Effects of training

on muscle 0, transport

at

VO,

max

JOSEP ROCA, ALVAR G. N. AGUSTI, ALBERT ALONSO, DAVID C. POOLE, CARLOS VIEGAS, JOAN ALBERT BARBERA, ROBERT RODRIGUEZ-ROISIN, ANTON1 FERRER, AND PETER D. WAGNER Servei de Pneumologia, Department of Medicine, Hospital Cliizic, Universitat de Barcelona, Barcelona 08036, Spain; and Section of Physiology, University of California, San Diego, La Jolla, California 92093-0623 (Caoz) and the cardiac output (QT). These investigators (6, 24) reported a substantial rise in QT at maximum work load without significant changes in Cao2. Because of the well-known linear relationship between V02max and &o, at maximum work load (24), it has been generally accepted that the improvement in the Qo, plays a key role in determining the increase in V02max with endurance training. Data on structural changes in muscle after training indicate that training may also produce an increase in tissue 0, diffusional transport (25). This is suggested by the rise in capillary density (25) as well as by the increase in the arterial-mixed venous 0, content difference. The latter has been observed particularly in the initially most sedentary subjects (24). The present investigation was conducted to examine the relative contributions to increases in Vo2max of changes in these two compo.nents of 0, transfer [convective 0, delivery to the leg (Qo,) and the associated muscle 0, diffusing capacity (DO,)] after 9 wk of a well-defined endurance-training program. The diffusive component of 0, transport was determined as a lumped parameter that includes all the steps of the 0, transfer process in muscle, from the red blood cells to the mitochondria (22). Twelve healthy previously untrained subjects were studied twice, once before and once after training. In each study, one-leg blood flow (Q,,,), DO,, and one-leg VO, (VO,,,,) were determined with the subjects cycling at whole body VO, m81t.These measurements, both before and after training, were carried out at three different inspired 0, concentrations (FI, 0.21, 0.15, and 0.12) necessary to estimate DO, (27). l!he seBohr integration; endurance training; exercise; femoral venous quence of the three inspirates was balanced. Femoral veblood flow measurement; femoral venous oxygen partial pressure; hypoxia; maximum oxygen uptake; musclecapillary par- nous blood flow was measured by thermodilution by use of the technique described by Andersen et al. (1) moditial pressure; oxygen delivery fied to obtain femoral venous PO, (Pfvo ) measurements (21) from the same catheter. With use OFQlegand arterial and femoral venous PO, measurements, average muscle IT IS WELL ESTABLISHED that maximum 0, uptake capillary PO, (Pmco,) and, hence, DO, were estimated by m 2max ) in normal subjects can increase after a rela- a Bohr integration (5, 26, 27,29). Subsequent numerical tively short period of physical training (14, 19, 20). The analysis allowed us to determine the relative contribugain in V02 m8X with endurance training varies over a wide tions of Qo, and DO, to the increase in VO,~~~at whole range (8, 12, 24), being markedly influenced by two fac- body Vo2 mEu[ after training. tors: 1) the age and degree of prior activity of the subjects and 2) the characteristics of the training program. Classical studies by Ekblom (6) and Saltin et al. (24) METHoDS showed that the increase in iToZmax with training is ac- Subjects companied by an improvement in convective 0, delivery Selection of subjects and preliminary studies. Twelve (Qo,), as defined by the product of the arterial 0, content healthy sedentary-subjects were studied and first underROCA,JOSEP,ALVARG.N.AGUSTI,ALBERTALONSO,DAVID C.POOLE,CARLOS VIEGAS,JOANALBERTBARBERA,ROBERT RODRIGUEZ-ROISIN,ANTONIFERRER,ANDPETER D. WAGNER. Effects of training on muscle O2 transport at vo2,,. J. Appl. Physiol. 73(3): 1067-1076,1992.-To quantify the relative contributions of convective and peripheral diffusive. componentsof 0, transport to the increase in leg 0, uptake (Vozl,,) at maximum 0, uptake (VO2-) after 9 wk of endurance training, 12 sedentary subjects (age 21.8 .+ 3.4 yr, vo236.9 t 5.9 ml. min-l kg-‘) were studied. Vo, max,leg blood flow (Q,,,), and arterial and femoral venous PO,, and thus VO, leg,were measured while the subjects breathed room air, 15% 02, and 12% 0,. The sequenceof the three inspirates was balanced. After training, VO, maxand Vo2 legincreased at each inspired 0, concentration [FI, , mean over the 3 FI,, values 25.2 t 17.8 and 36.5 k 33% (Sb), respectively]. Before training, vo2 legand mean capillary PO, were linearly related through the origin during hypoxia but not during room air breathing, suggesting that, at 21% O,, %702,, was not limited by O2 supply. After training, VO, legand meancapillary PO, at each FI,, fell along a straight line with zero intercept, just as in athletes (Rota et al. J. Appl. Physiol. 67: 291-299, 1989). Calculated muscle0, diffusing capacity (DO,) rose 34% while &,, increased 19%. The relatively greater rise in DO, increasedthe Do2/Qleg, which led to 9.9% greater O2 extraction. By numerical analysis, the increasein QLeg alone (constant DO,) would have raised VO, leg by 35 ml/min (mean), but that of DO, (constant Q,,) would have increasedVO 21eg by 85 ml/min, more than twice as much. The sum of these individual effects (120 ml/min) was less (P = 0.013) than the observed rise of 164ml/min (mean). This synergism (explained by the increase in D?2/Qleg)seemsto be an important contribution to increasesin VO,,, with training. l

