Relation of Plasma to Interstitial Fluid Volume in ...circ.ahajournals.org/content/circulationaha/40/3/357.full.pdf · of plasma volume to interstitial fluid volume (PV/IF) ... blood

Relation of Plasma to Interstitial Fluid Volumein Essential Hypertension

By ROBERT C. TARAZI, M.D., HARRIEr P. DUSTAN, M.D., AND

EDWARm D. FROHLIGH, M.D.

SUMMARYExtracellular water (radiobromine), plasma volume (radioiodinated human serum

albumin), and peripheral plasma renin activity were measured simultaneously in men

with uncomplicated, untreated essential hypertension and in normal subjects. The ratioof plasma volume to interstitial fluid volume (PV/IF) was significantly lower inhypertensive patients (0.194 vs. 0.223, P < 0.001). This could not be explained onlyon the basis of the diminished plasma volume found in hypertensive patients (17.3 ml/cm of body height vs. 18.7 ml/cm, P < 0.05), as three normal subjects with markedplasma volume contraction had normal PV/IF ratios (0.224). This disturbed ratio inhypertensives suggests, therefore, an abnormality in the mechanism regulating the distri-bution of extracellular water in essential hypertension. Peripheral plasma renin activitycorrelated inversely with plasma volume, but not with extracellular water volume,suggesting that these two indices of body fluid volume are not always functionally inter-changeable.

Additional Indexing Words.Extracellular fluid volume

V ARIOUS STUDIES1-3 have shown thatplasma volume is reduced in patients

with essential hypertension. This reduction,the cause of which is not apparent, raises thequestion of whether such patients have anoverall contraction of extracellular fluid vol-ume or a selective diminution of its intravascu-lar compartment. The volume of extracellularwater (ECW) has been reported to be eitherexpanded4-7 or normal8-12 in uncomplicatedhypertension. However, in most of thesestudies plasma volume was not measuredsimultaneously, and the types of hypertensionwere not strictly defined. Yet differences havebeen reported in extracellular water,12-14plasma volume,3 15 and cardiac output'6 be-tween essential hypertension and the elevated

From the Research Division, Cleveland Clinic,Cleveland, Ohio.

Supported in part by grants from the HeartAssociation of Northeastern Ohio, and from theNational Heart Institute (1H-6835), National Institutesof Health, U. S. Public Health Service.

Circulation, Volume XL, September 1969

Plasma renin activity

blood pressure associated with renal paren-chymal disease, renoprival states, primaryaldosteronism, and renal arterial stenosis.These differences between forms of hyper-tension that are often similar clinicallystress the need for careful definition of thetype studied and hence warrant reappraisal ofprevious conclusions concerning extracellularwater. This report summarizes our experienceswith simultaneous measurements of extracel-lular water and plasma volume in men withuncomplicated and untreated essential hyper-tension.

It became evident during the course of thestudy that the partition of extracellular fluidinto its intravascular and interstitial compart-ments was altered in hypertensive patients.This raised serious doubts as to the validity ofusing plasma volume and extracellular fluidvolume interchangeably in the study of therenin-angiotensin system, for example.'7 Sincepreliminary results had shown that peripheralplasma renin activity was inversely related tointravascular volume,'8 its relation to plasma

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and extracellular fluid volume was studied todetermine which compartment correlated bet-ter with it and whether extrapolation from one

volume index to the other was valid.

MethodsThe subjects of this study were 20 men with

uncomplicated, untreated, essential hypertensionand 26 normal male volunteers. This restriction tomen was intended to avoid the possibility ofvariations of extracellular water within themenstrual cycle. Plasma volume was measured inall 26 normal men; this larger number was

obtained by adding as many normals as possibleto the previously reported normal group.3 Assimultaneous extracellular water measurementswere begun later, only 11 normal volunteers couldbe studied, and plasma renin activity was deter-mined in nine.

