Effect of plasma proteins on oxygen diffusion in the pulmonary capillaries

MICROVASCULAR

RESEARCH

7,120-130 (1974)

Effect of Plasma

Proteins

on Oxygen

in the Pulmonary

Diffusion

Capillaries

SARAH C. BRYANT AND R. M. NAVARI’ Department of Chemistry, Hollins College, Hollins College, Virginia 24020 Received June 27,1973 In the consideration of the gaseous diffusion capacities of the pulmonary membrane, the blood plasma, and the red blood cell, it has been calculated that the pulmonary membrane, and, in particular, the blood plasma may be major resistances to the gas transfer from the alveoli of the lungs to the hemoglobin molecules of the red cells. In vitro measurements of the effect of plasma protein concentrations on the diffusivity of oxygen show that the diffusivity can undergo a fivefold change as the plasma protein concentration is varied between the extremes of the normal physiological range. As a result, it appears that the overall gas transfer may be affected and possibly limited by altering the gaseous diffusion coefficient in plasma through changes in the concentration of the plasma proteins. INTRODUCTION

The movement of the alveolar gases from the inside of the alveoli to the hemoglobin of the red blood cells contained by the pulmonary capillaries is a mass transfer process (Gurtner and Fowler, 1971; Johnson, 1966). The pathway of oxygen in the lungs from the alveolus to the inside of the red blood cell consists of the pulmonary membrane, the plasma, and the red blood cell membrane. The mass transfer in the pulmonary membrane consists of both convection and/or molecular diffusion (Johnson, 1966; Roughton, 1959; Sinha, 1969). The transfer through the plasma which separates the inside surface of the capillaries from the red cells is a process of molecular diffusion and some convection due to the hydrodynamic conditions in the capillaries (Aroesty and Gross, 1970; Roughton, 1959; Sinha, 1969). Following the passage through the plasma layer, there is diffusion through the red cell membrane followed by diffusion plus chemical reaction in the interior of the red cell (Forester et al., 1959; Sinha, 1969; Wise and Houghton, 1969). A knowledge of the relative resistances of the various sequential mass transfer processes of oxygen in the pulmonary capillaries is necessary in order to determine the rate limiting step(s). This may lead to a possibility of controlling the gas transfer processes both in the pulmonary and the systemic capillaries. Many authors have considered the magnitude of the resistance associated with the red blood cell membrane in the oxygen multistage mass transfer path (Kreuzer and Yahr, 1960; Roughton, 1963; Sirs, 1970; Stein et al., 1971). Comparatively few studies, 1Present address: Division of Cardiopulmonary Laboratories and Research, Virginia, P. O.,Box 614, MCV Station, Richmond, Virginia 23298. Copyright 0 1974 by Academic Press, Inc. 120 All rights of reproduction in any form reserved. Printed