l

0161-7567/92 $2.00 Copyright 0 1992 the American Physiological

Society

1067

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went a preliminary noninvasive exercise protocol. They were selected on the basis of no previous history of physical training or recreational sports. All were fully informed of any risks and discomfort associated with the experiment, and informed consent was obtained in accordance with the Committee on Investigations Involving Human Subjects at the Hospital Clinic, University of Barcelona. The preliminary procedures included 1) standard clinical questionnaire and physical examination, 2) conventional pulmonary function tests, 3) 12-lead electrocardiogram, 4) chest X ray, 5) venous hematocrit, and 6) three preliminary exercise studies carried out with catheters on different days within the 2 wk before the pretraining study. The purposes of the preliminary study were 1) to exclude subjects with electrocardiogram (ECG), chest X ray, or hematologic abnormalities, 2) to characterize each subject’s exercise performance, and 3) using step 6 above, to ensure that a “learning effect” could not account for part of the increase in VO, maxwith training. In each of the three exercise tests, a standard incremental test (30-W increments every 2 min) until exhaustion was performed while the subjects breathed room air (cycle ergometer, Jaeger, Wtirzburg, FRG). The “target” maximum work load for room air breathing in subsequent studies (see below) was defined from these tests as the work load producing the highest Vo2 that could be maintained for 245 s and that did not produce a further rise in Vo2 when an additional 30-W increase in work load was applied for 1 min. Mixed expired 0, (FEo,) and CO, (FE& (Multi-gas mass spectrometer, Medishield, Ohmeda-BOC, UK), expiratory flow measured using a screen pneumotachograph, and ECG were continuously recorded and digitized. On-line calculations of VO,, Co, Output (h02), minute ventilation (VE), respiratory exchange ratio (R), heart rate (HR), and respiratory rate (RR) were averaged over sequential 15-s intervals and then displayed on a screen monitor to observe the progress *of the tests. The steady state was defined as HR and VO, being constant to t5%/min even if \;7E was increasing. Anthropometric data, spirometric results, respiratory arterial blood gases at rest, pretraining maximum work loads, and Vozrnax while the subjects breathed room air are shown in Table 1. Subject preparation. For the pre- and posttraining catheter-based studies, each subject had the following three catheters introduced percutaneously with 1% lidoCaine used for local anesthesia: 1) a 20-gauge radial arterial cannula (Seldicath, Plastimed, Saint-Leu-La Foret, Cedex, France) in the nondominant arm (after determination of adequate ulnar collateral circulation), 2) a 7-Fr polyurethane catheter (Seldiflex 66525 J, Plastimed) entering the femoral vein 2-3 cm below the inguinal ligament and advanced distally 7-10 cm to minimize contamination from skin or saphenous vein blood, and 3) a 2.5Fr thermodilution probe (model 94-030, Edslab, Irvine, CA) entering the same femoral vein 2-3 cm below the inguinal ligament and advanced 5 cm proximally. Sterile technique was observed at all times during catheter placement and sampling. The effect of the site of sampling in the measurement of femoral venous blood gaseshas been reported elsewhere (21). Simultaneous blood samplings

0,

SUPPLY

AFTER

TRAINING

from a 7F catheter placed in the femoral vein as in the present study and from a 7F Swan-Ganz catheter placed in the same vessel and advanced 7 cm proximally were carried out in six volunteers undergoing three maximal cycle bouts on 1 day (n = 18; FI,~ 0.21). No difference in Pfvo, ,‘, between proximal and distal samplings was shown at Vozmax. Safety precautions. Subjects were instructed to stop exercising immediately if unusual symptoms (other than normal shortness of breath and leg discomfort) developed; however, this never occurred. At least four physicians were present at all times, with one directing his attention exclusively to the subject. Continuous oscilloscopic recordings of ECG, arterial saturation by pulse oximetry, and systemic pressure were used to monitor the volunteer during the study. General Protocol: Outline In each of the 12 subjects, both before and after training, three bouts of exercise producing Vozmax were carried out on a single day while the subject breathed I) room air (FI+ 0.21), 2) 15% 0,, and 3) 12% 0,. Between runs the subject rested for 1 h to ensure adequate recovery. There are six possible orders of presentation of these three inspirates. Therefore, with 12 subjects, each specific order of presentation was assigned twice, one to each subject. In the posttraining study, the order of the three inspired 0, mixtures assigned to each subject was the same as that before training. Each exercise test was designed as follows: 1) warm-up for 5 min at ~30% of the target work load, 2) submaximal exercise at 60% of the target work load for 3 min, 3) transition step at -80% of the target work load for 1 min, 4) target work load for 3 min, and 5) target work load plus 30 W for an additional 1 min (“last minute”) to ensure that voB max had been reached. In the pretraining study with catheters, the target work load (room air breathing) was set according to the preliminary study (Table 1). Throughout the training period, incremental exercise tests, as described in the preliminary study, were carried out every 15 days (weeks 2,4, 6, and 8) to examine progress in the subjects’ exercise performance. In the posttraining study, the target work load (room air) was set at the 8wk maximum work load. The target work loads while subjects were breathing low0, mixtures were set at 85% (Fr,, 0.15) and 75% (FI,, 0.12) of the subjects breathing room air both preand posttraining. These percentages were selected according to previous studies (22,24,28) to produce VO, max in each case. A 30-W push to additional loads over the last minute (see above) was used to ensure that VO, max had in fact been reached in hypoxia. In each run a complete set of measurements was performed: 1) during submaximal exercise (at 60% of the target work load), 2) at target work load, and 3) during the last minute. Measurements made in each set were as follows: I) PO,, Pco,, pH, hemoglobin (Hb) concentration, oxyhemoglobin saturation (SO,), and blood lactate concentrations from simultaneous arterial and femoral venous blood samples, 2) femoral venous blood flow and arterial pressure, and 3) VE, FE,,, and F&, . At rest, only blood sampling was carried out. At the target work load, blood sampling for -

-aa

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CONVECTIVE

AND

DIFFUSIVE

0,

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1. Anthropometric data, lung function results, and exercise performance during room air breathing before training TABLE

Age,

Ht,

Subj No.

Sex

Yr

cm

1 2 3 4 5 6 7 6 9 10 11 12

F M M M M M F M F M F M

22 23 23 18 29 19 18 22 27 20 20 21

162 177 186 181 175 186 165 176 167 179 162 171

22 -+3

174 k9

Mean tSD FEV,, arterial

forced

POT; work

expired load,

w kg

tll

FEV, ml

% pred

FEVJFVC, %

P%,7 Torr

Work

Load, W

knax, ml min-’ 0kg-l l

67 64 75 71 79 86 58 67 65 99 59 79

3,120 4,330 5,410 5,030 5,030 5,840 3,160 3,930 3,320 4,190 2,960 4,620

94 98 113 132 117 120 97 92 102 98 92 117

82 85 85 79 79 82 83 71 90 73 86 89

91 92 102 97 99 95 96 95 96 95 93 103

160 240 270 230 200 250 160 210 180 230 220 240

28.1 45.1 39.8 41.0 30.7 25.8 35.0 42.6 37.4 35.1 40.8 42.0

73

4,245 k969

106 t13

82 k6

96 -+4

216 +35

36.9 k5.9

volume in 1 s; FVC, forced vital capacity; pred, predicted target work load required to produce maximum 0, uptake

(Ref.

