breathing CO₂(P < 0.01). These data indicate thatolder subjects have little reserve for accommodating an increase inventilatory demand and suggest that mechanical ventilatory constraintsinfluence both the magnitude of Eduring maximal exercise and the regulation ofE and respiratory mechanics duringheavy-to-maximal exercise.

     

Ventilatory response to helium-oxygen breathing during exercise: effect of airway anesthesia

Krishnan, Bharath S., Ron E. Clemens, Trevor A. Zintel,Martin J. Stockwell, and Charles G. Gallagher. Ventilatory response to helium-oxygen breathing during exercise: effect of airwayanesthesia. J. Appl. Physiol. 83(1):82-88, 1997.The substitution of a normoxic helium mixture(HeO₂) for room air (Air) during exercise results in a sustained hyperventilation, which is present evenin the first breath. We hypothesized that this response is dependent onintact airway afferents; if so, airway anesthesia (Anesthesia) shouldaffect this response. Anesthesia was administered to the upper airwaysby topical application and to lower central airways by aerosolinhalation and was confirmed to be effective for over 15 min. Subjectsperformed constant work-rate exercise (CWE) at 69 ± 2 (SE) % maximal work rate on a cycle ergometer on three separate days: twiceafter saline inhalation (days 1 and3) and once after Anesthesia(day 2). CWE commenced after a briefwarm-up, with subjects breathing Air for the first 5 min (Air-1),HeO₂ for the next 3 min, and Airagain until the end of CWE (Air-2). The resistance of the breathingcircuit was matched for Air andHeO₂. BreathingHeO₂ resulted in a small butsignificant increase in minute ventilation(I) anddecrease in alveolar PCO₂ in both theSaline (average of 2 saline tests; not significant) and Anesthesiatests. Although Anesthesia had no effect on the sustainedhyperventilatory response to HeO₂breathing, theI transientswithin the first six breaths ofHeO₂ were significantly attenuatedwith Anesthesia. We conclude that theI response to HeO₂ is not simply due to areduction in external tubing resistance and that, in humans, airwayafferents mediate the transient but not the sustained hyperventilatoryresponse to HeO₂ breathing duringexercise.

     

Periodic breathing induced on demand in awake newborn lamb

Canet, Emmanuel, Jean-Paul Praud, and Michel A. Bureau.Periodic breathing induced on demand in awake newborn lamb. J. Appl. Physiol. 82(2): 607-612, 1997.Spontaneous periodic breathing, although a common feature infullterm and preterm human infants, is scarce in other newborn mammals.The aim of this study was to induce periodic breathing in lambs. Four10-day-old and two <48-h-old awake lambs were instrumented withjugular catheters connected to an extracorporeal membrane lung aimed atcontrolling arterial PCO₂(Pa_CO2). ArterialPO₂(Pa_O2) was set and maintained at thedesired level by changing inspiredO₂ fraction and providingO₂ through a small catheter intothe "apneic" lung. At a criticalPa_O2/Pa_CO2combination, the four 10-day-old lambs exhibited periodic breathingthat could be initiated, terminated, and reinitiated on demand. In the2-day-old lambs with low chemoreceptor gain, periodic breathing washardly seen, regardless of the trials done to find the criticalPO₂/PCO₂combination. We conclude that periodic breathing can be induced inlambs and depends on criticalPa_O2/Pa_CO2combinations and maturity of the chemoreceptors.

     

Brain stem lesion size determined by DEAD red or conjugation of neurotoxin to fluorescent beads

Neurotoxinmicroinjected into the retrotrapezoid nucleus of anesthetized ratsdecreases phrenic activity and eliminates the response toCO₂. In unanesthetized rats, suchtreatment has no effect on awake, resting breathing and decreasesCO₂ sensitivity by 40% (M. Akilesh, M. Kamper, A. Li, and E. E. Nattie. J. Appl. Physiol. 82: 469-479, 1997). One important factorin explaining these disparate results is the actual size of theanatomic lesion. In the present study, we injected ibotenic acid intothe retrotrapezoid nucleus of anesthetized rats and evaluated lesionsize by using two new approaches: 1)DEAD red, a fluorescent probe that enters impaired cells through leakymembranes and binds to nucleic acids, and2) conjugation of toxin tofluorescent beads. With the use of DEAD red, the region containinglabeled dying cells was 313 ± 104 nl(n = 4), six times larger than theinitial injected volume, and the physiological effects on phrenicamplitude, the CO₂ response, andblood pressure began within minutes and were substantial. Withconjugated toxin, in theory, neuronal damage would be limited to theregion of detectable fluorescence (49 ± 10 nl;n = 4). Effects on phrenicamplitude, CO₂ sensitivity, andblood pressure were absent until ~2 h postinjection. Controlexperiments, with 2 h of in vitro incubation of theneurotoxin-microbead conjugate and injection of the supernatant aftercentrifugation, showed similar results that suggest release ofconjugated neurotoxin. We conclude that DEAD red provides a usefulmeans to monitor neuronal impairment in acute studies in vivo.Conjugation of neurotoxin to microbeads may be less reliable in this regard.

