The carbon monoxide diffusing capacity in permanent residents at high altitudes

Respiration Physiology (1969) 6, 233-244; North-Holland Publishing Company, Amsterdam

THE CARBON MONOXIDE DIFFUSING CAPACITY IN PERMANENT RESIDENTS AT HIGH ALTITUDES’

J. E. REMMERS~AND J. C. MITHOEFER Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire 03755, U.S.A., and Instituto Bolivano de Biologio de Altura, La Paz, Bolivia

Abstract. DL, DM and Vc were determined by the steady-state carbon monoxide method in five residents of 3700 m and in four residents of 4500 m. Observed DL (Pao,; 100-150 mm Hg) and derived DM were greater than normal in residents of 3700 m but were nearly equal to sea level normal values in residents of 4500 m. Derived Vc was near normal in the first group, but was greatly increased in the second group. These differences most likely result from differences in true DM and Vc, with the exception that apparent DL and DM for the residents of 4500 m may be spuriously low. The changes in Vc agree well with the differences in predicted central blood volume, but the greater DM in residents of high altitude is difficult to reconcile with anatomical measurements in other high altitude species. It is concluded that in permanent residents at high altitude the diffusion and reaction components of the total resistance to oxygen uptake in the lung are decreased, an adaptation not present in acclimatized low-landers. Diffusing capacity High altitude

Membrane diffusing capacity Pulmonary capillary blood volume

At least for resting man at sea level, it is likely that pulmonary capillary blood reaches diffusion equilibrium with alveolar gas. However, under hypoxic conditions equilibrium for oxygen may not be achieved, and the rate of oxygen uptake by blood flowing through the pulmonary capillaries may limit the maximal rate of oxygen consumption. Based on calculations using normal sea level values for the oxygen diffusing capacity of the lung, it has been predicted that the resistance to diffusion of oxygen into the pulmonary capillary blood should begin to limit oxygen consumption during exercise at altitudes of 3500 to 4500 meters (BATES et al., 1966; JOHNSON, 1967). A greater pulmonary diffusing capacity, therefore, might impart considerable advantage to the high altitude resident. Accepted for publication 25 September 1968. 1 This work was supported by grants from the United Health Foundations, Inc. and from the U.S. Public Health Service, National Institutes of Health, HE 02888-l 1. 2 Postdoctoral fellow and Trainee in Physiology supported by NIH Training Grant, 5Tl HE-5322-06. 233

234

J. E. REMMERSAND J. C. MITHOEFER

Reported measurements of pulmonary diffusing capacity at high altitudes vary. Several investigations of acclimatized sojourners at high altitude have found no change in the carbon monoxide diffusing capacity (BARCROFT, 1925; WEST, 1962; KREUZER and VAN LOOKEREN CAMPAGNE, 1965). Yet, others have concluded that permanent residents of high altitude possess a greater than normal diffusing capacity (VELASQUEZ, 1956; DE GRAFF et al., 1965; GROVER, 1966). Part of the discrepancy may be a methodological in origin, but real differences may exist, both between acclimatized lowlanders and high altitude residents, and between long-term residents of different altitudes. Only scanty information is available regarding the pulmonary diffusing capacity in native residents of high altitude. VELASQUEZ(1956) observed a greater DL~* in residents of 4300 m than in sea level controls. In subjects native to 3200 m, DE GRAFF et al. (1965) and GROVER (1966) observed that the membrane diffusing capacity for CO, DM, was increased relative to sea level control, but the pulmonary capillary blood volume, Vc, was equal to the sea level value. Because of the questionable validity of the DL~~ determination, and because the subjects studied by DE GRAFF et al. (1965) and GROVER (1966) resided at an intermediate altitude, we feel that the question of possible alterations in diffusing capacity of permanent high altitude residents remains unanswered. This paper described the results of an investigation of DL~~, DM and Vc in two groups of high altitude residents, one native to 3700 m and the other native to 4500 m.