All hypertensive patients were hospitalized butnot restricted as to diet or activity; all had renalarteriography performed and determinations ofplasma volume (PV), extracellular water (ECW)volume, and peripheral plasma renin activitywithin the first 5 days. Known secondary causes

of hypertension were carefully excluded. None ofthe patients had either past history or presentevidence of cardiac failure or of diminished renalexcretory function: blood urea and serum cre-atinine concentrations and creatinine clearancewere normal, and there were no clinical or

hemodynamic (cardiac output, Valsalva maneu-

ver) signs of cardiac decompensation. Supinearterial pressure ranged from 140/90 to 175/123mm Hg (average, 157/108); three patients hadfluctuating hypertension while the other 17always had high blood pressure when off therapy.All had grade 1 to 2 hypertensive funduscopicchanges, and none had hemorrhagic or exudativeretinopathy. Antihypertensive therapy, includingdiuretics, was discontinued in all cases for at least1 month before investigation.

Extracellular Water

Extracellular fluid volume was determined withradiobromine (82Br) as described by Moore'sgroup.19 Following intravenous injection of sodi-um radiobromide (30 to 35 microcuries in 50 mlsaline), multiple samples of peripheral venous

blood were obtained over a period of 3 to 5 hoursat intervals varying from 20 min to 1 hour. Thefinal sample was drawn the following morning (8to 9 a.m.) about 18 hours after the injection.Urine voided during the initial postinjectionperiod (first 3 to 5 hours) was collectedseparately from that voided from then until thefinal sample of blood was obtained (18 hoursafter injection). These samples provided a

measure of the amount of radioactivity excretedduring each equilibration period, thus avoidingunwarranted extrapolations of isotope excretionfrom overnight to afternoon periods. Gastrointes-tinal secretions were not taken into account sincenone of the patients had vomiting or diarrhea.20Blood was withdrawn into tubes containing dryheparin; 2-ml aliquots of plasma and urine were

pipetted into tubes of fixed geometry and countedin duplicate in an automatic gamma-ray scintilla-tion counter. Standards were similarly counted inquadruplicate, using a 1:100 dilution of theradiobromine solution injected. In some cases,counting was done with a discriminator set at the

previously determined peak for radiobromineemission while in others no discriminator was

used. In six sets of samples from six patients, bothmethods used concurrently gave similar results.Time of counting varied from 2 to 5 min(nonselective counting) to 100 min (selectivecounting) to obtain at least 4,000 counts persample per period.

Bromide space was calculated as: Q ECl-c2

when Q = total counts per minute injectedE = total counts per minute excreted dur-

ing the period of equilibrationC, = counts per minute per ml of postmix

plasma sampleC2 = counts per minute per ml of premix

plasma sample.

Extracellular water was then calculated from thebromide space by correcting for red cell uptake,serum water, and Donnan equilibrium factor:21

ECW = Br sp-PV-0.6 RCM + 0.92 PV1.11

Where Br sp = bromide spacePV = plasma volumeRCM = red cell mass, calculated from plasma

volume and large vessel hematocrit after correc-

tion of the latter for its difference from total bodyhematocrit.22 23

Equilibration Time for Extracellular WaterDetermination

In both normal and hypertensive subjects,injected radiobromine achieved a stable level ofdilution within 3 hours. Its equilibration curve

was practically flat from the third to the 18thhour, as demonstrated by the small variationsbetween bromide spaces calculated from thedifferent samples (table 1). These results agreewith those derived from seven patients by Rovnerand Conn.24 There was no significant differencebetween normotensive and hypertensive subjects

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EXTRACELLULAR FLUID IN HYPERTENSION

in equilibration time or in the bromine equilibra-tion curve either in its later (3 to 18 hours) orearlier (20 min to 3 hours) parts. The values forECW reported below have all been calculatedfrom the 18-hour samples, as these were obtainedat the time plasma volume and renin activity weredetermined.

Plasma VolumePlasma volume (RISA) was measured in the

morning immediately after withdrawing the lastpostmix sample for the radiobromide equilibrationcurve. As previously described,3 the patient wasallowed to rest in the supine position for at least30 to 45 min before the injection of 5 microcuriesof radioiodinated (1s3I) human serum albumin.Plasma volume was computed directly by theVolcmetron from plasma samples obtained 10 minafter injection; simultaneous counting of thepremix and postmix plasma samples insuredproper cancellation of residual 82Br radioactivity.The accuracy of this instrument for plasmavolume determination from separated plasma wasverified in three patients by comparing resultsobtained both with it and with deep wellcounting. Total blood volume was calculated fromplasma volume and venous hematocrit; the latterwas determined in duplicate by means ofcapillary microcentrifugation from four samples ofblood drawn without stasis. No correction factorwas used for plasma trapping,3 but the largevessel hematocrit was corrected for its differencefrom total body hematocrit.22