     

Thermal drive contributes to hyperventilation during exercise in sheep

The etiology of exercise hypocapnia is unknown.The contributions of exercise intensity (ExInt), lactic acid,environmental temperature, rectal temperature(T_re), and physicalconditioning to the variance in arterialCO₂ tension(Pa_CO2) in the exercising sheep werequantified. We hypothesized that thermal drive contributes tohyperventilation. Four unshorn sheep were exercised at ~30, 50, and70% of maximal O₂ consumption for30 min, or until exhaustion, both before and after 5 wk of physicalconditioning. In addition, two of the sheep were shorn and exercised ateach intensity in a cold (<15°C) environment.T_re andO₂ consumption were measured continuously. Lactic acid and Pa_CO2 weremeasured at 5- to 10-min intervals. Data wereanalyzed by multiple regression onPa_CO2. During exercise,T_re rose andPa_CO2 fell, except at the lowest ExIntin the cold environment. T_reexplained 77% of the variance in Pa_CO2,and ExInt explained 5%. All other variables were insignificant. Weconclude that, in sheep, thermal drive contributes to hyperventilation during exercise.

     

Ultrasound evaluation of piglet diaphragm function before and after fatigue

Kocis, Keith C., Peter J. Radell, Wayne I. Sternberger, JaneE. Benson, Richard J. Traystman, and David G. Nichols. Ultrasound evaluation of piglet diaphragm function before and after fatigue. J. Appl. Physiol. 83(5):1654-1659, 1997.Clinically, a noninvasive measure of diaphragmfunction is needed. The purpose of this study is to determine whetherultrasonography can be used to 1)quantify diaphragm function and 2)identify fatigue in a piglet model. Five piglets were anesthetized withpentobarbital sodium and halothane and studied during the followingconditions: 1) baseline (spontaneous breathing); 2) baseline + CO₂ [inhaledCO₂ to increase arterial PCO₂ to 50-60 Torr (6.6-8kPa)]; 3) fatigue + CO₂ (fatigue induced with 30 minof phrenic nerve pacing); and 4)recovery + CO₂ (recovery after 1 hof mechanical ventilation). Ultrasound measurements of the posteriordiaphragm were made (inspiratory mean velocity) in the transverseplane. Images were obtained from the midline, just inferior to thexiphoid process, and perpendicular to the abdomen. M-mode measures weremade of the right posterior hemidiaphragm in the plane just lateral tothe inferior vena cava. Abdominal and esophageal pressures weremeasured and transdiaphragmatic pressure (Pdi) was calculated duringspontaneous (Sp) and paced (Pace) breaths. Arterial blood gases werealso measured. Pdi(Sp) and Pdi(Pace)during baseline + CO₂ were 8 ± 0.7 and 49 ± 11 cmH₂O, respectively, anddecreased to 6 ± 1.0 and 27 ± 7 cmH₂O,respectively, during fatigue + CO₂. Mean inspiratory velocityalso decreased from 13 ± 2 to 8 ± 1 cm/s during theseconditions. All variables returned to baseline during recovery + CO₂. Ultrasonography can beused to quantify diaphragm function and identify piglet diaphragm fatigue.