Methods All altitude experiments were conducted in La Paz, Bolivia (3700 m; average barometric pressure, 490 mm Hg) under ordinary laboratory conditions. Nine Andean Indians were studied, five had been local residents since birth and four had resided at 4500 m for 10 or more years preceding the study. The latter group was studied within 3 days after arriving in La Paz from 4500 m. All were judged to be free of pulmonary disease on the basis of history, physical examination, and chest X-ray. Experiments were also performed on five sea level residents in Hanover, New Hampshire (altitude 160 m). Because of differences in race and in physical characteristics, the sea level subjects cannot be considered a true “control” group for comparison with the residents of high altitude; the primary purpose of including this group is to document that our Deco procedure yields values of DL, DM and Vc which approximate published data for normals. DL,, was determined by a steady-state procedure, using end-tidal P,, to estimate were made with an infra-red analyzer alveolar P,,. Carbon monoxide measurements (Beckman, model 215) equipped with a 4-inch breathe-through cell. The meter housed in the analyzer was used for all CO readings. The response time of the meter was 0.5 set for 90% of full scale. Before and after each determination the analyzer was calibrated with N,, 0.19 “/, CO and 0.49 ok CO, and the gain was adjusted so that the last mixture produced full scale deflection. Although greater gain was required to

Dco achieve this sensitivity

IN RESIDENTS

AT HIGH ALTITUDES

in La Paz, reproducibility

and the shape of the calibration

235 curve

were similar to that observed at sea level. A mouthpiece was fitted to one port of the breathe-through cell, and a low dead space, non-rebreathing valve was attached to the other port. The latter separated inspired and expired gas. The total dead space of the circuit was 150 cc, and a flushing volume of 200 cc was found to be adequate for an accurate CO measurement of a single sample. Inspired mixtures containing 30, 60 or 1OO’A 0, (in N,) were prepared in 100 1 Douglas bags, using a dry gas meter to measure volumes. The subject, seated in an upright position, equilibrated with the inspired mixture for at least 5 min; then the inspired line was switched to a second bag containing approximately the same percent 02, to which enough CO had been added to produce a concentration of 0.04 to 0.05’%. After a one minute equilibration period, mixed expired air was collected for 2 min while consecutive meter readings of end-tidal CO concentration were recorded. Deco was measured at the three levels of FIN, in random order, allowing at least one-half hour between experiments. The CO tension of mixed venous blood, PV,,, was estimated by a breath-holding method (FORSTER et al., 1957) before and after each D,, procedure while the subject breathed the appropriate CO-free 0,/N, mixture. A brief period of hyperventilation was followed by a 30 set breath-hold; a forced expired sample was obtained and analyzed for Pco and PO,. If the latter differed from the measured Pa,, by more than loo/ the Pco was corrected according to the Haldane equation, M (Pc,/Po,)= COHb/O,Hb, using M=200 (arterial pH range: 7.40-7.50). “Effective” PA,,, end-ttdal Pco minus PV,,, was used in the calculation of DL as described by FORSTER et al. (1957). During the DL measurement on the altitude residents, arterial blood was sampled; for the sea level subjects end-tidal gas was sampled in a greased syringe. Pco2 and PO1 of these samples and of the mixed expired gas were determined by blood gas electrodes as described in a separate report (MITHOEFER et al., 1969). For each experiment a value of 8, the specific CO uptake rate of blood, was derived from the in oitro data of ROUGHTON and FORSTER (1957) from an estimate of mean pulmonary capillary oxygen tension, PCo2, assuming 1= 2.5 (2 is the ratio of red cell membrane to red cell interior permeabilities). PCoZ was assumed to be 10 mm Hg lower than PAN* for the sea level subjects. Somewhat different criteria were used in the case of the high altitude residents. Because of evidence which has been interpreted as indicating a greater than normal inequality of the regional distribution of ventilation relative to perfusion in these subjects (see below) and because of their polycythemia, it is likely that the difference, Therefore, PA,, - PC,,, was greater than normal at the lowest level of oxygenation. for the altitude residents, it was assumed that Pao2 and PCo, were equal for Pao2 > 150 mm Hg and that (Pa,, - Pco,) = 20 mm Hg for Pa,, < 150 mm Hg. 8 was multiplied by the ratio of the measured [Hb] to the normal value (14.9 g %) on the assumption that the CO uptake rate by blood is first order with respect to reduced Hb for any given I and Po,.