23); FEVJFVC ratio expressed as actual subject breathed room air.

values;

Pao,,

(Vozmax ) while

respiratory gas measurements was carried out twice: during the second half of the 2nd and the 3rd min. During the last minute, there was time for only a single set of measurements. Blood sampling and flow measurements were generally timed to coincide with peak pulmonary VO,. However, in three subjects during the air-breathing pretraining run (but under no other conditions), blood sampling was unavoidably performed at slightly below peak VO,. As a result, none of the normoxic pretraining data were used to estimate muscle DO,.

period. No changes in VOW,,, or in the relationship between Vo2 and work load were observed in either of these individuals. Hemodynamic measurements. Systolic and diastolic values of systemic arterial pressure were continuously recorded. The transducer was set at right atria1 level and zeroed before each run to account for amplifier drift and changes in body position. HR was measured from the continuously monitored ECG signal. Femoral venous blood flow was measured using a modification of the thermodilution technique reported by Andersen and Saltin (1). Briefly, the 7-Fr catheter distally oriented in the Measurement Details femoral vein was used for brief periods (lo-20 s) of conVE and expired gas tensions. The ventilation circuit stant-rate infusion of cold saline (=OOC). This catheter consisted of a one-way Y valve connected in series by a was provided with four side holes in helical formation large-diameter (3-cm-ID) heated expired line to a screen over a distance of 1 cm, starting 1 cm from the tip. The pneumotachograph and a mixing box. The entire circuit distance between the infusion holes and the tip of the offered minimal expiratory resistance. For low-O, mix2.5-Fr thermistor proximally oriented in the same vessel tures (FIEF 0.15 and 0.12) the inspired gas was bled into a was -12 cm. Constant infusion rates of loo-360 ml/min meteorological balloon connected to the inflow side of were selected to obtain a drop of - l.5OC in blood temperthe Y valve. Expiratory flow and 0, and CO, analyzer ature during iced saline infusion. The total volume of the (mass spectrometer) outputs were continuously moniinjectate was ~100 ml for each measurement. The 2.5-Fr tored with a chart recorder and connected in series to the catheter was connected to an Edslab computer (model interface of an IBM PS 50 computer system that dis- 9520A, Edwards Laboratories, Santa Ana, CA), the anaplayed on-line calculations of bE, VO,, VCO,, R, HR, and log output of which was digitized with an IBM PS 30 RR every 15 s (by use of data averaged over 15-s sequensystem that provided the on-line graphical display of the tial intervals). Correction for water vapor was automatidrop in blood temperature during the constant infusion cally performed by the mass spectrometer. The latter of cold saline (1). Measurements were carried out in duwas calibrated immediately before and after each run plicate. To test the system, in vitro measurements were with room air and three different 0, and CO, mixtures made over a flow range of l-8 Umin in an experimental (N2 balanced): 1) FI,, used in the particular run and 0 system designed to simulate the in vivo situation as FI coZ) 2) 0.1501 Fo2 and 0.0498 Fco,, and 3) 0.1005 Fo, closely as possible (1). The results obtained with the and 0.0152 Fco,. Flow calibration with a rotameter was thermodilution technique (T) were tested against simulcarried out before and after each run. Timed samples of taneous flow measurements made with a graduated cylinexpired gas were collected in meteorological balloons, der (GC). We found equivalence between the two methand VE used for calculations was measured (ATPS) with a ods and a linear relationship as follows: T = 1.011 X Tissot spirometer (120 liters) from these balloons. To GC - 0.088 (r’ = 0.984, SEE = 0.28 l/min, n = 25, range test the stability of the exercise equipment throughout l-8 Urnin). In a previous study with normal subjects (2l), the study, two control subjects who did not participate in the intraindividual reproducibility of maximal femoral any training program were exercised to maximum while venous flow measurements was 5.0%, a value similar to breathing room air before and after the 9 wk of the study that reported by Andersen and Saltin (1). Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (165.190.089.176) on September 27, 2018. Copyright © 1992 American Physiological Society. All rights reserved.

1070

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Blood gas analysis and blood lactate levels. Simultaneous arterial and femoral venous samples (4 ml each) were collected anaerobically in heparinized glass syringes and kept on ice for measurement of PO,, Pco,, and pH (model 1302, pH/blood gas analyzer and tonometer model 237, Instrumentation Laboratories, Milan, Italy) and Hb and SO, (OSM-2 hemoximeter, Radiometer, Copenhagen, Denmark). Samples were run in duplicate. Linearity of the blood gas analyzer was checked for PO, over a range of O-150 Torr with tonometered blood. All blood gas measurements were made at 37*C and corrected to the temperature measured during the sampling period by the thermistor probe in the femoral vein, which was checked in vitro after each study against a standard mercury thermometer. Blood lactate concentrations were determined using a blood lactate analyzer (model 23L, Yellow Springs Instruments, Yellow Springs, OH). Bicarbonate concentration was calculated from measured pH and PCO~ by use of the HendersonHasselbalch equation. Calculations of base excess (BE) were normalized to 100% SO, (%SO,) (3). Estimation of mean Pmco2 and 00~. On the assumption that, in normal humans at 00, max, perfusion-Vo, heterogeneity and shunts (perfusional and diffusional) are negligible, it is possible to estimate mean Pmcoz by numerical analysis. The calculations are tantamount to the Bohr integration (5, 26, 29) approach wherein, by forward integration, a lumped parameter tissue diffusing capacity-to-muscle blood flow ratio (DoJQ,,,) is selected to produce the measured Pfv,, if the actual arterial PO, is given. Pfvop measured distal to the saphenous vein is considered to be effluent muscle PO, in maximal running or cycling exercise (17, 21). These calculations, described elsewhere (22), are based on Fick’s first law of diffusion. By keeping the system simple (i.e., defined by the single ratio DOJQleg), we avoid the uncertainties of chemical reaction rates for 0, off-Ioading (13), capillary blood volume, and capillary transit time. Pmc,, is a timeweighted average PO, along the capillary. In this analysis, mitochondrial PO, is taken to be zero at Vo2mar [on the basis of myoglobin-associated PO, estimates of l-3 Torr at VO 2 max(ll)]. Then, DO, can be estimated as the ratio of VO 2 maxto Pmco, over the three inspired 0, conditions. Trainingprotocol. The subjects exercised 5 days/wk for 9 wk. The exercise consisted of cycling on an ergometer 3 days/wk and running on the alternate days. The cycling days each week consisted of interval and endurance training as follows. On 1 day, the subjects performed eight repetitions of 1-min intervals interspersed with continued cycling during recovery until Vo2 fell to -60% . vo 2 max, as estimated by HR. On another day, the protocol consisted of five repetitions of 3-m+ intervals with continued cycling during recovery until VO, had fallen to 60% of Vo, max. In each of these sessions, the work load was calculated to elicit 100% vo2 max, incremented each 2 wk for gains recorded in VO, max. The third cycling session consisted of a constant 30-min work load at ~80% vo 2 max. During the cycling sessions, HR was continuously recorded and compared with that measured in the exercise studies carried out in the laboratory (in weeks 2, 4, 6, and 8). The running program consisted of continu-

O2 SUPPLY

AFTER

TRAINING

ous jogging for 30 min/day during the 1st wk, increasing ~5 min every 2 wk. The pace was designed to produce exhaustion by the end of the run. Statistics

Results are expressed as means t SD. Multivariate analysis of variance was used to examine the differences among treatments. However, because of the interaction observed between FI,, and training, the differences among FIEF before and after training were separately analyzed by a two-way analysis of variance (ANOVA) and Duncan’s multiple range test, while the comparisons between pre- and posttraining were done by Student’s paired t test. Regression analysis was used to explore the relationships between variables. Regressions refer to group mean data unless otherwise stated. In all statistical analyses, the 0.05 level of significance was used. RESULTS