     

Effect of different levels of hyperoxia on breathing in healthy subjects

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

     

Effects of inhaled CO2 and added dead space on idiopathic central sleep apnea

Xie, Ailiang, Fiona Rankin, Ruth Rutherford, and T. DouglasBradley. Effects of inhaledCO₂ and added dead space on idiopathic central sleep apnea. J. Appl.Physiol. 82(3): 918-926, 1997.We hypothesizedthat reductions in arterial PCO₂ (Pa_CO2) below the apnea threshold play akey role in the pathogenesis of idiopathic central sleep apnea syndrome(ICSAS). If so, we reasoned that raisingPa_CO2 would abolish apneas in thesepatients. Accordingly, patients with ICSAS were studied overnight onfour occasions during which the fraction of end-tidalCO₂ and transcutaneous PCO₂ were measured: during room airbreathing (N1), alternating room airand CO₂ breathing(N2),CO₂ breathing all night(N3), and addition of dead space viaa face mask all night (N4).Central apneas were invariably preceded by reductions infraction of end-tidal CO₂. Bothadministration of a CO₂-enrichedgas mixture and addition of dead space induced 1- to 3-Torr increasesin transcutaneous PCO₂, whichvirtually eliminated apneas and hypopneas; they decreased from43.7 ± 7.3 apneas and hypopneas/h onN1 to 5.8 ± 0.9 apneas andhypopneas/h during N3(P < 0.005), from 43.8 ± 6.9 apneas and hypopneas/h during room air breathing to 5.9 ± 2.5 apneas and hypopneas/h of sleep duringCO₂ inhalation during N2 (P < 0.01), and to 11.6% of the room air level while the patients werebreathing through added dead space duringN4 (P < 0.005). Because raisingPa_CO2 through two different meansvirtually eliminated central sleep apneas, we conclude that centralapneas during sleep in ICSA are due to reductions inPa_CO2 below the apnea threshold.

     

Human ventilatory response to acute hyperoxia during and after 8h of both isocapnic and poikilocapnic hypoxia

Tansley, J. G., C. Clar, M. E. F. Pedersen, and P. A. Robbins. Human ventilatory response to acute hyperoxia during andafter 8 h of both isocapnic and poikilocapnic hypoxia.J. Appl. Physiol. 82(2): 513-519, 1997.During 8 h of either isocapnic or poikilocapnic hypoxia,there may be a rise in ventilation(E) thatcannot be rapidly reversed with a return to higherPO₂ (L. S. G. E. Howard and P. A. Robbins. J. Appl. Physiol. 78:1098-1107, 1995). To investigate this further, threeprotocols were compared: 1) 8-hisocapnic hypoxia [end-tidalPCO₂(PET_CO2 ) held atprestudy value, end-tidal PO₂(PET_O2) = 55 Torr],followed by 8-h isocapnic euoxia(PET_O2 = 100 Torr);2) 8-h poikilocapnic hypoxia followed by 8-h poikilocapnic euoxia; and3) 16-h air-breathing control.Before and at intervals throughout each protocol, theE response to eucapnichyperoxia (PET_CO2 held1-2 Torr above prestudy value,PET_O2 = 300 Torr) wasdetermined. There was a significant rise in hyperoxic E over 8 hduring both forms of hypoxia (P < 0.05, analysis of variance) that persisted during the subsequent 8-heuoxic period (P < 0.05, analysis ofvariance). These results support the notion that an 8-h period ofhypoxia increases subsequenthyperoxic E, even if acid-base changes have been minimized through maintenance ofisocapnia during the hypoxic period.

     

Skeletal muscle chemoreflex and pHi in exercise ventilatory control

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

     

Effects of unilateral lesions of retrotrapezoid nucleus on breathing in awake rats

Akilesh, Manjapra R., Matthew Kamper, Aihua Li, and EugeneE. Nattie. Effects of unilateral lesions of retrotrapezoid nucleuson breathing in awake rats. J. Appl.Physiol. 82(2): 469-479, 1997.In anesthetizedrats, unilateral retrotrapezoid nucleus (RTN) lesions markedlydecreased baseline phrenic activity and the response toCO₂ (E. E. Nattie and A. Li.Respir. Physiol. 97: 63-77,1994). Here we evaluate the effects of such lesions on restingbreathing and on the response to hypercapnia and hypoxia inunanesthetized awake rats. We made unilateral injections [24 ± 7 (SE) nl] of ibotenic acid (IA; 50 mM), an excitatoryamino acid neurotoxin, in the RTN region(n = 7) located by stereotaxic coordinates and by field potentials induced by facial nervestimulation. Controls (n = 6) receivedRTN injections (80 ± 30 nl) of mock cerebrospinal fluid. A secondcontrol consisted of four animals with IA injections (24 ± 12 nl)outside the RTN region. Injected fluorescent beads allowed anatomicidentification of lesion location. Using whole body plethysmography, wemeasured ventilation in the awake state during room air, 7%CO₂ in air, and 10%O₂ breathing before and for 3 wkafter the RTN injections. There was no statistically significant effectof the IA injections on resting room air breathing in the lesion groupcompared with the control groups. We observed no apnea. The response to7% CO₂ in the lesion groupcompared with the control groups was significantly decreased, by 39%on average, for the final portion of the 3-wk study period. There wasno lesion effect on the ventilatory response to 10%O₂. In this unanesthetized model,other areas suppressed by anesthesia, e.g., the reticular activatingsystem, hypothalamus, and perhaps the contralateral RTN, may providetonic input to the respiratory centers that counters the loss of RTNactivity.