J. E. REMMERSAND J. C. MITHOEFER

236 Results

Age, height, weight, arterial hemoglobin concentration and altitude of residence are listed for each subject in table 1. Each high altitude resident is identified by the same number in this report as in the report of MITHOEFER et al. (1969), and the alveolararterial PO, differences for these subjects at three levels of Pro* will be presented in that report. In agreement with the results of a previous investigation (KREUZER et al., 1964), both groups of high altitude residents displayed abnormally large alveolar-arterial PO, differences for PI,, about 160 mm Hg, indicating that the regional distribution of alveolar ventilation, VA, relative to perfusion, Q, is more uneven than normal. TABLE 1 Subject characteristics. Age

Height

Weight

[Hbl

yrs

cm

kg

8%

Subject

Residents

of sea level

L.C.O.

35

150

60

R.E.

27

180

75

B.A.G.

28

185

87

C.W.

27

187

102

A.N.

24

182

75

Residentsof 3700 m 5

18

165

56

16

6

18

161

56

17

7

?

?

?

18

8

20

172

73

17

13

18

163

57

17

Residents of 4500 m 3 34 10 37

164

167

75 57

23.4 25.4

11

27

165

61

22.7

12

27

164

57

22.7

Calculation of diffusing capacity from the CO, dead space, as described by FILLEY, MACINTOSH and WRIGHT (1954), yielded extremely variable results, probably because the high VD/VT ratio for these subjects (0.3-0.45) made the estimate of PACT very sensitive to small measurement errors. Therefore, the results of that calculation have been omitted. Table 2 contains corresponding values of PAN, or Pao2, l/e, and DL for the three levels of F102. DL for each of the sea level subjects breathing air agrees well with predicted normal values based on age and height (BATES and CHRISTIE, 1964). At a comparable Pao2, mean DL,, for residents of 3700 m was significantly greater than for the sea level group (PC ,Ol); for residents of 4500 m, mean DL,, was very near the mean value for sea level subjects.

237

D,, IN RESIDENTS AT HIGH ALTITUDES TABLE 2 Results of Dco at three levels of FIO, for residents of sea level, 3700 m and 4500 m Mid-range High Oxygen Low oxygen Oxygen FIO, = .3 at altitude Fro, z 0.6 FIO, = 1.0 Fro, = .21 at sea Ievel Subject

Pao,*

l/et

DL

1.3 1.2 1.2 1.2 1.2

15.4 19.0 28.3 26.1 21.7

-

Pao,* -.

l/et

DL

Pao,*

l/Of DL

DM

Vc

430 430 41.5 405 415

3.2 3.2 3.1 3.0 3.1

10.3 12.5 15.8 20.0 14.4

650 580 640 560 540

4.5 4.0 4.5 3.9 3.8

25.4 28.0 42.6 32.4 30.6

52.6 71.3 87.6 160 88

31.8 C6.6

91.9 +40.7

118 69.6 57.8 105 75.4

Sea level residents

L.C.O. R.E. B.A.G. C.W. A.N.

120 110 100 100 105

Mean S.D. Residents

22.1 k5.22

of3700 M

5

128

6 7 8 13

113 125 115 100

1.2 1.1 1.0 1.0 1.0

Mean S.D. Residents

30.0 37.1 33.4 33.6 36.0

Mean S.D.