Preliminary Studies and Changes in Exercise Performance Throughout the Training Period

A learning effect was observed between the first noninvasive preliminary study (v02max 2.43 t 0.35 l/min) and each of the two subsequent preliminary runs carried out on different days (VO, max2.68 t 0.39 and 2.74 t 0.42 l/min, respectively; P < 0.001 each). In contrast, no differences in TO, max were observed between the two latter preliminary tests and the pretraining study with catheters in place (2.66 t 0.48 l/min). Maximal exercise performance before training during room air breathing (Table 1) showed reasonable values for sedentary subjects (2) and maximum HRs of = 175 min-’ (Table 2), and lactate levels (Table 2) were consistent with this finding. . vo 2 m8xincreased steadily until week 6 of the training period, showing a plateau thereafter. It is interesting to note that a similar pattern of changes was observed in other variables that reflect physiological adaptations to exercise, namely, the reduction in the HR and in the R at a given submaximal work load, which also showed a plateau after week 6. The slopes of the linear portion of the relationship between Vo2 and work load in each subject did not show significant differences throughout the training period (overall slope 11.72 t 0.05 ml. min-’ W-l, range 11.66-11.77; r2 = 0.99). The calculated work efficiency in this population was 25.0 t 0.8% (7). l

Exercise Performance With Catheters: Pre- and Posttraining Studies

The exercise protocol was specifically designed to ensure Vo2 max in all conditions, as indicated in METHODS. Whole body VO, max data are shown for each FI,, before and after training in Table 2. Although higher maximum HRs might have been expected in young healthy subjects, the results of other markers of the intensity of the exercise performance, namely, the R, the pH, the plasma lactate concentrations, and the 0, extraction of the exercising leg, strongly indicate that for these subjects extreme levels of exercise were reached in each condition (Table 2). As expected, whole body 60, max (VO, max) and one-leg Vo2 at whole body Vo2-= (VO,~,,) significantly

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CONVECTIVE

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SUPPLY

AFTER

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TRAINING

2. Selected variables during maximum exercise at each FIN,

TABLE

FIO,

0.21

Work load, W vo 2 body l/min ml min-’ kg-’ vco 2body 7 llrnin RER VE, l/min BTPS HR, cycles/min l

l

Pao2, Torr Pace,, Torr AaPo,, Torr

P&i Pfvo,, Torr Pfvco,, Torr Pmcoz, Torr Hb, g/l Jgleg7 % &feg 7 l/min QO,,l/min VO 2 leg, l/min DO,, ~1 min? Do,/&l,,,ml/Torr BE,, meq/l La,, mM La,, mM La, mM/min l

l

0.12

Before

After

Before

After

Before

After

216k34

235~30

188+26

228+26

169222

201+24

2.66~0.48 36.9k5.9 3.51~~0.63 1.30+0.09 115.3k27.5 176.0+12.0

3.58kO.59 50.8k7.6 4.35kO.76 1.22kO.09 126.4k24.9 179.OHO.8

2.39kO.43 33.1k4.5 2.8OkO.52 1.17+0.08 94.5kl8.0 174.3k8.6

2.82kO.37 40.21~5.8 3.42kO.46 1.22kO.10 113.4k18.5 176.0~6.6

2.lOkO.25 29.222.0 2.54kO.40 1.21kO.12 94.0k18.4 173.6k11.2

2.521~0.48 35.7k5.3 3.03kO.56 1.21kO.07 109.2+19.0 171.6k8.6

115.2H.O 30.7k3.1 9.3k5.8 7.3220.05 24.9k4.3 65.1k5.1

108.7t-7.5 30.8k2.1 14.5k6.1 7.28kO.06 20.5k3.6 69.1k6.5 40.322.9 7.09kO.04 13.521.1 81.9k6.2 6.45-tl.01 1.211~0.25 0.99kO.20 24.8k5.5 3.8420.59 -12.91-2.4 10.4k1.3 11.2k1.6 5.33k5.26

57.826.32 3O.lk3.0 20.5k5.3 7.33kO.05 20.2k3.3 58.924.8 34.Ok3.3 7.17+0.04 13.9kl.l 76.2k7.9 5.31k1.09 0.90+0.21 0.68kO.15 19.3k4.3 3.69kO.57 -10.8t2.8 9.3k1.4 10.2~1.3 4.4Ok2.74

58.2k4.0 29.1t2.2 22.9k4.3 7.3020.04 17.4k3.1 60.8k5.5 32.8k2.5 7.13-to.04 13.421.0 83.5k5.7 5.98LO.88 0.99kO.18 0.82~0.13 24.4k4.0 4.10+0.48 -12.8d.9 9.9kl.5 10.9Ll.4 6.2524.01

40.4k3.9 28.2k2.7 21.6k4.1 7.361~0.05 16.6k2.5 53.123.5 27.422.5 7.2OkO.05 13.6kO.8 79.3k6.2 4.9821.15 0.71~0.18 0.57LO.17 19.4k6.2 3.86kO.48 -10.8k2.7 9.1k1.7 9.8k1.6 3.67k4.86

41.3k3.5 27.4k1.8 20.5k3.1 7.33kO.05 13.7k3.1 53.7k5.5 26.2k2.3 7.17kO.05 13.4k1.2 85.625.9 6.34kO.88 0.88LO.19 0.75kO.14 27.5k4.9 4.351~0.61 -12.7k2.4 10.4kl.l 11.4kl.l 6.21k3.82

7.14+0.004 13.8kl.O 72.2k7.5 5.13+0.80 0.98kO.14 0.71-to.13

PH"

0.15

Torr-’

-10.9k2.3 9.5H.5 10.4-tl.3 4.76k2.85

Values are means 2 SD of 12 subjs. VO, body, whole body O2 uptake; VCO, body, whole body CO, output; RER, respiratory exchange ratio; VE, minute ventilation; HR, heart rate; Paoz and PacOz, arterial PO, and PCO~ ; AaPo,, alveolar-arterial PO, difference; pH,, arterial pH; Pfvo2 and venous PO, and Pco~; Pmco2, mean capillary PO,; pH,, venous pH; Hb, hemoglobin concn; ER*,,, leg 0, extraction ratio; Qleg, Pfvco, 7 femoral leg blood flow; Qo,, convective 0, delivery; VO, leg:, leg 0, uptake; DO,, 0, diffusing capacity; BE,, femoral venous base excess; La,, arterial lactate; La,, femoral venous lactate; La, net lactate output across the leg.