PVi -O.91CV

where TBV = total blood volumeCV = large vessel hematocrit0.91 = ratio of total body hematocrit to

large vessel hematocrit.22

Plasma volume was expressed in ml/cm ofbody height as this index allows comparisonbetween groups of different ages and body con-stitution.3' 25

Plasma Renin ActivityPlasma renin activity was estimated by the

method of Pickens and associates,26 as modifiedby Dustan and co-workers,27 from peripheralblood samples obtained at approximately t-hesame time in the morning along with the plasmavolume determination, the patient having restedin the supine position for at least 30 to 45 min.

ECW = 1.236 + 0.046 (height)r-(0.798 F = 9.338ECW = 0.721 + 0.043 (height)r = 0.798 F = 14.87


Table 1

Bromide Spaces Calculated atFollowing Injection of 82Br andcent of the Space DeterminedInjection.

Different TimesExpressed as Per18 Hours After

Number ofSampling time (hr) subjects Bromide space*

1 27 92.2 (±0.8)2 23 96.1 (+0.7)3 37 98.2 (±0.9)5 8 99.5 (41.4)

Extrapolation tozero time 26 89.6 (±1.4)

* Expressed as a per cent of 18-hour space i 1 stan-dard error of mean.

Statistical analysis was performed by acceptedmethods for calculating correlation coefficients(r), regression analysis, and significance tests.28

ResultsThe volume of extracellular water of normal

subjects and of hypertensive patients was notsignificantly different (tables 2 and 3).However, the hypertensive patients wereheavier (88.1 kg vs. 75.1 kg) and, therefore,were expected to have less ECW per unit ofbody weight than normal controls.20 Todetermine whether the insignificant differencebetween the two groups represented a relativeincrease of ECW in the hypertensives, eightpatients and eight normal subjects matchedfor body weight were compared (table 4);their ECW volumes were practically identical.Furthermore, as compared with normal valuesderived from published regression equationsbased on total body water,19 the ECW volumeof both normals and hypertensives was withinthe expected normal range (table 3).Age was not found to be a significant factor

influencing ECW values; its introduction into,or omission from, the regression equation forECW did not alter either the correlationcoefficient (r) or the F value. In the followingequations, height is expressed in centimeters,weight in kilograms, age in years, and ECWin liters:

(1)+ 0.142 (weight) + 0.003 (age)P < 0.01 for the F test

+ 0.142 (weight)P <0.01 for the F test

(2)

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Table 2

Plasma Volume, Extracellular WVater, and Peripheral Plasmaand Essential Hypertensive Subjects

Renin Activity in Normal

Weight Height PV ECW ReninNo. (kg) (cm) (L) (L) PV/IF (ng/ml/4 hr)

Normotensive Patients1.2.3.4.5.6.7.8.9.

10.11.

73.5877465.5678072.277.566.47785.5

171180175176.5171188163.7169.4170186.7193

2.853.303.002.853.053.603.403.052.553.503.73

15.218.116.516.116.721.118.815.813.918.721.4

0.2310.2230.2230.2160.2230.2060.2210.2390.2240.2300.211

0.442.01.51.81.00.54

1.22.50.4

Patients with Essential Hypertension1.2.3.4.5.6.7.8.9.

10.11.12.13.14.15.16.17.18.19.20.

86.188.369.510883.682.710678.177781209781868563.5

10165.9

106.898

177.5185170.2185194165.5186173183170183188177178166165.3180160185.4178

2.93.102.43.052.982.63.753.483.253.353.483.12.852.63.52.163.253.03.153.6

18.520.415.223.517.315.822.520.918.917.423.921.817.118.817.913.421.815.822.221.0

0.1860.1790.1870.1490.2070.1970.2000.2000.2080.2380.1700.1660.2010.1610.2430.1930.1750.2350.1640.207

0.440.2

1.51.30.420.20.421.70.40.860.930.91.50.6

0.50.40.60.4

Abbreviations: PV = plasma volume; ECW = extracellular water; PV/IF = ratio of plasmavolume to interstitial fluid.