175 250 220 140

1.7 1.9 1.7 1.2

26.1 28.2 26.5 33.3

325

2.6

22.0

44.8

325

2.5

20.5

94.4

308

2.2

22.4

81.2

325

2.5

23.3

48.8

300

2.4

21.8

68.2

67.5 +21.1

34.0 f2.74

85.2 525.3

of 4500 m

3

10 11 12

7.5 10.9 13.9 18.2 14.2

135 126 88

0.8 0.8 0.7

22.2 24.0 23.0 23.1 +0.90

180 195 195 144

1.2 1.1 1.2 1.0

22.0 22.0 23.0 25.0

275 285 245 310

1.6 1.5 1.6 1.9

22.6 22.0 21.1 22.0

22.0 22.0 28.2 25.2

CT,

co

144 385

24.4 121.1

* Alveolar PO, is given for sea level residents. 7 ljff is based on estimated mean capillary PO, as described in the text and has been corrected for the subject’s Hb. PO, in mm Hg; l/3 in (ml/min . mm Hg per ml)-l; DL and DM in ml/mm . mm Hg (STUD);Vc in ml.

DL was separated into &independent and a e-dependent CO conductances according to the equation of ROUGHTON and FORSTER (1957).The parameters of this equation are equivalent values of DM and Vc for a homogeneous lung, and equal the true values only when DM and Vc are proportionately distributed throughout the lungs. It can be shown that when these two variables are distributed disproportionately, the derived DM and Vc must be less than the true values. DM and Vc for each subject, derived from the least squares regression of ~/DL on l/0, are given in table 2. Individual correlation coefficients exceeded 0.96 both for sea level subjects and for residents of 3700 m, but were lower for residents of 4500 m,

238

J. E. REMMERS

AND J. C. MITHOEFER

0.02

0.01 1.0

be

2.0

3.0

(m’/min.mmHy/m~)-’

Fig. 1. Relationship between ~/DL and l/e. Each symbol indicates the values for a given subject; open symbols: residents of 3700 m; closed symbols: residents of 4500 m. The lines are the least square regressions for each group. 0 Subject No. 5 n Subject No. 3 o Subject No. 6 l Subject No. 10 a Subject No. 7 A Subject No. 11 x’ Subject No. 8 i Subject No. 12 C$ISubject No. 13

60

D,

-

1 400

300

60

v

c

(ml 1

(tnin.tlnklg) 40

200

T 20

T too

Fig. 2. Bar graph illustrating mean and S.D. of DM and Vc for each group of subjects. Hatched bar is DM and open bar is Vc. Brackets indicate & 1 S.D.

Dco IN RESIDENTSAT HIGH ALTITUDES

239

probably because of the lesser slope in these subjects. However, considering the sea level subjects as a group, there is considerable variation around the least squares regression for the group (R=.184), apparently due to individual differences in DM and Vc. On an aggregate plot of ~/DL vs l/0 (fig. 1) the points for residents of 3700 m and for residents of 4500 m lie closely about two different lines, with correlation coefficients of 0.956 and 0.184, respectively. Group means of DM and Vc are presented in table 2 and fig. 2. Comparing residents of 3700 m with the sea level group, mean DM for the former was about twice that for the latter (PC .Ol), whereas mean Vc was nearly the same for both groups. Mean DM for residents of 4500 m was significantly less than for residents of 3700 m (P< .Ol), and was nearly equal to the mean value for the sea level group. Because the derived Vc for two of the residents of 4500 m was infinite, a mean value cannot be calculated. However, the reciprocal of the slope of the least square regression of ~/DL on l/e for the group was 377 cc, corresponding to a Vc three times mean Vc for the other two groups. Discussion Our results evidence two differences in the apparent pulmonary diffusion characteristics among the three groups. First, DL (PA,,; 100-l 50 mm Hg) and DM are greater in residents of 3700 m than in the other two groups. Second, Vc is greater in residents of 4500 m than in either other group. To assert that these apparent differences stem from differences in true DL, DM and Vc requires examination of the uncertainties in the measurement of DL by the steady-state procedure and in the derivation of DM and Vc. SOURCES OF ERROR A. Measurement of PA,, The rather large external