in Great

Britain

Medical College of

DIFFUSION IN PULMONARY

CAPILLARIES

121

however, have considered the resistancesprovided by the plasma and the pulmonary membrane. This situation exists even though Roughton (1959) pointed out that these resistancesmay be at least one-third to one-half of the total resistanceto gas transfer, and other investigators (Johnson, 1966; Sirs, 1970) regard the mass transfer of the respiratory gasesthrough the plasma and the pulmonary membrane as important steps in the masstransfer process. Recently, Sinha (1969) attempted to evaluate the relative magnitude of the mass transfer resistance of the plasma layer, the capillary walls, and the surrounding tissue in the systemic and the pulmonary circulation. Through the use of a microspectrophotometer technique, he measured the uptake of oxygen by red cells with a measured thickness of plasma over them, inside a cat’s mesenteric capillaries, and inside frog lung capillaries perfused with cat blood. He found that with a plasma layer of approximately 3 pm, the red cells were responsible for fifty percent of the resistance,but plasma layers of 3-10 pm in thickness can account for 50-90 “/, of the total resistanceto gaseous masstransfer. The work of Sinha suggeststhat in the pulmonary capillaries where the masstransfer path of the combined pulmonary membrane and plasma layers is approximately 3 pm, 2 pm for the pulmonary membrane (Johnson, 1966)and 1 pm for the plasma layer (Meessen, 1961; Whitmore, 1968), the resistance may be 50% of the total resistance. This result compares favorably with Roughton’s (1959) estimation of the relative resistances.Sinha’s measurementsalso suggestthat in the systemiccapillaries where the oxygen molecule must travel through a path of greater than 3 pm in the plasma layer, the red cell resistancemay become less than one-half of the total resistance. Since the work of Roughton (1959), there have been many investigations on the lung diffusion capacity of carbon monoxide (Brashear and Pamintuan, 1971; Gurtner and Fowler, 1971; Suwa and Bendixen, 1972) and of oxygen (Cohen et al., 1971; Rosenhamer et al., 1971; Wagner and West, 1972). Johnson (1966) and Wagner and West (1972) have given values for the oxygen diffusion capacity of the combination of the plasma and the pulmonary membrane, and these data indicate that the combined resistanceof the plasma and the pulmonary membrane is over 50 ‘A of the total resistance to the overall gaseous mass transfer. None of these investigators have attempted to approximate the individual resistancesof the plasma layer and the pulmonary membrane. It is the purpose of this work to estimate the relative contribution of the pulmonary membrane and the plasma layer to the overall masstransfer resistance,and to illustrate that the overall masstransfer of the alveolar gasesin the pulmonary capillaries may be affected and possibly limited by altering the value of the gaseousdiffusion coefficient in plasma. ANALYSIS Roughton and Forester (1959) proposed the following for the diffusion capacity of the lung (DL) : (1) (l/D3 = (l/&i) + W~c’,). where D, is the diffusion capacity of the pulmonary membrane and the plasma combined, 8 is the diffusion capacity of 1 ml of blood, and V, is the pulmonary capillary

122

BRYANT AND NAVARI

volume. The resistance to mass transfer provided by the pulmonary membrane and the plasma is given by R = (l/&J,

(2)

and the individual resistances of the pulmonary membrane (RPM) and the plasma (RPL) can be described by

R = (1/&) = RPM+ RpL.

(3)

Both RPMand RpL have the form RPM= bk.&dPM) and&. = GAdPLI whereL is the ej2ctiue pathlength of the masstransfer process,k is the masstransfer coefficient, and A is the area available for masstransfer. The separate resistancesof the plasma and the pulmonary membrane could be obtained if the individual values of L, k, and A were known. Although reasonably good estimations of L and A can be made from the available data in the literature, the values for k,, and kpL are much more difficult to obtain. The mass transfer coefficient k includes both the convection and the molecular diffusion portions of the masstransfer process,and it appearsthat no values for kPMexist. However, Aroesty and Gross (1970) have shown that in plasma, mass transfer due to convection is important only in the transfer of materials such as macromolecules, and the mass transfer of gases is a diffusion process.This appears to be true at least for the Bolus flow model. As a result, for gaseous mass transfer such as oxygen in the pulmonary capillaries, kpL can be considered to be the diffusion coefficient of oxygen in plasma (d,,,3, and the plasma resistanceto the diffusing oxygen can be expressedas RpL = (LPL/dPLAPL).Itshould now be possible to estimate the individual resistancesof the pulmonary membrane and the plasma by calculating RpL from the available data in the literature and comparing it with the combined plasma-pulmonary membrane resistance R = (I/&) which can be obtained from the available values of & for oxygen. Using values from the literature for LpL, APL,and dpL, maximum and minimum values of the diffusion resistance (RPL) of the plasma to oxygen masstransfer were calculated, and they are shown in Table 1. Maximum and minimum values of R were calculated using the value of D, for oxygen reported by Roughton (1959) and Johnson (1966) for a resting physiological state at a wide range of oxygen partial pressures (40 mm Hg, venous blood-100 mm Hg, saturated alveolar gas). The normal value of R was calculated at a normal arterial blood partial pressure of oxygen of 95 mm Hg. The values of the masstransfer path length and surface area will vary among individuals as shown by the range of values listed in Table 1. There have been somesuggestions in the literature (Bloch, 1962) that the red cell passesthrough the capillaries in a deformed manner such that there is effectively no plasma barrier. Although this may be true for somevessels,this does not appear to be true in most instances (Meessen, 1961; Sinha, 1969; Whitmore, 1968). The path length and surface area variations will obviously affect the resistances.However, it does not seemlikely that there would be any convenient method to alter or control the dimensions of pathlength or surface area. It may be possible, however, to exert some control over the diffusion coefficient in the plasma layer. Navari, Gainer, and Hall (1971) have shown that the mean diffusivity of oxygen in plasma is altered from 45 to 70 % as the concentrations of the plasma proteins albumin