Table 3

Extracellular Water in Normal and Essential Hypertensive MIen

ECW (% body weight)wt

Group Number (kg) Determined* Predictedt

Normal subjects 11 75.1 23.3 (±0.69) 24.3Essential hypertensives 20 88.1 21.9 (±0.38) 23.0

* Average ± 1 standard error of mean.t Predicted according to published regression equations.20

Ratio of Plasma Volume to Interstitial FluidPlasma volume averaged 18.7 + 0.42 ml/cm

of body height; this figure is lower than the

one (19.6) previously reported and agreesmore closely with the findings (18.3) ofChien's group.25 This probably reflects a better

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Table 4

Extracellular Water in Eight Normotensive Subjects and Eight Hypertensive Patients Matchedfor Body Weight

Group Weight (kg) ECW* PV/IFt

Normal subjects 75.7 23.4 (±0.81) 0.222 ± 0.0037Essential hypertensives 75.9 22.8 (i0.72) 0.196 i 0.0085P >0.5 <0.05

* ECW = extracellular water expressed in % of body weight 4 1 standard error of mean.t PV/IF = ratio of plasma volume to interstitial fluid ± 1 standard error of mean.

representation of normal range by the largersample.

Nevertheless, hypertensive patients still hadlower plasma volumes than normal subjects(17.3 + 0.49 vs. 18.7 + 0.42, P < 0.05).The ratio of plasma volume to interstitial

water (calculated as ECW - PV) was deter-mined for those individuals in whom bothvalues were available from simultaneousdeterminations (11 normals and 20 hyperten-sives); it averaged 0.223 in normal sub-jects and 0.194 in hypertensive patients(P < 0.001) (table 5). Since hypertensivepatients had lower plasma volumes thannormnal subjects, it could be inferred that thisreduction was the cause of their diminishedPV/IF ratio. This, however, did not seem tobe the case since several of the 11 normalsubjects in whom ECW and plasma volumewere measured simultaneously had low plas-ma volume, resulting in an average for thatgroup of 17.9 ml/cm. In three who had someof the lowest plasma volumes of the entirenormal group (15.1, 16.1, and 16.1 ml/cm),the PV/IF ratio measured 0.224, 0.216, and0.231, respectively.

Table 5

Plasma Volume/Interstitial Fluid Ratio (PV/IF)in Normal and Essential Hypertensive Men

PV/IF

Group Number Average SD SE

Normal men 11 0.223 0.010 0.003Essential 20 0.194 0.026 0.058

hypertensivest-value 4.46P <0.001

* SD = standard deviation.t SE = standard error of mean.


Whatever their plasma volume, therefore,and this ranged from 15.1 to 20.8 ml/cm,normal subjects had a stable PV/IF ratio, afact reflected in the close and highly signifi-cant relation of their plasma volume toextracellular water (r = 0.971, P <0.001). Incontrast, the wider variation of this ratioamong hypertensive patients reflected itself inthe less close relationship between theirplasma and extracellular water volume(r = 0.694, P < 0.01) whether expressed inabsolute figures or as percentage of bodyweight (figs. 1 and 2).

Peripheral Plasma Renin Activity, IntravascularFluid Volume, and Extracellular Water

Peripheral plasma renin activity was in-versely related to plasma volume in bothnormal and hypertensive subjects (P < 0.05)(table 6). The stable ratio between theintravascular and the interstitial componentsof ECW in normal subjects was reflected in thepersistence of an inverse relation of plasmarenin activity to ECW, as well as to plasmavolume. In contrast, there was no correlationbetween plasma renin activity and ECW inhypertensive patients (r = - 0.040), despitethe inverse relation between their plasmavolume and renin activity. This is probablythe result of the wide variation in the ratiobetween the two phases of their extracellularwater compartment.

DiscussionNo significant difference was found in the

extracellular water volume of normal subjectsand men with essential hypertension uncom-plicated by exudative retinopathy, cardiacdecompensation, or diminution in renal excre-tory function. The two groups were compar-

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5.0-

4.0-

3.0-

2 0-(

*

* Essential hypertensive (20)

o Normotensive ( )00k

q

qt<

Q,

* * 0

0

00

,__ Y = .57 +.15 ECW0

II II II Il I I

13 14 15 16 17 18 19 20 21 22 23 24

Extracellular Water-Liters

Regression line and 95 % confidence limits fornormotensive subjects.