decreased with acute hypoxia before and after training (Fig. 1). VO, maxand VO, legincreased with training at each FIEF (mean averaged over all FI,~ values 25.2 and 36.5%, respectively; P < 0.001). Maximum work load (Table 2) and endurance at maximum work load also increased with training. Although completely. independent measurements were used to calculate VO, max and VO, leg, these two variables were closely linearly related through the origin in all conditions, that is, both before and after training and at each FI,~. The slope of this regression line (Fig. 1) indicates that the contribution of To2 leg(one leg) to whole body vo2 was 27.2%, a value that is in keeping with previous studies (4). Femoral venous blood flow tQ,,,) was unaffected by FI,, in both the untrained and trained conditions. After training (Fig. 2), Qlegwas significantly increased at each Fro2 (mean averaged over all FIEF values 19.2%; P < 0.001). There were no changes in arterial PO,, Pco,, or Hb concentration. Consequently, an increase in Qo, was observed at each FI,, (P < 0.001). Leg 0, extraction (100 VO, leg/Q~2) also increased at each FI, after training (mean over all FI,~ values 75.5 t 6.6% before and 83.0 t 6.6% after; P < 0.001). VCO, (ko2,,,) and iTE #Em,,) at maximum work load rose at each FI,, with training, and arterial and femoral venous pH fell (P < 0.001, Table 2). Maximum blood lactate concentrations were unaffected by training. l

Relationships Between Vozleg and Pmcq or Pfvo, at Maximum Work Load (Fig. 3) Before training, TO, legand Pfvo2 did not show a linear proportionality as FI,~ decreased from air to O.150.12. After training, as FI,~ was decreased from 0.21 to 0.15 to 0.12, Vo 2legand Pfvo2 showed a linear relationship compatible with zero intercept over all three FIEFvalues, similar to that previously observed in athletes (22). Similar relationships, before and after training, were evident between VO 2legand the Pmc02 (Fig. 3). The plots relating whole body vo2max to PO? (Pfvo2 or Pmco2) were analogous to those shown for VO,~,, (as expected from Fig. 1, bottom) and are thus not presented. The peripheral DO, was estimated by Bohr integration as the DO, required to explain the measured Pfvq2 for each subject at each FI,~. Except for the pretraining measurement while the subjects were breathing room air, DO, was statistically not different at different FI,~ values (2-way ANOVA). In other words, DO, was not influenced bY FIo2. The lack of linearity between v021eg and PO, (Pmco2 or Pfvo2) during room air breathing in the pretraining study suggests that either the assumptions of our . analysis were not fulfilled in this condition or that vo 2maxis not limited by 0, supply to the tissues in this group of sedentary subjects breathing room air [DO, was calculated at each FI,? from the pretraining data, and

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1072

CONVECTIVE

AND

DIFFUSIVE

4000

-3000

*’

01 rnc w *go00

0’

/ 0 M---O l

0

DISCUSSION

1 i

6

post-training

/'

0 pre-training

E 300

LEG irO2 AT

7j02MAX

LO

0

20

% INSPIRED

30

OXYGEN

1200,

1

O~ZMAX 900 -

i

0

, ml min-1

pre-training

1000

WHOLE

v...= A

f-

r2 0

3000

2000

of vo2 171~~

A key point in the development of the present study was to ensure that VO, maxhad been reached at each Fro2 both before and after training. The protocol used to reach vo2 IllaX(involving a target maximum load followed by a 30-W increment, see METHODS) and the physiological responses measured at the highest work load in each of. the treatments (Table 2) support the claim that vo 2m8Xfor each subject was achieved in all conditions. Repeatability of pretraining VO, maxvalues in three separate occasions, the systematic rise in vo2max with training, the maximal blood lactates (Table Z), and maximal heart rates (Table 2) are all compatible with this conclusion. Moreover, each subject was in fact pushed to exhaustion so that, at any FIEF, no higher work load could have been sustained. The magnitude of the increase in . vo 2 max after training was similar to that reported by some authors (8, 13, 23), but it was in the upper limit of the range compared with other series in the literature that include subjects with previous history of regular physical activity (13, 18, 24). Q, Measurement

=

0.96 4000

BODY ml min-1

FIG. 1. Maximum 0, - uptake and after training, showing an iMiddLe: corresponding data for similar increments with training. showing close correspondence.

TRAINING

pre - trarnmg

irO2

1 I

AFTER

l

Attainment

MAXIMUM

1000

SUPPLY

l

J, OE z 3

Ls

rise in DO,/&,, from 3.78 t 0.53 to 4.22 t 0.56 ml 1-l Torr-’ (p < 0.005, Fig. Z), which in turn accounts for the increase in tissue 0, extraction (see DISCUSSION).

? post-training > c)

0,

- measured at mouth (top) before increase at all inspired 0, fractions. exercising leg iio, at ~TO, max, showing Bottom: relationship between the two, (VO,)

this showed that the 0.12 and the 0.15 FI,~ results were not different from each other but were significantly (P < 0.034, Z-way ANOVA) greater than the room air values]. Accordingly, to exclude underestimation of the pretraining DO, (and thus overestimation of the increase in the effective tissue DO, with training), the Do2 before training was calculated from only the hypoxic measurements (FIEF 0.15 and 0.12). The increase in DO, (34%) was from 19.4 t 5.3 to 25.9 t 4.7 ml. min-’ Torr-1 (P < 0.001, Figs. 2 and 3). The expected (10, 22, 25) linear relationship through the origin between Vo21eg and Qo, (both before and after training) is shown in Fig. 3 (bottom). The slope of each straight line is the fractional tissue 0, extraction. After training, as mentioned above, tissue Q2extraction increased such that the VO 2legat a given Qo, was higher. The relatively greater increase in DO, (34%) than in femoral venous blood flow (19%) explains the concomitant

In the present study, the femoral venou s flow wa.s a fund .amental variable i.n the calcul .ation Of ‘O2 len at whole body Vo2,,, (VO,,,,) by the Fick principle. The measurements were carried out using an adaptation of the continuous thermodilution technique described by Andersen and Saltin (1). Our modifications were designed to maximize mixing of infused saline in the femoral vein (see METHODS). Femoral venous flow values at maximum work load were similar to those reported by others in healthy subjects (1). The strong correlation observed between VO 2legand whole body VO, maxunder all conditions (Fig. 1) constitutes a marker of the consistency of the flow measurements in that Vo2 legand whole bodY v"2 max were obtained using completely independent methods. The parallel increase observed in VO,~~, and in whole body VO 2maxwith training also suggestsreliability of the methods, and the reproducibility and absolute values of the flow measurements further give confidence in the methodology. However, there is no independent in vivo method currently available in normal humans for validation of these critical data. Relationships Between BOB,,, and Mean Capillary PO,

l

The slope of the linear relationship between VO, legand mean capillary (or femoral venous) PO, measured at different FI,~ values has been considered to reflect the effective DO, (10, 22, 27), and this rose substantially with training. The statistical analysis (Z-way ANOVA) showing that DO, (with the exception of the pretraining measurements during room air breathing) was not influenced by FI,~ is consistent with such a linear relationship, and we believe that thev give us iustification for the granhical

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CONVECTIVE

AND

1 :,A/;

1

I b/Y---:, I

E?