     

Individual variation in response to altitude training

Moderate-altitude living (2,500 m), combined with low-altitude training (1,250 m) (i.e., livehigh-train low), results in a significantly greater improvement inmaximal O₂ uptake(O_{2 max}) and performance over equivalent sea-level training. Although the meanimprovement in group response with this "high-low" training modelis clear, the individual response displays a wide variability. Todetermine the factors that contribute to this variability, 39 collegiate runners (27 men, 12 women) were retrospectively divided intoresponders (n = 17) and nonresponders(n = 15) to altitude training on thebasis of the change in sea-level 5,000-m run time determined before andafter 28 days of living at moderate altitude and training at either lowor moderate altitude. In addition, 22 elite runners were examinedprospectively to confirm the significance of these factors in aseparate population. In the retrospective analysis, respondersdisplayed a significantly larger increase in erythropoietin (Epo)concentration after 30 h at altitude compared withnonresponders. After 14 days at altitude, Epo was still elevated inresponders but was not significantly different from sea-level values innonresponders. The Epo response led to a significant increase in totalred cell volume andO_{2 max} in responders; in contrast, nonresponders did not show a difference in total red cellvolume or O_{2 max}after altitude training. Nonresponders demonstrated a significantslowing of interval-training velocity at altitude and thus achieved asmaller O₂ consumption during those intervals, compared with responders. The acute increases in Epoand O_{2 max}were significantly higher in the prospective cohort of responders,compared with nonresponders, to altitude training. In conclusion, aftera 28-day altitude training camp, a significant improvement in 5,000-mrun performance is, in part, dependent on1) living at a high enough altitudeto achieve a large acute increase in Epo, sufficient to increase thetotal red cell volume andO_{2 max}, and2) training at a low enough altitudeto maintain interval training velocity andO₂ flux near sea-level values.

     

Fast and slow components of cerebral blood flow response to step decreases in end-tidal PCO2 in humans

This study examined the dynamics of the middlecerebral artery (MCA) blood flow response to hypocapnia in humans(n = 6) by using transcranial Dopplerultrasound. In a control protocol, end-tidalPCO₂(PET_CO2) was heldnear eucapnia (1.5 Torr above resting) for 40 min. In ahypocapnic protocol, PET_CO2was held near eucapnia for 10 min, then at 15 Torr below eucapnia for20 min, and then near eucapnia for 10 min. During both protocols,subjects hyperventilated throughout andPET_CO2 and end-tidalPO₂ were controlled by using thedynamic end-tidal forcing technique. Beat-by-beat values werecalculated for the intensity-weighted mean velocity (_IWM),signal power (), and theirinstantaneous product(_IWM).A simple model consisting of a delay, gain terms, time constants(_f,on, _f,off) and baseline levels offlow for the on- and off-transients, and a gain term(g_s) and time constant(_s) for a second slower component was fitted to the hypocapnic protocol. The cerebral bloodflow response to hypocapnia was characterized by a significant (P < 0.001) slowprogressive adaptation in_IWM, with g_s = 1.26 %/Torr and_s = 427 s, that persistedthroughout the hypocapnic period. Finally, the responses at the onsetand relief of hypocapnia were asymmetric(P < 0.001), with_f,on (6.8 s) faster than_f,off (14.3 s).

