Effects of Five Per Cent Dextrose-WaterInfusions in Normal and Hypertensive Man

Evidence for Increased Proximal and Distal TubularSodium Rejection by Hypertensive Patientsand Its Relation to Renal Hemodynamics

By PAUL J. CANNON, M.D.

SUMMARYDuring infusions of 5% dextrose in water urinary sodium excretion and the renal

tubular rejection of filtered sodium (E/F Na %) were significantly higher in hyperten-sive than in normotensive subjects. Increased E/F Na % did not result from alterationsin plasma sodium, in filtered sodium, or from an osmotic diuresis.

Fractional sodium reabsorption in proximal (isosmotic) portions of the nephron wasdiminished in the hypertensive patients. Free water forrnation (CH20) rose with in-creased "distal" sodium delivery (V) in both groups; however, fractional sodiumreabsorption in the "distal" nephron was significantly impaired in the hypertensivepatients and urinary osmolality was increased.Mean arterial blood pressure and E/F Na % were related in curvilinear fashion

in the 31 studies, and there was a direct relation between E/F Na % and the mag-nitude of renal vascular resistance. The data suggested that alterations of renalarterial pressure and vascular resistance in hypertensive disease modify sodiumtransport in proximal and diluting segments of the nephron and determine to amajor extent the increased natriuresis exhibited by hypertensive subjects during in-fusions that expand extracellular fluid volume.

Additional Indexing Words:Sodium excretion Extracellular fluid volume expansionNatriuresis

Hypertension

FACTORS that influence the rate of renaltubular sodium reabsorption under nor-

mal circumstances have not been completelyclarified. Studies from many laboratories haveindicated that the diminished renal tubularsodium reabsorption developing in responseto infusions of saline or Ringer's solution innormal animals does not result from changes

From the Department of Medicine, College ofPhysicians and Surgeons, Columbia University andthe Presbyterian Hospital, New York, New York.

Supported by U.S. Public Health Service GrantsHE 10182 and HE 05741.

Dr. Cannon is a recipient of U.S. Public HealthService Career Development Award HE 15032 of theNational Heart Institute.

832

in glomerular filtration rate, the filtered loadof sodium, or aldosterone secretion.1 6 Toexplain this phenomenon of "saline diuresis"attention has recently been directed towardthe presence of a "third factor,"7 which mayeither be a "natriuretic" hormonel 8410 or anintrarenal hemodynamic adjustment to extra-cellular fluid (ECF) volume expansion5 11,12or a combination of both.13

Patients with arterial hypertension exhibitan exaggerated natriuresis in response to in-fusions of saline or mannitol.14-27 The mech-anism limiting tubular sodium reabsorptionin hypertensive more than in normal subjectsduring the infusions remains unexplained. Itis probably a functional abnorrnality rather

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FIVE PER CENT DEXTROSE-WATER INFUSIONS

than the result of structural damage to therenal tubules since (1) increased natriuresisby hypertensive subjects is manifest only dur-ing the infusions of saline or mannitol, and(2) renal salt wasting is not apparent inhypertensive subjects not receiving infusionswhen they are maintained on a normal or lowsodium intake.2' 28The present studies were designed to inves-

tigate hemodynamic factors that might beinvolved in the phenomenon of salt rejectionin normal and hypertensive man during amild degree of expansion of the extracellularfluid volume. To this end renal hemodynamicsand the natriuretic responses of hypertensivepatients were examined during rapid infu-sions of 5% dextrose in water and were com-pared to those of normal and salt-depletedcontrol subjects. The studies confirm observa-tions of Ek29 that an exaggerated natriuresisdoes occur in hypertensive patients in responseto infusion of 5% dextrose and water. In addi-tion they demonstrate (1) that in hypertensivepatients during the infusions, sodium reabsorp-tion is impaired not only in the proximaltubules but also in distal "diluting" segmentsof the nephron, and (2) that the degree ofsodium rejection is correlated with the meanarterial blood pressure and the renal vas-cular resistance.

MethodsThirty-one renal clearance studies were per-

formed in nine normal volunteers and 18 patientswith essential hypertension and one patient withhypertension caused by an aldosterone-secretingadenoma. Each of the hypertensive subjects andsix control subjects prior to study received a dietcontaining 4 to 6 g of sodium; five studies wereperformed after the control subjects had re-ceived a low-sodium diet (less than 0.875 g ofNaCl per day) for 4 to 7 days. None of thepatients received medication other than occa-sional bedtime sedation with barbiturates. Nonehad papilledema or congestive heart failure ora blood area nitrogen level above 26 mg/100 ml.