DIFFUSION

IN PULMONARY

123

CAPILLARIES

and gamma-globulins are varied over a normal physiological range. Such a variation would certainly alter the diffusion resistance of the plasma to a large degree, and it may be practical to clinically control the concentrations of the plasma proteins in an individual (Bennhold, 1966; Van Beaumont et al., 1972; Van Beaumont et al., 1973). In order to obtain a complete description of the variation of the diffusivity of oxygen in plasma with the concentration of the plasma proteins, a series of experiments were performed in this study using the fabricated plasma steady-statediaphragm cell system previously employed by Navari, Gainer, and Hall (1971). The fabricated plasma is an aqueous solution containing all of the constitutents of normal human plasma which TABLE 1 OXYGEN

MASS TRANSFER

RESISTANCE

OF THE PULMONARY

Normal

AND THE PLASMA

Plasma and pulmonary membrane

Plasma Minimum

MEMBRANE

Maximum

Minimum

Normal

Maximum

1.1 x 10-4 1.75 x 10-h 3.1 x 10-e 0.75 x 1o-4 (Meessen, 1961; Whitmore, 1968) (Johnson, 1966) 2.3 x lo3 4.7 x lo3 (Whitmore, 1968) (A, cm’) Oxygen diffusion coefficient 1.6 x 1O-5 (& 37”C, cm2/sec.) (Navari, Gainer, and Hall, 1971) Oxygen diffusion capacity 65 >65 (D,, cm3/min/mm Hg) (Johnson, 1966; Roughton, 1959) Oxygen mass transfer 0.99 2.97 9.23 23.1 1.49 9.72 resistance (1O-3 sec/cm3) Diffusion pathlength 6% cm) Surface area

includes proteins, nonprotein nitrogen compounds, carbohydrates, lipids, organic acids, and inorganic ions. In this study, oxygen diffusion coefficients were measured as a function of the concentration of the plasma proteins a,-globulins, a,-lipoproteins, and &-lipoproteins. Theseproteins have a normal physiological range of concentration and have not previously been studied in terms of their effects on oxygen diffusivity. The oxygen diffusion coefficients were separately measured as a function of the concentration of each of the above mentioned plasma proteins. During each measurement, the concentration level of the remaining proteins, the nonprotein nitrogen compounds, the carbohydrates, the lipids, the organic acids, and the inorganic ions were held at the average levels in normal human plasma. MATERIALS

AND METHODS

The fabricated plasma was prepared by dissolving the various plasma constituents in completely degaseddistilled water at 37°C. Table 2 lists the various protein constituents in the fabricated plasma. Following dissolution, the solution was buffered to the desired pH of 7.41, and measurements of pH and density were made throughout the experiments. No changes were noted in the values of pH or density before and aft-r