I+

IO

I5

AFTER

1073

TRAINING

1

pre-lrainlng

25

30

IMEAN 1 5

cv

INCREASE WITH TRAINING = 20% IO

I5

20

25

pre- lraining

dEAN INCREASE WITH TRAINING = 9.9X 1

60

20

I5

IO

MEAN 0

30

25

5

z

post-training

DECREASE a WITH TRAINING = 16% I5

IO

20

1

1I

1

354

--- .--t-z-- f, / pre-tz-alrlng

30

25

30-

* e

1

,;

b=

30

pod-lraining

70

6\0

SUPPLY

post -lrarnilly

20

80

X lr3 cl2 0

0,

INCREASE WITH TRAINING = 19% \

MEAN

5

is 2 z

1

DIFFUSIVE

9 ,

A

*-w 1

Y

nnst-traintna

I

I----

I

-- --“---e

/ A/

1

t

0

1

prc-training

I -‘:

DECREASE1 WITH I5

TRAINING 20

= 4.0% 25

g

1

~~

d, l\A

‘\A

posl I

I:

‘( 30

E

15+ 5

MEAN

INCREASE 1

WITH

TRAINING = 34% , 30

0”

training -

1 pre - training

INCREASE WITH TRAINING = 12X( LO LNl EL”

-

5

IO

15

% INSPIRED

20

30

OXYGEN

2. O2 transport variables at each inspired 0, changes averaged over each FIEF. Convective 0, delivery while muscle 0, diffusing capacity increased 34% (lower femoral venous PO,, as shown. FIG.

23

fraction (FI,J before and after training, indicating percent (blood flow X arterial 0, content) increased 20% (top right) right). This allowed greater O2 extraction with a reduction in

analysis expressed in Fig. 3 (top). Thus, although we draw the line through the origin, we have not “forced it” through the zero intercept. An unexpected finding in the pretraining study was the behavior of these relationships during room air breathing. As Fig. 3 indicates, Vo2 legwith room air breathing (FI?, 0.21) lay (P = 0.034, 2-way ANOVA) below the straight line through the origin, as defined by the two hypoxic measurements that gave DO, estimates not different from each other. Several possibilities can explain such behavior. First, the subjects may not have been cycling at Vozmax in this condition. According to the DO, limitation hypothesis (10,22,27), the straight line with positive slope and zero intercept defined by the regression of the Vozmax against the mean capillary (or the femoral venous) PO, measured at differ-

ent FI,~ determines the value of Vozrnax for a given amount of Qo~. Hypothetical values of VO, maxabove this line are not consistent with the hypothesis (27), whereas the VO, measurements below the line may represent submaximal runs (see METHODS). Undue heterogeneity of perfusion-to-Vo, ratios (&/VO,) in the exercising muscle on room air could also explain the lack of linearity in the pretraining VO, m8xdata (27). However, the linear relationship through the origin between Vo2 legand mean capillary (or femoral venous) PO, observed 1) during hypoxia (FIEF 0.15 and 0.12) in this study before training, 2) in the current posttraining study (FI,~ 0.21, 0.15, and 0.12), 3) in athletes (22), and 4) in isolated muscle (10) all indicate that inhomogeneity of muscle &/VO, is unlikely to systematically perturb the linearity of these relation-

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1074

CONVECTIVE

AND

DIFFUSIVE

0

0

FEMORi\

20

VENOUS

PO2

, torr

30

post-training

l? 2

600

SUPPLY

AFTER

1-e

pvo2 = pao2 . ewDo2’PQ

(I) where PvoZ is effluent venous PO,, Pao2 is arterial PO,, DO, is effective tissue 0, diffusing capacity, ,8 is capacitance coefficient for 0, content vs. PO, dissociation curve, and Q is blood flow. Then VO, maxcan be expressed as . vo 2 cv()2) = QO ’ (Pa02 - pv02) t2) where Cvo2 is venous 0, content and . vo 2max= QPPaoZ. (1 - e-Do2’Bg) = Q02. (1 - evDo2/BQ) (3) Because 0, extraction is the ratio of vo2max to Qo, max

I

CA&&U?Y301=02 , ‘0Orr

A&N 1200

T

900

600

TRAINING

the 0, transport pathways in the muscle. One way is to use the concept of Piiper and Scheid (16), who modeled the diffusion process with a linear dissociation curve. Although the O,-Hb dissociation curve is nonlinear over the normal range, almost all the 0, unloading takes place on the steep linear portion of the 0, dissociation curve, even in normoxia. Clearly, this is even closer to being true in hypoxia. Accordingly, the assumption of linearity is considered reasonable for the following qualitative analysis of 0, extraction. Piiper and Scheid showed that

600

d I

0,

training

A 7-

i

1

pm-training

1. 300

LEG

I

600

02

DELIVERY

I 1200

1

900

I 1500

, ml min-1

FIG. 3. Relationships between leg VO, (at TO, m,) and femoral venous PO, (top), calculated mean muscle capillary PO, (middle), and leg 0, delivery (bottom). Training increases VO, max at a given PO, or level of delivery.

ships. Unfortunately, there is no technique available to directly test this assumption, but Hogan et al. (9) recently showed that heterogeneity could not account for vo 2maxchanges (in isolated muscle) caused by changes in O,-Hb affinity (9). The data of Hogan et al. provide the best evidence so far that diffusion limitation rather than perfusion-Vo2 heterogeneity explains the residual 0, in femoral venous blood and the linear relationship between VO, and PfvoZ. A third, most likely, explanation for the pretraining VO, legat room air is that 0, supply to the tissues was not limiting V02max in these sedentary subjects breathing room air. A1thoug.h analysis shows that this behavior of the pretraining VO,~,, at 0.21 FI,, does not reflect random error, further studies are needed to determine reproducibility of the phenomenon and to explore its basis. Interpretation of 0, Extraction Data (Fig. 3, bottom) The changes in VO, maXcan be analyzed in terms of the diffusive (DO,) and the convective (Qo,)