dead space resulting

from the use of a breathe-through

cell

could have introduced a systematic error. Other investigations have used automatic devices for end-tidal sampling (BATES, BOUCOT and DORMER, 1955; BATES and CHRISTIE,1964;FORSTER et al., 1957) yet our values of DL, DM and Vc for sea level man agree well with theirs. The simplicity of a breathe-through cell for measuring end-tidal Pco has obvious advantages for field experimentation. Furthermore, since F,, of the end-tidal gas probably varies during expiration, a breathe-through cell of relatively large volume tends to yield a value of PA,, approximating a volume mean. On this account, group differences resulting from sequential inhomogeneity of the alveolar expirate should be minimized. Incomplete washout of the CO meter sample cell by the alveolar expirate will result in an erroneous DL,,. Since a single 200 cc flush was found adequate to wash out the sample and, since the smallest calculated alveolar tidal volume was 400 cc, complete washout must have been achieved in all cases. Moreover, an error arising from incomplete dead space washout cannot explain the observed differences amongst the groups because the alveolar tidal volume was smallest in the residents of 3700 m, the

240

.I. E. REMMERSAND J. C. MITHOEFER

group which displayed the largest values of DL,,. Insufficient washout of the sample cell, causing an overestimation of PAco, leads to a spuriously low value of DL,,. B. Regional

inequality

of

VA/DL ratio and DM/VC ratio

The dependence of DL, measured by the steady-state method, upon regional differences in the ratio VAIDL has recently been analyzed by HATZFELD, WIENER and BRISCOE (1967) with a two compartment model. Measured DL equals true DL only when VA is distributed in proportion to diffusing capacity. In the presence of unequal VA/DL ratios, measured DL is less than the sum of the component diffusing capacities and, with increasing disparity of VA/DL ratio, measured DL falls progressively. Underestimation of DL will be associated with an equal underestimation of DM if the distribution of DL is independent of 0, that is, when the relationship of the 8-independent to the o-dependent conductance is the same in all regions of the lung. However, if DM is not distributed in proportion to Vc throughout the lung, i.e., if regional differences in DM/VC ratio exist, the distribution of DL will vary with 0. As a consequence derived Vc will be in error, and an additional error may be introduced into the estimate of DM which depends upon the regional distribution of both the VA/DL ratio and the DM/VC ratio. Theoretically, Vc can be either overestimated or underestimated, and the underestimation of derived DM resulting from regional VA/DL inequality may either be increased or decreased. Since measured DL must always be less than true DL, derived DM can never exceed true DM. In calculations with a two compartment model in which the distributions of Vc and DM were separately altered by four fold, derived Vc was found to deviate from true Vc by as much as + 40 %, whereas derived DM was as much as 80 ‘A less than true DM. Conceptually, this relatively greater possible error in DM results from the dependence of derived DM on the inequality in both ratios, VA/DL and DM/VC. The equation for DL as a function of the fractional distribution of VA and DL in a two compartment model given by HATZFELD et al. (1967) (eq. 3) predicts that measured DL will be a function of barometric pressure, such that a decrease in barometric pressure will lessen the deviation of measured DL from true DL for a given distribution VA and DL. However, this effect is extremely small for changes in barometric pressure over the range encountered in this study. In summary, errors in the determination of DL, DM and Vc by the steady-state procedure can be related to two types of regional inhomogeneity of the lungs, namely, inequality of the ratio VA/DL and inequality of the ratio DM/VC. The first causes underestimation of DL and DM, and the second can cause further underestimation of DM and either underestimation or overestimation of Vc. It is predicted that while DM can be greatly underestimated, it will not be overestimated, and errors in Vc will be small relative to those in DM. C. Uncertainties

in estimating

PC,, and h-,

Systematic errors in the estimation of PC,, may have biased the derived values of DM and Vc. Polycythemia,per se, will decrease PC,,, and an increase in Vc alone will have