124

BRYANT AND NAVARI TABLE

2

PROTEIN CONSTITIJENTSOF NORMAL HUMAN PLAFMA

Constituent Proteins Albumin a,-globulins: q-lipoprotein (1.093-l .148 g/ml) c&obulins p-globulins : &lipoprotein (0.99-l .03 g/ml) a-metal binding globulin Gamma-globulins Fibrinogen

Normal range Wl~ ml)

Average value (l3/1~ ml)

2.80-4.50

3.50

0.35-0.53 0.40-0.90

0.44 0.65

0.33-0.45 0.40 0.70-1.50 0.30

0.39 0.40 1.10 0.30

each diffusion measurement; this indicated that no significant denaturation or degradation of the solutions occurred. The diaphragm cell, shown in Fig. 1, was immersed horizontally in a thermostated water bath controlled to O.Ol”C. The cell was filled with the plasma at a constant temperature and under vacuum according to the procedure recommended by Gordon (1945). Oxygen was passedthrough one of the compartments saturating this side of the cell. The carrier gas used for the Beckman GC-2A gas chromatograph was helium, and this was passedcontinuously through the other cell compartment, removing any diffused oxygen from the solution and keeping the oxygen concentration in this compartment very close to zero. When the helium-oxygen gas stream passedthrough the compartment, it was vented either through a soap bubble meter for measuring the flow rate or passedinto the gas sampling valve of the gas chromatograph for analysis of oxygen content. The oxygen solubility on each side of the cell was measured before each diffusion coefficient measurement. To Gas Chromatograph Bar Magnet ‘” glass Water

Enclosed

7

.I

Bath

I

i

Metering Valve

Tube

L--l

(9cm. dia.. 5 micron

F

iP

L presoturator

LPresatur.tor

FIG. 1. Schematic of diaphragm cell apparatus.

DIFFUSION IN PULMONARY CAPILLARIES

125

The gas dispersion method and the glass stirrers provided the necessary mixing of the fabricated plasma in each compartment. Diffusivity values of oxygen in water at 25°C (2.25 x 10e5 cm Z/set) and at 37°C (2.75 x 1O-5cm ‘/set) were used to calibrate the cell and were found to be independent of the speed of rotation of the glass stirrers. This was also found to be true for the measurements of oxygen diffusivity in the more concentrated plasma protein solutions. The maximum relative error of each diffusivity measurement was +3.15 %. A detailed description of the fabricated plasma and the steady-state diaphragm cell can be found elsewhere (Navari, Gainer, and Hall, 1971). This experimental technique has been used extensively with good success by other investigators for gaseous diffusion in both pure liquids (Tham, Bhatia, and Gubbins, 1967) and single protein solutions (Jalan and Walker, 1973). RESULTS The measurement of the oxygen diffusivity was performed with fabricated plasma solutions which contained all of the constituents of normal plasma at an average concentration except that plasma protein which was being studied. This particular protein was initially withheld from the solution and then added in equal increments after each diffusion determination was made. In this way, values of oxygen diffusivity as a function of the normal physiological concentration range of the plasma protein were obtained. Figures 2 and 3 illustrate the previously mentioned data of Navari, Gainer, and Hall (1971) which show the effect of the concentrations of albumin and gamma-globulin on oxygen diffusivity. Note that there is a large change in the diffusivity over the normal physiological concentration range. Figures 46 gives the variation of the oxygen

e

0

e

0

e 6

1.25

0

0

e

? 8

0

e

t

GRAMS

ALBUMIN/l00

ml.

FAB

PLASMA

FIG. 2. Variation of oxygen diffusivity in plasma with albumin concentration

(0 - 37°C; 0 - 25°C).

126

BRYANT AND NAVARI 2.