&

l

(Ca02

-

0, extraction

1

post-

0-Y 0

30

=

components of

= 1 - e-Do2’Sg

(4) Thus, if Do,l& is constant at each FI,, (0.21, 0.15, and 0.12), then vo2 max and &o, measured at different FI,~ values fall on a straight line (Eq. 3). The slope of this line is the extraction ratio. This behavior is compatible with the actual pre- and posttraining measurements at each FI,~ (Fig. 3, bottom), although the slope of the VO, leg/Q~2 relationship increased with training. Assuming a constant slope of the content curve (p) (reasonable because Hb concentration was unaffected by training), changes in 0, extraction will rely on changes in the ratio of DO, to blood flow (QleJ. Then the contribution of the changes in $0, and DO, to the increase in VO,,, after training can be analyzed qualitatively as shown in Fig. 4, where the effects of all six hypothetical combinations of directional changes in Qlegand DO, are portrayed. 1) Lack of changes in both DO, and Qlegafter training (top left panel) (as is obvious) results in no changes in the tissue 0, extraction or in the VO, max measured at each FI?~. 2) A hypothetical increase in DO, (with training) without concomitant changes in Qleg(top right panel) raises Do2/Q1,, and, consequently, tissue 0, extraction. In this condition, VO, max after training will be higher for a given Qo,. The latter, by definition, will remain unchanged at each FI,~. 3) The converse situation, i.e., increase in Qlegwithout changes in DO, will decrease Do2/Q1,, and, in turn, tissue 0, extraction. This fall in 0, extraction partially offsets the rise in VO 2maxat each FI,~ caused by the increase in the (30, (middl e 1eft panel). 4) Another hypothetical situation consists of the parallel increase in both DO, and Qlegwith no change in Do,/Q,,. After training, VO, maxat each FI,~ will rise because of the increase in &o,, but the VO, maxat a given Qo, will not change because Do,/~&,, does not change (middle rightpanel).. 5) The bottom leftpanel mimics the actual behavior of Qo, and V02maxin the present study (Fig. 3, bottom).. It is the result of DO, increasing relatively more than Qleg.This increases Do,/&~,,. Thus, after training, the Vo2max at a given &o, (and hence the

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CONVECTIVE

DIFFUSING OXYGEN

AND

DIFFUSIVE

0,

SUPPLY

AFTER

1075

TRAINING

CAPACITY UNCHANGED DIIPFUSING CAPACITY INCREASED UfW-MNGm OXYGEN DELIVERY UNCHANGED

DELIVERY

DIFFUSING CAPACITY UNCHANGED OXYGEN DELIVERY INCREASED

DIFFUSING DELIVERY

CAPACITY INCREASED

& OXYGEN BY SAME

pr= x-

%

post

Ho /O 0*

4 /

DIFFUSING CAPACITY INCREASED DIFFUSING CAPACITY INCREASED MORE THAN OXYGEN DELIVERY LESS THAN OXYGEN DELIVERY

prc

o/9/’

/ /J post

/ 0

6 /I*;.

CONVECTIVE 02 DELIVERY CONVECTIVE 4. Six theoretical 0, delivery and muscle FIG.

potential outcomes of training: effects of chapges (by various relative diffusive transport on relationships between VO, max and O2 delivery.

tissue 0, extraction) rises. Additionally, because of the increase in Qo,, a movement of Vo2 maxupward and to the right is seen at each FI?,. The simultaneous increase in DO, and Qlegtogether with a rise in DO&&, constitutes an advantageous strategy in terms of tissue gas exchange. The deleterious effect of a shorter capillary transit time due to the increase in Qlegis overcome by the increase in DO,, thus increasing 0, extraction. 6) Finally, the bottom right panel shows the converse situation (i.e., a relatively greater increase in Qlegthan in Do2 with a subsequent decrease in Do,/Q1,,). In this hypothetical situation. the tissue 0, extraction decreases but the . vo 2max at each FI,~ may increase because of the rise . in Qo,. Thus the only situation consistent with our data (Fig. 3, bottom) is in the bottom left panel of Fig. 4, indicating that training 1) increased both Qo, and DO, and 2) that DO, increased relatively more than &o,. This analysis does not involve the numerical calculations necessary to compute mean capillary PO,, nor does it rely on VO,Pfv,, plots. It simply uses established theory (16) and direct measurements of Vo2 and Qo2 as the basis for argument. Relative Contributions of Convective and Diffusive Adaptations to Training to the Increase in VO,,,, The actual changes in DO, (mean over FI,, 0.15 and 0.12 of +6.5 ml. min-’ Torr-‘) and in Qleg(mean + 1.0 l

02

DELIVERY

amounts)

in convective

l/min) were used to estimate by numerical analysis the relative contribution of each of these two factors to the increase in VO 2legafter training. The cross-hatched bars in Fig. 5 correspond to the hypothetical increase in VO, ,&mean 35 ml/min) that would have been expected from the rise in Qleg alone, assuming that DO, had remained unchanged. The open bars indicate that by raising . DO, alone, assuming that Qeg had remained constant, vo 2legwould have increased by a greater amount (mean 85 ml/min), i.e., by a factor of >2 (P < O.Ol), than effects of blood flow alone. The sum of the individual effects (of DO, and Qlegeach increasing alone) on vo2 leg(35 + 85 = 120 ml/min) was less (P < 0.013) than the increase in the observed rise in v021eg (mean 164 ml/min), as indicated by the solid bars. This synergism is explained by the simultaneous increase in Qo, and in 0, extraction by preserving the Do,/Q,, (see EQ. 3). This interaction would seem to be an important contribution to increases in VO 21118X after training. In summary, 9 wk of exercise training increased vo21eg by 36.5%. This was accomplished by improvement in both convective and peripheral (diffusional 0, transport to the mitochondria) aspects of 0, delivery. Although blood flow increased by 19.2%, lumped parameter 0, diffusing capacity of muscle (DO,) increased by 33.5%. As a result, increased DO, contributed about twice as much to the increase in vo2 i,, as did increased blood flow. Synergism is exhibited by the simultaneous increases in

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1076

CONVECTIVE

AND DIFFUSIVE

0, SUPPLY

AFTER

TRAINING

creased HbO, affinity on vo2,, at constant 0, delivery in dog muscle in situ. J. AppZ. Physiol. 70: 2656-2662, 1991. 10. HOGAN, M. C., J. ROCA, P. D. WAGNER, AND J. B. WEST. Limitation of maximal 0, uptake and performance by acute hypoxia in in situ dog muscle. J. Appl. Physiol. 65: 815-821, 1988. 11. HONIG, C. R., T. E. J. GAYESKI, W. J. FEDERSPIEL, A. CLARK, AND P. CLARK. Muscle 0, gradients from hemoglobin to cytochrome: new concepts, new complexities. Adu. Exp. Med. BioZ. 169: 23-38,

250

1984. 12. HOWALD, H., H. HOPPELER, H. CLAASSEN, 0. MATHIEU-COSTELLO, AND R. STRAUB. Influences of endurance training on

5

”

12

15

% INSPIRED OXYGEN

5. Relative contributions to training-induced increase in 2maxfrom augmented diffusive transport in muscle (open bars) and increased O2 delivery alone (cross-hatched bars) and with increased 0, diffusive transport (filled bars). FIG.

the ultrastructural composition of the different muscle fiber types in humans. Pfluegers Arch. 403: 369-376, 1985. 13. KLOCKE, R. A. Kinetics of pulmonary gas exchange. In: Pulmonary Gus Exchange, edited by J. B. West. New York: Academic, 1980, vol. 1, chapt. 6, p. 174-213. 14. KNEHR, C. A., D. B. DILL, AND W. NEIJFELD. Training and its effects on man at rest and at work. Am. J. Physiol. 136: 148-156,

00

1942. 15. MOORE, SINOWAY,

and DO, in that the gain in VO, maxfrom both changes occurring together was greater than the sum of the calculated independent effects of these changes had they occurred alone. This synergism occurs because the effects of reduced transit time resulting from higher blood flow are offset by the increased diffusing capacity.