6 25

Figure 1

Relation of plasma volume to extracellular water(ECW) in normal men and men with essential hyper-tension. Most patient points lie below the 95% con-fidence limits of the regression equation defining thisrelation in normal subjects. Correlation coefficient (r)equals 0.971 for normal subjects and 0.694 for hyper-tensives.

able, though the hypertensive patients wereon the average somewhat older and heavierthan normal controls. No significant age groupdifferences in ECW have been demonstratedby others,19 nor was age found to be asignificant factor in multiple correlation analy-sis of ECW in our group. Moreover, Chienand associates25 in a careful longitudinal studycould find no difference in plasma volumewith age. Differences due to body weight aremore difficult to evaluate since extracellularwater, in common with other aqueous phasesof the body, varies inversely with weightwhen expressed in reference to it.19 However,when matched for body weight with normalsubjects, the hypertensive patients had nor-mal ECW; furthermore, all hypertensives hadECW well within the normal averages de-rived from published regression equationsbased on total body compositional ratios.19

These results are similar to some8'2 but atvariance with other reports4-7 in the litera-ture; this discrepancy between findings of

28 -

27 -

26 -

25 -

24 -

23 -

22 -

21 -

20 -

19 -

18 -_2.5

*Essential hypertensive (20)o Normotensive ( ) *O e *

0

00 A* i?/ °

0

* o

I I I1 12.7 2.9 3.1 3.3 3.5 3.7 3.9 4.1 4.3 4.5 47 4.9

Plasma Volume - % Body wt.

fitted regression line for normal subjects

Figure 2Relation of plasma volume to extracellular water(both expressed as a percentage of body weight) dem-onstrating the abnormal spread of this relation inhypertensive subjects (see text).

normal and of expanded ECW in hyperten-sion cannot be explained by methodologicdifferences since both expanded and normalvalues were reported by workers utilizingthe same methods (radiosulfate4, 5' 9' t1 andinulin6, 8, 10). The differences probably resultfrom varying criteria for patient selection.Thus, lack of reference to antihypertensivetherapy,5 inclusion of patients with "minimalcardiac impairment,"4 and selection of thosewith increased exchangeable sodium7 aresome of the more obvious factors that mayinfluence the results obtained. Treatment withdrugs inhibiting autonomic nervous activityhas been associated with fluid retention,29expansion of plasma volume, and disturbanceof fluid balance.30 31 Extracellular fluid expan-sion is the rule in cardiac decompensation

Table 6

Relationship of Peripheral Plasma Renin Activityto Plasma and ECW Volumes in Nine Normotensiveand 18 Essential Hypertensive Men

Fluid compartment

Pia,lnia volume (ml/cm)ECW (X? of body

weight)

Correlation coefficient (r)

Normal subjects Hypertensives

-0.629

-0.408

-0.502

-0.040

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even in the absence of obvious edema.9' 12Patients with increased total exchangeablesodium and expanded ECW usually haveadvanced fundal changes7; this combinationof hypertensive retinopathy, expanded ECW,and increased exchangeable sodium corre-spond to the findings of Hollander andassociates in malignant hypertension.12

Possible differences between clinically simi-lar types of hypertension are as relevant,therefore, to explanations of variations inECW, as obvious factors like body weight,cardiac impairment, or antihypertensive ther-apy; specific diagnostic investigations, such asrenal arteriography, may then be needed toallow as accurate a classification of patients aspossible.32 Without strict definition of thehypertension studied, accurate evaluation andvalid comparison of various reports seemimpossible.

In contrast with essential hypertension butlike malignant hypertension, the increasedblood pressure produced in man by primaryaldosteronism or by mineralocorticoid ad-ministration is associated with expandedECW.13' 14 While the hypertension of chronicparenchymal renal disease without nitrogenretention appears to be characterized bynormal body sodium, potassium, and radio-sulfate spaces,12 the development of renoprivalhypertension seems to depend in part on thedegree of ECW expansion.33 Dustan andPage34 demonstrated a direct parallelismbetween changes in body weight, presumablyrepresenting ECW variations, and changes inblood volume and blood pressure in terminalrenal failure before and after bilateral ne-phrectomy. This was recently confirmed byBlumberg and associates35 utilizing radio-bromine for direct measurements of extracel-lular fluid volume.