I

I

I

I

0 8

1.7

0 8

t

0 e

0

1. 8

Q

0

e

+ l.25-

0

e 8

l.co-

8 0

075 0.0 GRAMS

1 I 0.4 0.8 GAMMA-GLOBULINS/100

I 1.2

8

I 1.6 20 ml. FAB. PLASMA

FIG. 3. Variation of oxygen diffusivity in plasma with gamma-globulin concentration (O - 37°C; @- 25°C).

diffusion coefficients as a function of the concentration of the proteins az-globulins, a,-lipoproteins, and /&-lipoproteins. The manner in which the az-globulins affect the oxygen diffusivity appears to closely resemble both in magnitude and specific shape of variation the effects of albumin and gamma-globulins on the oxygen diffusivity. It is especially important to note that the variation over the normal physiological range is quite similar.

GRAMS

K2-GLOBULINS/100

ml. FAB.

PLASMA

FIG. 4. Variation of oxygen diffusivity in plasma with a&obulin

concentration.

DIFFUSION IN PULMONARY CAPILLARIES

0.6 0.0 cl2 04 GRAMS c-z,-LIPOPROTEIN

127

0.8 1.0 1.2 1100 ml FAB. PLASMA

FIG. 5. Variation of oxygen diffusivity in plasma with a,-lipoprotein concentration.

However, the changes in concentration of q-lipoprotein and p,-lipoprotein over their normal physiological ranges do not appear to have a large effect on the oxygen diffusivity. In fact, each of the proteins appears to have the same small effect in the physiological range. In order to investigate the possibility of even larger variation in the oxygen diffusion coefficients than those shown in Figs. 2-6, measurementsof oxygen diffusivities were performed in fabricated plasmas in which all of the previously investigated proteins

“$ , , , , , 1 0.0 a2 a4 0.6 GRAMS ~iLIPOPROTEIN/lOO

0.8 1.0 1.2 ml. FAB. PLASMA

FIG. 6. Variation of oxygen diffusivity in plasma with /3,-lipoprotein concentration.

128

BRYANT

AND

NAVARI

were simultaneously held at either extreme of the normal physiological concentration range, while the concentration levels of the remaining constituents were the sameas the averagelevels in normal human plasma. Table 3 shows the results of these experiments, and it is obvious that the variation in the diffusion coefficient is much greater when the concentration of the plasma proteins are simultaneously varied in the samedirection. Table 3 also contains a calculation of the oxygen masstransfer resistanceof the plasma based on the values of the diffusion coefficients of oxygen in the high protein and low protein plasma solutions. It is very important to note that the five-fold variation in TABLE 3 EFFECTSOF PLASMA CONSTITUENTSON OXYGEN DIFFUSIVITY AND ON OXYGEN MASS TRANSFER RESISTANCEOF PLASMA

Oxygen mass transfer resistance of plasma (RpL, 10v3 sec/cm3) Plasma constituents concentration (g/100 ml)

Oxygen diffusivity at 37°C (cm’/sec)

Minimum

Maximum

High albumin (4.50) 0.53 x 10-S High gamma-globulins (1.50) High a,-lipoprotein (0.53) High a,-globulins (0.90) High &lipoprotein (0.45) All remaining constituents at an average concentration

3.01

9.03

Average concentration of all constituents

0.99

2.97

0.64

1.93

1.61 x 1O-5

Low albumin (2.50) 2.49 x lo-5 Low gamma-globulins (0.70) Low a,-lipoprotein (0.35) Low a&obulins (0.40) Low PI-lipoprotein (0.33) All remaining constituents at an average concentration

oxygen diffusion coefficients produces a large variation in the plasma resistance. A comparison of the magnitude of the range of the plasma resistance (RPL= 0.649.03) with the combined resistanceof the plasma and the pulmonary membraneunder normal conditions (R = 9.72, Table 1) shows that the plasma resistancecan vary from approximately 10% to over 90 % of the combined resistanceof the plasma and the pulmonary membrane during a normal resting physiological state. During exercise, the value of & increases (Gurtner and Fowler, 1971; Miller and Johnson, 1966), thus reducing the value of R, and as a result, the portion of the combined resistancedue to the plasma layer alone should be increased. DISCUSSION The measurement of the diffusivity of oxygen in the fabricated plasma solutions has shown that the diffusivity will vary over a fivefold range as the proteins’ concentrations simultaneously changefrom the lower to the higher extremesof the normal physiological