All experiments were performed at the sameearly morning hour with the subjects fasting,resting quietly in bed. Water diuresis was in-duced by oral administration of 500 ml of waterduring the hour prior to the infusion and wasmaintained by intravenous administration of a5% dextrose solution at a rate of 15 ml/min in

Circulation, Volume XXXVII, May 1968

26 studies and 9 ml/min in nine studies, heldconstant by a motor-driven pump. Urine col-lections were made and discarded until a steadystate of maximal urine flow was achieved. Threeor four 10-minute clearance periods were thenobtained.Venous blood samples were collected at appro-

priate intervals through an indwelling needle.Urine was collected continuously via an in-dwelling catheter. Blood pressure was measuredfrom the arm during the clearance periods by astandard cuff mercury sphygmomanometer.The rates of glomerular filtration (GFR) and

of effective renal plasma flow (ERPF) weremeasured by the administration of inulin or14C-inulin and para-aminohippuric acid (PAH). Ade-quate priming doses were given intravenously;then these substances were added to the 5% dex-trose infusion in amounts to maintain constantplasma concentrations. PAH was added to thesustaining infusion immediately before use toavoid the depression in PAH extraction that canoccur when PAH and dextrose are incubatedtogether for several hours.30 Plasma and urinesamples were analyzed for inulin by the anthronemethod,31 for 14C-inulin by the method of Cot-love,32 and for PAH by the method of Smith.33Sodium and potassium concentrations in plasmaand urine were measured by an InstrumentationAssociates flame photometer. Chloride concentra-tions were measured by potentiometric titrationwith the Cotlove chloridometer. Urine and plasmatotal-solute concentrations were measured with anAdvanced Instruments osmometer.

Calculations: Mean arterial blood pressurewas calculated as the average of systolic anddiastolic pressures in millimeters of mercury.Effective renal blood flow was calculated asthe clearance of PAH divided by 1 - hct andwas expressed in milliliters per minute. Renalvascular resistance was calculated by dividingeffective renal blood flow by the mean arterialblood pressure and was reported in arbitraryresistance units (RU). The glomerular filtrationrate was estimated from the clearance of inulin(CIN) and expressed in milliliters per minute.Osmolar and free water clearances were calcu-lated in the manner described by Smith:33COSm =UOSm V/POSM; CH20= V -UOSm V/Posm,where V is the urine flow in milliliters per minuteand Uosm and Posm are the solute concentrationsof urine and plasma in milliosmoles per kilogramof water. Filtered solute load was calculated asthe osmolality of plasma in micro-osmoles permilligram. H20 X CIN in milliliters per minutewas expressed as micro-osmoles per minute. Thepercentage of the urinary solute concentration dueto salt was calculated by the formula:UNamEq/L + UclmEq/L + UosmmOsnM/kgH20 x 100.

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Table 1Electrolyte Excretion During Five Per Cent Dextrose-Water Infusions in Hypertensive Patients (Regular SodmDiet-5% D/W Infusion i.v. at 15 ml/min)BP.

CIN CPAH RBF(ml/min) (ml/min) (mllmin)

1087284781461095953596076

480412413350594574451270285485471

813654688593990973764450475866826

*Conn's syndrome 1-initial2-K + repleted3-post op.

Table 2Electrolyte Excretion During Five Per Cent Dextrose-Water Infusions in Hypertensive Patients (Regular SodiumDiet-5% D/W Infusion i.v. at 9 ml/min)

Filtration RenalBP CIN CPAH RBF fraction resistance UN&V

Subject (mm Hg) (ml min) (ml min) (ml/mmin) (%) (RU) (gEq/min)P.E.R.B.O.O.D.A.V.C.H.A.D.I.A.L.A.W.R.I.C.K.L.A.W.I.*

210/120250/140200/115220/140230/122260/170270/170235/125230/120

73100887210053389894

302345399289398353219416322

817625664499795543359743608

24.1728.9922.0624.9125.1315.0117.3523.5629.19

20.2031.2023.8036.0722.1439.5961.2824.2328.78

176219194363272686481341117

*Pt. partially restricted Na + intake.