Various animal studies have confirmed theseclinical observations. Braun-Menendez36 foundthat only rats with expanded ECW de-veloped hypertension following subtotal ne-phrectomy, and similar results were foundin dogs.37'38 In contrast, plasma volume andECW remained normal in dogs made hyper-tensive by renal artery clipping.39 LedinghamCirculation, Volume XL, September 1969

and Cohen40 found that the development ofhypertension in rats following clipping of arenal artery was associated with a brief initialperiod of ECW expansion, but hypertensionpersisted while ECW returned to normal.Although total extracellular water volume

remained relatively normal in patients withuncomplicated essential hypertension, its dis-tribution between the intravascular and inter-stitial fluid compartments was altered. Moore41pointed out that the relation of plasmavolume to ECW is particularly stable with ahigh correlation coefficient (r = 0.83); a simi-lar relation also obtained in our normals. ThePV/IF ratio is an expression of this relation;the ratio (0.223) determined in our normalsubjects by tagged albumin and radiobromineis in close agreement with the ratio (0.23)reported by others using Evans blue andradiobromine.1' This ratio was similar in allour normal subjects, even in three with aparticularly low plasma volume. Thus, con-traction of plasma volume was not sufficientby itself to alter the distribution ratio in theextracellular compartment.

In contrast, the partition of ECW inhypertensive patients was significantly altered(PV/IF = 0.194, P <0.001) and the ratiovaried widely, measuring more than 0.220 inthree patients, 0.200 in six, and less than 0.200in 11. The lower ratio in hypertensives was notapparently due to their heavier weight: thesame difference from normals was foundbetween groups matched for body weight(table 4). In comparing the relation of plasmavolume to extracellular water with expectednormal regressions (figs. 1 and 2), it would beequally correct to infer that hypertensivesubjects either have too low plasma volumesfor their extracellular water or relativelyexpanded ECW for their actual plasmavolumes. This altered ratio was also found byWalser and co-workers9 who compared totalblood volume derived from red cell mass de-termination to extracellular water. The lack ofstatistical significance in their results may beascribed to the inclusion of red cell mass instudy of the partition between water compart-ments, and possibly to the small number of

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patients. This alteration in volume distributionbetween the compartments of ECW in es-sential hypertensives, their lower plasmavolume,'-3 and their greater diuresis follow-irng intravenous infusions42 seem to agree withTobian's suggestion that in hypertension themechanism regulating extracellular fluid vol-ume is set as though ECW were expanded.43The normal close correlation between ECW

and PV seem to allow the interchangeabilityof these two indices in considering functionsrelated to them. This conclusion, however, isnot valid when the ratio of plasma volume tointerstitial fluid is disturbed. Though, asreported elsewhere,27 44 peripheral plasmarenin activity was inversely related to plasmavolume in hypertensive patients, no relation-ship was found when ECW was substitutedfor PV. Unless direct measurements of bothvolume indices demonstrate a stable PV/IFratio under the particular conditions investi-gated, it does not seem valid to extrapolatealterations from ECW to PV or vice-versa,since particular functions may correlate withone and not the other volume.

AcknowledgmentWe wish to thank Doctor P. Khairallah for

assistance with radioisotope technics and to acknowl-edge the fine technical work performed by KathleenKoenig, R.N., and Helen Kleinhenz, R.N., as well asthe secretarial assistance of Mrs. A. Raulinaitis andMiss D. Henkin, and the laboratory help of Mrs. M.Kukla and Miss I. Patterson. We are particularlygrateful to Prof. C. Berretoni for his help withstatistical analysis of the results.

References1. BELLO, C. T., SEVY, R. W., AND HARAKAL, C.:

Varying hemodynamic patterns in essentialhypertension. Amer J Med Sci 250: 24, 1965.

2. TIBBLIN, G., BERGENTZ, S. E., BJuRE, J., ANDWILHELMSEN, L.: Hematocrit, plasma protein,plasma volume and viscosity in early hyperten-sive disease. Amer Heart J 72: 165, 1966.