DIFFUSION

IN PULMONARY

CAPILLARIES

129

concentration range. It appears that the changesin the concentrations of the proteins albumin, gamma-globulins, and q-globulins have the most effect on the magnitude of the oxygen diffusivity. The large changesin the oxygen diffusivity in plasma obviously have an enormous effect on the magnitude of the resistance of the plasma layer to oxygen mass transfer. This is especially important since the estimated values for the resistancesof the pulmonary membrane and the plasma show that when a mean value of oxygen diffusivity in plasma is employed, the plasma resistance is the same order of magnitude as the resistance provided by the pulmonary membrane. A fivefold change in the oxygen diffusivity in plasma will have large effectson the relative magnitudes of the resistances, and it appears that the plasma resistance can be a significant portion of the combined resistance of the plasma and the pulmonary membrane. These observations show the importance of the plasma layer and the pulmonary membrane in the normal gaseousmasstransfer in the pulmonary capillaries. This work concentrated on the diffusion coefficients in plasma since it is the one variable in the resistancewhich has the possibility of being externally controlled. There does not seem to be any convenient method of externally altering or controlling the dimensions of the pathlength or the surface area. Thesedimensions are important, however, and can have large effectson the masstransfer resistances.In fact, Krueger, Bain, and Patterson (1961) have shown that there is a density gradient in the lung which may be due to uneven distribution of the blood in the capillaries or due to an uneven size distribution of the alveoli and/or the capillary vessels.A larger blood volume in certain capillaries might increase the diffusion pathlength in the plasma layer, thus increasing the diffusion resistance of the plasma. The uneven size distribution of the alveoli and the capillary vesselscould, of course, alter the pulmonary membrane mass transfer resistance in either direction depending on the particular values of the pathlength and the surface area. ACKNOWLEDGMENT

The Research Corporation is gratefully acknowledged for providing part of the financial support for this investigation. REFERENCES AROFSTY, J., AND GROIN,J. F. (1970). Convection and diffusion in the microcirculation.

Microvasc. Res. 2, 247-267. BENNHOLD, H. (1966). Transport function of the serum proteins. In “Transport Function of the Plasma Proteins” (P. Desgrez and P. M. DeTraverse, eds.), pp. 1-5. Elsevier Publishing Co., New York. BU)CH, E. H. (1962). A quantitative study of the hemodynamics in the living microvascular system. Amer. J. Anat. 110, 125-145. BRASHEAR, R. E., AND PAMINTUAN, R. L. (1971). Increased pulmonary diffusing capacity and elevated cerebrospinal fluid pressure. J. Appl. Physiol. 30, 844-846. COHEN, R., OVERFIELD, E. M., AND KYL~TRA, J. A. (1971). Diffusion component of the alveolararterial oxygen pressure difference in man. J. Appl. Physiol. 31,223-226. FORESTER,R. E., ROUGHTON, F. J. W., KREUZER, F., AND BRISCOE,W. A. (1959). Photocolorimetric determination of rate of uptake of CO and 0, by reduced human red cell suspensions at 37°C. J. Appl. Physiol. 11, 260-268. GORWN, A. R, (1945). The diaphragm cell of measuring diffusion. Ann. N. Y. Acad. Sci. 46,285-310.