     

Relationship between T-wave amplitude and oxygen pulse in guinea pigs in hyperbaric helium and hydrogen

Diving isknown to induce a change in the amplitude of the T wave(A_Tw) ofelectrocardiograms, but it is unknown whether this is linked to achange in cardiovascular performance. We analyzed A_Tw in guinea pigs at 10-60atm and 25-36°C, breathing 2%O₂ in either helium (heliox;n = 10) or hydrogen (hydrox;n = 9) for 1 h at each pressure. Coretemperature and electrocardiograms were detected by using implantedradiotelemeters. O₂ consumption rate was measured by using gas chromatography. In a previous study (S. R. Kayar and E. C. Parker. J. Appl.Physiol. 82: 988-997, 1997), we analyzed theO₂ pulse, i.e., theO₂ consumption rate per heartbeat, in the same animals. By multivariate regression analysis, weidentified variables that were significant toO₂ pulse: body surface area,chamber temperature, core temperature, and pressure. In this study,inclusion of A_Tw made asignificantly better model with fewer variables. After normalizing forchamber temperature and pressure, theO₂ pulse increased with increasing A_Tw in heliox(P = 0.001) but with decreasingA_Tw in hydrox(P < 0.001). ThusA_Tw is associated with thedifferences in O₂ pulse foranimals breathing heliox vs. hydrox.

     

Phosphocreatine hydrolysis during submaximal exercise: the effect of FIO2

There isevidence that the concentration of the high-energy phosphatemetabolites may be altered during steady-state submaximal exerciseby the breathing of different fractions of inspiredO₂ (FI_O2). Whereasit has been suggested that these changes may be the result ofdifferences in time taken to achieve steady-state O₂ uptake(O₂) at differentFI_O2 values, we postulated that they are due to a direct effect ofO₂ tension. We used³¹P-magnetic resonancespectroscopy during constant-load, steady-state submaximal exercise todetermine 1) whether changes inhigh-energy phosphates do occur at the sameO₂ with variedFI_O2 and2) that these changes are not due todifferences in O₂onset kinetics. Six male subjects performed steady-state submaximal plantar flexion exercise [7.2 ± 0.6 (SE) W] for 10 minwhile lying supine in a 1.5-T clinical scanner. Magnetic resonancespectroscopy data were collected continuously for 2 min beforeexercise, 10 min during exercise, and 6 min during recovery. Subjectsperformed three different exercise bouts at constant load with theFI_O2 switched after 5 min ofthe 10-min exercise bout. The three exercise treatments were1)FI_O2 of 0.1 switched to0.21, 2)FI_O2 of 0.1 switched to1.00, and 3)FI_O2 of 1.00 switched to0.1. For all three treatments, theFI_O2 switch significantly (P  0.05) altered phosphocreatine:1) 55.5 ± 4.8 to 67.8 ± 4.9% (%rest); 2) 59.0 ± 4.3 to72.3 ± 5.1%; and 3) 72.6 ± 3.1 to 64.2 ± 3.4%, respectively. There were no significantdifferences in intracellular pH for the three treatments. The resultsdemonstrate that the differences in phosphocreatine concentration withvaried FI_O2 are not theresult of different O₂onset kinetics, as this was eliminated by the experimental design.These data also demonstrate that changes in intracellular oxygenation,at the same work intensity, result in significant changes in cell homeostasis and thereby suggest a role for metabolic control by O₂ even during submaximalexercise.

     

Physical exercise and normobaric hypoxia: independent modulators of peripheral cholecystokinin metabolism in man

The purpose ofthe present investigation was to determine the independent effects ofhypoxia and physical exercise on peripheral cholecystokinin (CCK)metabolism in humans. Thirty-two physically active men wererandomly assigned in a double-blind manner to either a normoxic (N;n = 14) or hypoxic (H; n = 18) group.During the acute study, subjects in the H group only participated in two tests, separated by 48 h, which involved a cycling test to exhaustion in normobaric normoxia and normobaric hypoxia (inspired O₂ fraction = 0.21 and 0.16, respectively). In theintermittent study, N and H groups cycle-trained for 4 wk at the samerelative exercise intensity in both normoxia and hypoxia. Acutenormoxic exercise consistently raised plasma CCK during both studies by 290-723%, which correlated with increases in the plasma ratio offree tryptophan to branched chain amino acids (r = 0.58-0.71, P < 0.05). In contrast, acute hypoxicexercise decreased CCK by 7.0 ± 5.5 pmol/l, which correlated withthe decrease in arterial oxygen saturation (r = 0.56, P < 0.05). In the intermittent study, plasma CCKresponse at rest and after normoxic exercise was not altered afterphysical training, despite a slight decrease in adiposity. We concludethat peripheral CCK metabolism 1) is more sensitive to acutechanges than chronic changes in energy expenditure and 2) ispotentially associated with acute changes in tissue PO₂ and metabolic precursors of cerebralserotoninergic activity.