Dco

IN

RESIDENTS AT HIGH ALTITUDES

241

a mixed effect. On the one hand, it will slow the rate of rise of PO, in blood flowing through the pulmonary capillaries while, on the other, it will increase the mean transit time for a constant 0. Although the net effect is not easily predicted, such errors in the estimate of PC,, will be greatest at the lowest Po2. ROUGHTONand FORSTER(1957) examined the variation in DM and Vc caused by varying the estimated PC,, over its maximum range at the lowest level of oxygenation. Their calculations indicate that uncertainty regarding PE,, in this range introduces a maximum variation in DM and Vc of 7 ‘A and 3 ‘A respectively. This excludes the possibility that errors in the estimation of PE,, can explain the observed differences in DM and Vc. It is possible that the in vitro data for 8 may not apply to blood of the Andean Indian. However, the similarity of the oxyhemoglobin dissociation curves for the Andean Indian and sea level man (HURTADO,1964) suggests that the kinetics of the reaction of Hb with 0, and, by inference, with CO are similar. 0 is also dependent upon the diffusion characteristics of the red cell which may be different in the Andean Indian. Unfortunately, no information is available on this point. But, as was demonstrated by ROUGHTONand FORSTER(1957), variations in ;1can produce large variations in DM and, hence, the observed differences in DM might be the result of differences in 1 amongst the groups. INTERPRETATION OF OBSERVED DM ANDVc A larger DL (PAN,; 100 to 150 mm Hg) for residents of 3700 m compared to the sea level subjects almost certainly represents a real increase in diffusing capacity. Assuming that differences in regional diffusing capacity result principally from differences in regional perfusion, the distribution of VA/DL should parallel the distribution of VA/Q. Our evidence indicates that regional VA/Q ratios and, presumably, regional VA/DL ratios are more unequal in the high altitude residents than in normal residents of sea level. Accordingly, the difference in true DL was probably at least as great as the observed difference. Unless the distribution of DM relative to Vc was grossly different for the two groups, an appreciable difference in true Vc is unlikely. As a corollary, the difference in apparent DM most probably stemmed from differences in true DM. The three-fold increase in apparent Vc for residents of 4500 m over the other two groups is too large to be accounted for by regional inhomogeneity. The finding that DM is 60 % less in residents of 4500 m than in residents of 3700 m might certainly be erroneous, but, of course, a lower true DM in residents of 4500 m is not excluded. It is of interest that acute increase in pulmonary blood volume in the anesthetized dog elevates apparent Vc without changing the derived DM (STAUB,NAGANOand PEARCE, 1967). In summary, the apparent differences among the groups probably reflect, in part, differences in true DL, DM or Vc with one exception: the derived DM for residents of 4500 m may have been underestimated, and the apparent difference in DM between the two groups of high altitude residents may be spurious.