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GURTNER,G. H., ANDFOWLER,W. S. (1971). Interrelationships of factors affecting pulmonary diffusing capacity. .I. Appl. Physiol. 30, 619-624. JALAN, V. M., AND WALKER, R. D. (1973). Diffusion of nitrous oxide in aqueous albumin solutions. Presentation at the 75 thNationa1 Meeting of the American Institute of Chemical Engineers, Detroit. JOHNSON, P. C. (1966). Respiratory gas exchange and transport. In “Physiology” 2nd edition (E. E. Selkurt, ed.), pp. 447-470. Little, Brown and Company, Boston. KREUZER,F., AND YAHR, W. Z. (1960). Influence of the red cell membrane on the diffusion of oxygen. J. Appl. Physiol. 15, 1117-l 122. KRUEGER,J. J., BAIN, T., PATTERSON,J. L. (1961). Elevation gradients of intrathoracic pressure. J. Appl. Physiol. 16,465-468. MEESSEN, H. (1961). Physiology of the pulmonary circulation. Stanford Med. Bull. 19, 19-21. MILLER, J. M., AND JOHNSON,R. L. (1966). Effects of lung inflation on pulmonary diffusion capacity at rest and exercise. J. Clin. Invest. 45,493~500. NAVARI, R. M., GAINER,J. L., ANDHALL, K. R. (1971). A predictive theory for diffusion in polymer and protein solutions. AZCHE J. 17, 1028-1036. ROSENHAMER, G. J., FRIESEN,W. O., AND MCILROY, M. B. (1971). A bloodless method for measurement of the diffusion capacity of the lungs for oxygen. J. Appl. Physiol. 30,603-610. ROUGHTON,F. J. W. (1959). Diffusion and simultaneous chemical reaction velocity in hemoglobin solutions and red cell suspensions. Progr. Biophys. Biophys. Chem. 9,54-104. ROUGHTON,R. J. W. (1963). Kinetics of gas transport in the blood. Brit. Med. BUN. 19,80-89. ROUGHTON, F. J. W., AND FORESTER, R. E. (1957). Relative importance of diffusion and chemical reaction rates in determining rate of exchange of gases in the human lung, with special reference to time diffusion capacity of pulmonary membrane and volume of blood in the lung capillaries. J. Appl. Physiol. l&290-302. SINHA, A. K. (1969). Oxygen uptake and release by red cells, capillary walls, and plasma layer. Ph.D. Dissertation, University of California, San Francisco Medical Center, San Francisco. SIRS,J. A. (1970). The interaction of COz with the rate of exchange of O2 by red blood cells. Zn“Blood Oxygenation” (D. Hershey, ed.), pp. 116136. Plenum Press, New York. STEIN, T. R., MARTIN, J. C., AND KELLER, K. R. (1971). Steady-state oxygen transport through red blood cell suspensions. J. Appl. Physiol. 31, 397402. SUWA,K., AND BENDIXEN,H. H. (1972). Pulmonary gas exchange in a tidally ventilated single alveolus model. J. Appl. Physiol. 32, 834-841. THAM, M. J., BHATIA, K. K., AND GUBBINS,K. E. (1967). A steady-state method for studying diffusion of gases in liquids. Chem. Eng. Sci. 22,309-311. VAN BEAUMONT,W., GREENLEAF,J. E., AND JUHOS, L. (1972). Disproportional changes in hematocrit, plasma volume, and proteins during exercise and bed rest. J. Appl. Physiol. 33, 55-61. VAN BEAUMONT,W., STRAND, J. C., PETROFSKY,J. S., HIPSKIND, S. G., AND GREENLEAF, J. E. (1973). Changes in total plasma content of electrolytes and proteins with maximal exercise. J. Appl. Physiol. 34, 102-106. WAGNER, P. D., AND WEST, J. B. (1972). Effects of diffusion impairment on O2 and CO, time courses in the pulmonary capillaries. J. Appl. Physiol. 33, 62-71. WHITMORE, R. L. (1968). “Rheology of the Circulation”, pp. 17-107. Pergamon Press, New York. WISE, D. L., AND HOUGHTON, G. (1969). Solubilities and diffusivities of oxygen in hemolyzed human blood solutions. Biophys. J. 9,36-53.