3. TARAZI, R. C., FROHLICH, E. D., AND DUSTAN, H.P.: Plasma volume in men with essentialhypertension. New Eng J Med 278: 762,1968.

4. GROLLMAN, A., AND SHAPIRO, A. P.: The volumeof the extracellular fluid in experimental andhuman hypertension. J Clin Invest 32: 312,1953.

5. TENG, H. C., SHAPIRO, A. P., AND GROLLMAN,A.: Volume of the fluid compartments inhuman and experimental hypertension. Metabo-lism 3: 405, 1954.

6. LEVIN, N. W., AND GOLDBERG, R.: Studies inhypertension: I. Extracellular fluid volume(inulin space) in hypertension. S Afr J MedSci 25: 1, 1960.

7. Ross, E. J.: Total exchangeable sodium in hyper-tensive patients. Clin Sci 15: 81, 1956.

8. KOVACH, J. C.: Extracellular fluid volume inhypertension. Canad Med Ass J 75: 934,1956.

9. WALSER, M., DUFFY, B. J., AND GRIFFITH, M.W.: Body fluids in hypertension and mild heartfailure. JAMA 160: 858, 1956.

10. DEGRAEFF, J.: Inulin space and total exchange-able sodium in patients with essential hyper-tension. Acta Med Scand 156: 337, 1957.

1 1. WINER, B. H.: Studies of the content anddistribution of sodium, potassium and water inarterial hypertension. (Abstr.) Circulation 18:800, 1958.

12. HOLLANDER, D., CHOBANIAN, A. V., ANDBuRuows, B. A.: Body fluids and electrolytecomposition in arterial hypertension: I. Studiesin essential, renal and malignant hypertension.J Clin Invest 40: 408, 1961.

13. CHOBANIAN, A. V., BuRRows, B. A., ANDHOLLANDER, W.: Body fluids and electrolytecomposition in arterial hypertension: II. Stud-ies in mineralo-corticoid hypertension. J ClinInvest 40: 416, 1961.

14. BIGLIERI, E. G., AND FORSHAM, P. H.: Studieson the expanded extracellular fluid and theresponses to various stimuli in primary aldo-steronism. Amer J Med 30: 564. 1961.

15. SLATON, P. E., AND BIGLIERI, E. G.: Hyperten-sion and hyperaldosteronism of renal andadrenal origin. Amer J Med 38: 324, 1965.

16. FROHLICH, E. D., ULRYCH, M., TARAzI, R. C.,DUSTAN, H. P., AND PAGE, I. H.: Hemodynam-ic comparison of essential and renovascularhypertension: Cardiac output and total peri-pheral assistance in supine and tilted patients.Circulation 35: 289, 1967.

17. BROWN, J. J., DAVIES, D. L., LEVER, A. F., ANDROBERTSON, J. I. S.: Renin and angiotensin: Asurvey of some aspects. Postgrad Med J 42:153, 1966.

18. TARAZI, R. C., DUSTAN, H. P., AND FROHLICH, E.D.: Relationships of blood volume, hemody-namics and neurogenic activity to plasma reninactivity in essential hypertension. (Abstr.) JLab Clin Med 40: 55, 1967.

19. MOORE, F. D., OLESEN, K. H., MCMURREY, J. D.,PARKER, H. V., BALL, M. R., AND BOYDEN, C.M.: The Body Cell Mass and Its SupportingEnvironment: Body Composition in Health and


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Disease. Philadelphia, W. B. Saunders Co.,1963, pp. 50, 84, 490, 521.

20. STAFFURTH, J. S., AND BIRCHALL, I.: Themeasurement of the extracellular fluid volumewith radioactive bromine. Clin Sci 19: 43,1960.

21. MCMURREY, J. D., ET AL.: Body composition:Simultaneous determination of several aspectsby the dilution principle. Metabolism 7: 651,1958.

22. CHAPLIN, H., JR., MOLLISON, P. L., AND VETTER,H.: The body venous hematocrit ratio: Itsconstancy over a wide hematocrit range. J ClinInvest 32: 1309, 1953.

23. WuiTAms, J. A.: Blood volume: Comments onmethodology. Amer Surg 30: 375,1964.

24. ROVNER, D. R., AND CONN, J. W.: A simple andprecise method for the simultaneous measure-ment in man of plasma volume, radiobrominespace, exchangeable potassium and exchange-able sodium. J Lab Clin Med 62: 492, 1963.