242

J. E. REMMERS

AND J. C. MITHOEFER

COMPARISON WITH RESULTS OF OTHER STUDIES

Investigations of DL,, after acclimatization of lowlanders to altitude have failed to demonstrate a change in DL, DM or Vc. (BARCROFT, 1925; WEST, 1962; KREUZER and VAN LOOKEREN CAMPAGNE, 1965). Both steady-state and single-breathe procedures have been used, and altitudes of acclimatization have ranged from 3200 to 5800 m. In contrast, a study of permanent residents of 3200 m by a single-breath method (DE GRAFF et al., 1965; GROVER, 1966) yielded results in accord with those of the present study, namely that DM in residents of this altitude was twice that of sea level residents and that Vc did not differ between the two groups. A greater membrane diffusing capacity in residents of high altitudes presents an enigma. Intraspecific comparison of alveolar dimensions of sea level and high altitude sheep and guinea pigs failed to demonstrate a differer_ce in total alveolar surface area or surface area per unit lung volume (TENNEY and REMMERS, 1966). Although an estimate of pulmonary capillary surface area might be more relevant, the finding that Vc does not differ from sea level values in residents of 3200 m or 3700 m suggests that a difference in functional capillary surface area is not a major factor. Assuming that the results of these morphologic comparisons apply to man, the differences in DM could be explained by a difference in lung volume or by a difference in the specific diffusing characteristics of the alveolar-capillary membrane or in the specific CO uptake rate of blood. The latter seems unlikely. An increased FRC over sea level control values has been well documented in acclimatized lowlanders (TENNEY et a/., 1953) and in residents of high altitude (HURTADO, 1964). However, these changes in lung volume (.3-.5 L) would seem to be too small to account for the observed differences in DM considering the magnitude of the variation of steady-state DL with changes in lung volume (8 ml/min/mm Hg per L) (GRAPE and TYLER, 1958). The observed changes in pulmonary capillary blood volume can be compared with predicted changes in central blood volume (CBV) for the two groups of high altitude residents. From the data of MEDAL et al. (1960) the total blood volume (TBV) should be slightly reduced in residents of 3700 m (70 ml/kg) and should be substantially increased in residents of 4500 m (90 ml/kg). Central blood volume comprises a greater fraction of the total blood volume in high altitude residents than in sea level residents (CBV/TBV: 0.15 for sea level subjects, 0.21 for residents of 4300 m) (MONGE et al., 1955). Using 0.17 for the ratio CBV/TBV for residents of 3700 m and 0.20 for residents of 4500 m, predicted CBV for these two groups is 0.71 and 1.04 L, respectively. For sea level subjects of comparable weight, a value of 0.675 is predicted. Therefore, when compared with sea level subjects. CBV should be about 35 cc greater for residents of 3700 m and about 325 cc greater for residents of 4500 m. The group differences in Vc closely match these predicted differences in CBV. This agreement might suggest that the capillary bed is the major site of increase in pulmonary blood volume in high altitude residents. But, in view of the uncertainty in our estimates of Vc, it seems warranted to conclude only that Vc and CBV undergo roughly similar increase with altitude.

243

Dco IN RESIDENTSAT HIGH ALTITUDES In summary,

our results

are consistent

with those obtained in residents of 3200 m Previous studies of the morphometry of the lungs of other species native to high altitude lead to the inference that the greater than normal DM of residents of 3700 m does not result from structural changes. The

(DE GRAFF et al., 1965; GROVER, 1966).

differences

in Vc among the three groups studied parallel

EFFECT OF CHANGESIN DM

AND

predicted

differences

in CBV.

Vc ON OXYGENUPTAKE RATE AT HIGH ALTITUDE

Increased DM or Vc could enhance the maximum capacity for aerobic work at high altitude by decreasing the membrane or the blood component of the total pulmonary resistance to oxygen uptake. In the presence of polycythemia without change of Vc, the blood component of total resistance will be reduced because of a greater 8o,. A relationship between maximum oxygen uptake rate and inspired Po, can be predicted for a given DM and Vc, but the independent effect of a change of DM or Vc will be determined by the relative extent to which the membrane and blood components are limiting. Estimation of the latter is greatly complicated by the nonlinearity of the oxyhemoglobin dissociation curve and by the dependence of do, on O,Hb% saturation. However, studies by MOSTYN et al. (1963) suggest that an increase of Vc over normal confers physiological advantage under conditions when the rate of 0, uptake in the lung might limit the maximum rate of oxygen consumption. Acknowledgements We wish to thank Professor J. VELLARD for making available to us the facilities of the Instituto Bolivano de Biologia de Altura, Dr. L. ALEXANDER for his cooperation in all phases of this work, and Dr. G. ZUBIETTA for his assistance in the execution of the study. We gratefully acknowledge the help of many discussions with Dr. S. M. TENNEY.

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244

J. E.

REMMERS

AND J. C. MITHOEFER

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