The excretion of "non-salt" solutes was calculatedby subtracting the urinary sodium and chlorideexcretion rates in microequivalents per minutefrom the total solute excretion in micro-osmolesper minute.

In studies performed during maximal waterdiuresis fractional reabsorption of sodium in theproximal tubules and in distal "diluting" seg-ments of the nephron (ascending limb of Henle'sloop, distal tubules) was assessed indirectly.The "distal sodium load" was calculated as

UNaV ,Eq/min + (PNa ,uEq/ml X CH20 ml/min)and was expressed in microequivalents per min-ute. This value is the sum of the amount ofsodium that must have been reabsorbed in freewater generation plus the amount simultaneouslyappearing in the urine; it represents the minimal

amount of sodium that must have been deliveredbeyond the proximal site of isosmotic reabsorp-tion to the distal segments of the nephronwhere free water is generated by selective re-absorption of sodium. The fraction of filteredsodium rejected by the proximal tubules wascalculated by dividing the "distal sodium load"by the filtered sodium load, and was expressedas a percentage, that is, UNaV + (PNa X CH2O)*-(CIN X PNa) X 100. Fractional rejection of sodi-tim in distal "diluting" segments of the nephronwas estimated by computing the percentage of the"distal sodium load" excreted in the urine, thatI UNa V (UNa V + PNa X CH20) X 100.

Results are reported in the text as mean andstandard deviation (SD). Differences betweenthe means found in groups of studies were

Circulation, Volume XXXVII, May 1968

Subject

S.M.G.A.R.J.O.N.H.I.

B.O.*1

B.O.2B.O.3R.O.R.D.P.A.P.A.W.

BP(mm Hg)

200/120180/110180/108250/150203/117182/111146/100203/122199/120209/118211/114

Filtrationfraction(%)

22.5017.4820.3422.2924.5818.9913.0819.6320.7012.3716.14

Renalresistance(RU)

20.3022.1720.9333.7316.1615.1116.1036.2233.6818.9419.73

UNaV(uEq 1min)

291552357638485501110760756326260

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FIVE PER CENT DEXTROSE-WATER INFUSIONS

UKV( uEq min)

50302744138121528584124121

UKVUKV

(uEqImin)433163275391524444

E/FNa(%)

2.165.283.266.352.373.261.419.899.094.002.57

E/FNa(No)

1.761.511.583.591.869.039.852.310.88

Uosm(mOsm/ kgH20)

8491

111105808686

Uosm(MOSM /kgH20)

9323361

13318012927118686

UNa + UCiUosm(%)33.3357.1448.6557.1432.5045.3519.77

UNa + UcIUosm(%)

50.5442.4942.6261.1653.8969.7761.2552.6933.72

Uosm V( aOsm/min)

138417861317203725162506906

Uosm V{AOsm /min)

69497977310551007183715201216587

Cosm(mi/min)

4.96.34.87.08.78.43.2

Cosm(ml/min)

2.43.52.63.63.46.15.34.12.1

CH2O(ml/min)11.513.26.8

12.522.719.97.3

C H20(ml/min)

5.11.09.94.62.28.20.32.54.7

VV

(mi/min)16.419.511.619.531.428.310.519.319.716.615.8

V(mi/min)

7.54.5

12.58.25.6

14.35.66.66.8

compared with the Student t test for unpairedvariables. Regression lines and correlation co-efficients were calculated according to standardstatistical techniques.34

ResultsThe results are presented in tables 1, 2, and

3 and in figures 1 to 7. Each number in thetables and each point on the graphs representthe mean of values obtained in one studyduring three or four 10-minute clearance pe-riods at a steady state of water diuresis.

Electrolyte Excretion

The patterns of electrolyte excretion ex-hibited by hypertensive patients during theCirculation, Volume XXXVII, MaY 1968

dextrose and water (D/W) infusions appearin tables 1 to 3 and figure 1. Also shown forcomparison are the patterns exhibited by nor-mal and sodium-depleted control subjects.An exaggerated natriuretic response to 5%

D/W infusion was observed in all but two ofthe hypertensive subjects (fig. 1). Urinarysodium excretion in the patients with elevatedblood pressure averaged 458 ± 210 IuEq/min,a value significantly higher than the meansodium excretion of normal subjects on simi-lar diets who received similar amounts offluid (15 ml/min), 133 ± 29 .tEq/min (P <0.01). The urinary sodium excretion of hy-pertensive patients who received the infusion

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Table 3Electrolyte Excretion During Five Per Cent Dextrose-Water Infusions in Normal Subjects

CIN CPAH(ml l min) (ml / min)

Regular SodiumB.U.S.M.S.U.S.M.I.P.E.F.R.