Physiol. 16. PIIPER,

Qo,

The authors thank Felip Burgos, Conxi Gistau, Teresa Lecha, Maite Sirno, and Carmen Argafia (Lung Function Laboratory) for technical support and Narcis Gusi for assistance in the training program. This study was supported by Direction General de Investigation Cientifica y Tecnica Grants DGICYT PA86-0345 and DEP90-0136, Direccib General de 1’Esport de la Generalitat de Catalunya Grant DGE 1988, Sociedad Espafiola de Patologia de1 Aparato Respiratorio Grant SEPAR-FAES 1988, National Heart, Lung, and Blood Institute Grant HL-17731, and California Tobacco-Related Diseases Research Program Grant TRD lRT-227. Address for reprint requests: J. Rota, Servei de Pneumologia, Hospital Clinic, Villarroel 170, Barcelona 08036, Spain. Received 10 April 1991; accepted in final form 7 February 1992. REFERENCES 1. ANDERSEN,

P., AND B. SALTIN. Maximal perfusion of skeletal mus-

cle in man. J. Physiol. Land. 366: 233-249, 1985. P. O., AND K. RODAHL. Textbook of Work Physiology. New York: McGraw-Hill, 1986, p. 330-348. 3. BARCLAY, J. K. A delivery-independent blood flow effect on skeletal muscle fatigue. J. Appl. Physiol. 61: 1084-1090, 1986. 4. BENDER, P. R., B. M. GROVES, R. E. MCCULLOUGH, R. G. MCCULLOUGH, S. Y. HUANG, A. J. HAMILTON, P. D. WAGNER, A. CYMERMAN, AND J. T. REEVES. Oxygen transport to exercising leg in chronic hypoxia. J. AppZ. Physiol. 65: 2592-2597, 1988. 5. BOHR, C. Uber die spezitische Tatigkeit der Lungen bei der Respiratorischen Gasaufnahme und ihr Verhalten zu der durch die Alveolarwand stattfindenden Gasdiffusion. Stand. Arch. Physiol. 22: 2. ASTRAND,

221-280, 6. EKBLOM,

1909.

B. Effect of physical training on oxygen transport system in man. Acta Physiol. Stand. Suppl. 328: l-45, 1969. 7. HENSON, L. C., D. C. POOLE, AND B. J. WHIPP. Fitness as a determinant of oxygen uptake response to constant-load exercise. Eur. J. AppZ. Physiol. Occup. Physiol. 59: 21-28, 1989. 8. HICKSON, R. $2, H. A. BOMZE, AND J. 0. HOLLOSZY.

Linear increase in aerobic power induced by a strenuous program of endurance exercise. J. AppZ. Physiol. 42: 372-376, 1977. 9. HOGAN, M. C., D. E. BEBOUT, AND P. D. WAGNER. Effect of in-

R. L., E. M. THACKER, G. E. KELLEY, T. I. MUSCH, L. I. V. L. FOSTER, AND A. L. DICKINSON. Effect of training/ detraining on submaximal exercise responses in humans. J. AppZ. 63: 1719-1724,

1987.

J., AND P. SCHEID. Model for capillary alveolar equilibration with special reference to 0, uptake in hypoxia. Respir. Physiol.

46: 193-208,198l. 17. PIRNAY, F., M. LAMY,

J. DUJARDIN, R. DEROANNE, AND M. PETIT. Analysis of femoral venous blood during maximum exercise. J.

AppZ. Physiol. 33: 289-292, 1972. 18. POOLE, D. C., AND G. A. GAESSER.

lactate thresholds

to continuous

Response of ventilatory and and interval training. J. AppZ.

Physiol. 58: 1115-1121, 1985. 19. ROBINSON, S., AND P. M. HARMON.

Effects of training and of gelatin upon certain factors which limit muscular work. Am. J. Physiol.

133: 161-169, 20. ROBINSON,

1941.

S., AND P. M. HARMON. Lactic acid mechanism and certain properties of the blood in relation to training. Am. J. Phys-

iol. 132: 757-769, 21. ROCA, J., A. A. RER, C. VIEGAS,

1941.

G. N. AGUST~, A. ALONSO, J. A. BARBER& A. FERR. RODRIGUEZ-ROISIN, AND P. D. WAGNER. Effect of the site of sampling in the measurement of femoral venous blood gases (Abstract). Physiologist 32: 229, 1989. 22. ROCA, J., M. C. HOGAN, D. STORY, D. E. BEBOUT, P. HAAB, R. GONZALEZ, 0. UENP, AND P. D. WAGNER. Evidence for tissue diffusion limitation of VOzmax in normal humans. J. AppZ. Physiol. 67: 291-299,1989. 23. ROCA, J., J. SANCHIS, R. RODRIGUEZ-ROISIN,

A. AGUST&VIDAL, F. SEGARRA, D. NAVAJAS, P. CASAN, AND S. SANS. Spirometric reference values from a Mediterranean population. Bull. Eur. Physio-

pathol. Respir. 22: 217-224, 1986. 24. SALTIN, B., G. BLOMQVIST, J. H. MITCHELL, R. L. JOHNSON, K. WILDENTHAL, AND C. B. CHAPMAN. Response to exercise after bed rest and after training. CircuZation 38, Suppl. 7: l-78, 1968. 25. SALTIN, B., AND P. D. GOLLNICK. Skeletal muscle adaptability: significance for metabolism and performance. In: Handbook of Physiology. SkeZetaZ MuscZe. Bethesda, MD: Am. Physiol. Sot., 1983, sect.

10, chapt. 19, p. 555-631. P. D. Diffusion and chemical reaction in pulmonary gas exchange. Physiol. Rev. 57: 257-312, 1977. 27. WAGNER, P. D. An integrated view of the determinations of maximum O2 uptake. In: Oxygen Transfer From Atmosphere to Tissues, edited by N. Gonzalez and N. R. Fedde. New York: Plenum, 1988, p. 26. WAGNER,

245-256. 28. WAGNER, P. D., J. R. SUTTON, GROVES, AND M. K. MALCONIAN.

J. T. REEVES, A. CYMERMAN, B. M. Operation Everest II: pulmonary gas exchange during a simulated ascent of Mt. Everest. J. AppZ.

Physiol. 63: 2348-2359, 29. WAGNER, P. D., AND

1988.

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