25. CHIEN, S., NASMI, S., SIMMONS, R. L.,MCALLISTER, F. F., AND GREGERSEN, M. I.:Blood volume and age: Repeated measure-ments of normal men after 17 years. J ApplPhysiol 21: 583, 1966.

26. PICKENS, P. T., BuMLus, F. M., LLOYD, A. M.,SMEBY, R. R., AND PAGE, I. H.: Measurementof renin activity in human plasma. CirculationResearch 17: 483, 1965.

27. DUSTAN, H. P., TARAzI, R. C., AND FROHLICH, E.D.: Functional correlates of peripheral plasmarenin acfivity. Unpublished data.

28. CROXTON, F. E., AND COWDEN, D. J.: AppliedGeneral Statistics. New York, Prentice HallInc., 1944, pp. 327, 347, 653.

29. PAGE, I. H., HURLEY, R. E., AND DUSTAN, H. P.:Prolonged treatment of hypertension withguanethidine. JAMA 175: 543, 1961.

30. RoSE, J. C., AND FREIs, E. D.: Alterations insystemic vascular volume of dog in response tohexamethonium and norepinephrine. Amer JPhysiol 191: 283, 1957.

31. WEIL, J. V., AND CHIDSEY, C. A.: Plasma volumeexpansion resulting from interference withadrenergic function in normal man. Circulation37: 54, 1968.

32. DUSTAN, H. P., AND PAGE, I. H.: Renal hyper-tension suspect: Clinical characteristics. AmerJ Surg 107: 35, 1964.

33. MERRILL, J. P., GIORDONE, C., AND MEETDERKS,D. R.: Role of the kidney in humanhypertension: I. Failure of hypertension todevelop in the renoprival subject. Amer J Med31: 931, 1961.

34. DUSTAN, H. P., AND PAGE, I. H.: Some factors inrenal and renoprival hypertension. J Lab ClinMed 64: 948, 1964.

35. BLUMBERG, A., NELP, W. B., MEGSTROM, R. M.,AND SCRIBNER, B. M.: Extracellular volume inpatients with chronic renal disease treated forhypertension by sodium retention. Lancet 2:69, 1967.

36. BRAUN-MENENDEZ, E.: Blood volume and extra-cellular fluid volume in experimental hyper-tension. In Hypertension, edited by E. T. Bell.Minneapolis, University of Minnesota Press,1951, p. 98.

37. ORBISON, J. L., CHRISTIAN, C. L., AND PETERS,E.: Studies on experimental hypertension inbilaterally nephrectomized dogs. Arch Path 54:185, 1952.

38. HouCK, R. C.: Effect of hydration and dehydra-tion on hypertension in the chronic bilaterallynephrectomized dog. Amer J Physiol 176: 183,1954.

39. DESAULLES, E. J.: Les compartiments corporelschez le chien hypertendu. These pour ledoctorat en medecine. Faculte de Medicine deStrasbourg, 1966.

40. LEDINGHAM, J. M., AND COHEN, R. D.: Changesin the extracellular fluid volume and cardiacoutput during the development of experimentalrenal hypertension. Canad Med Ass J 90: 292,1964.

41. MooRE, F. D.: The effects of hemorrhage in bodycomposition. New Eng J Med 273: 567,1965.

42. BALDWIN, D. S., BIGGs, A. W., GOLDRING, W.,HULEr, W. H., AND CHASIS, H.: Exaggeratednatriuresis in essential hypertension. Amer JMed 34: 893, 1958.

43. TOBIAN, L.: Interrelationship of electrolytes,juxtaglomerular cells and hypertension. PhysiolRev 40: 280, 1960a.

44. BROWN, J. J., DAVIES, D. L., LvEEV, A. F.,MCPHERSON, D., AND ROBERTSON, J. 1. S.:Plasma renin concentration in relation tochanges in posture. Clin Sci 30: 279, 1966.

Circulation, Volume XL, Septembe-r 1969

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ROBERT C. TARAZI, HARRIET P. DUSTAN and EDWARD D. FROHLICHRelation of Plasma to Interstitial Fluid Volume in Essential Hypertension

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