Diet-5% D/W infusion i.v. at 15 ml/min128/68113/77109/70111/72108/60114/76

Low-Sodium Diet-5% D/WS.M. 110/72S.M.I. 105/60P.E. 94/64P.E.T. 100/64P.E. 98/70

103126160124148112

infusion i.v.

108129123179142

698897990613789654

at 15 ml/min640630592751630

800 r-

700 H

600 [

500 F

400 1-

300

200

100 F

0

U

0

0

a

a

a

a

a

a

..0

0

a

OCP 0

0

10 20 30V ml/min

Figure 1

Sodium excretion of hypertensive patients and normalsubjects during 5% D/W infusions is plotted againstthe simultaneous urinary volume in each study. Anexaggerated natriuresis was apparent in the hyperten-sive patients. In studies performed with a D/W in-fusion rate of 15 ml/min, the sodium excretion rate(UNa V) was higher in the hypertensive (-) than inthe normal (o) subjects, even when the urinary flowrates (V) were comparable. Values from studies ofhypertensive patients receiving D/W at 9 ml/minare indicated by a and from studies of salt-depletednormal subjects are indicated by a.

of D/W at the slower rate of 9 ml/min wasalso above normal and averaged 317 + 178uEq/min (P<0.02).Mean serum sodium concentration was not

significantly different in the hypertensive andnormal subjects (139 ± 6 mEq/L and 140±4 mEq/ L, respectively), and the mean fil-tered load of sodium was somewhat lowerin the hypertensive group as a consequenceof a lower mean glomerular filtration rate(vide infra). Despite this, the fraction offiltered sodium excreted in the urine (E/FNa(averaged 4.51 + 2.84% in the hypertensivesubjects and was significantly higher thanthe E/FNa of 0.74 + 0.17% noted in the controlsubjects (P <0.001). Mean E/FNa in hyper-tensive subjects who received the slower in-fusion was also increased to 3.60 ± 3.40%.

Dietary sodium depletion diminished thesodium excretion observed in the control sub-jects during a D/W infusion; in these studiesurinary sodium output averaged 39 + 18 ,uEq/min, and there was a corresponding declinein the tubular rejection fraction for sodiumto 0.21 ± 0.08%.

Urinary potassium output was 80 + 41 ,tEq/min and 50 ± 11 ,uEq/min in the two sets ofstudies of hypertensive patients, not signifi-cantly increased above the values observed innormal persons on regular sodium diets, 52 +

Circulation, Volume XXXVII, May 1968

SubjectBP

(mm Hg)RBF

(ml/min)

Filtrationfraction(N)

Renalresistance(RU)

UXaV(,aEqImin)

7.876.355.189.016.507.84

124614951736102112931211

1066105097012941068

79155148151119147

14.7614.0516.1620.2218.7717.13

16.8820.4820.7823.8322.54

8.547.908.146.347.87

2024466344

UNaVuEq/min

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FIVE PER CENT DEXTROSE-WATER INFUSIONS 837

Uosm UNa + UcIUKV E/FNa (mOsm/kg Uosm Uosm V Cosm CH20 V

(,uEqlmin) (%) H20) (%) (,Osm/min) (mllmin) (ml/min) (ml/mmin)

242972548154

12895353718

0.5430.8780.6510.8390.5950.958

0.1370.1390.3220.2100.226

645171595958

7470575635

12.529.418.330.515.324.1

4.054.287.008.90

11.40

1142797104682312051150

12461156908928512

4.12.93.72.94.24.1

4.54.23.33.21.8

13.612.711.211.016.115.6

12.412.312.413.512.9

17.715.614.913.920.319.7

16.916.515.716.714.7

23 uEq/min, or after sodium deprivation 63+ 47 ,iEq/min.Renal Hemodynamics

Mean arterial blood pressure of the hyper-tensive patients was significantly elevated andaveraged 158 ± 19 mm Hg during the 11studies with 5% D/W at 15 ml/min and 185 ±mm Hg during the nine studies at 9 ml/min(tables 1 and 2). Mean blood pressure during

studies of the control subjects who receivednormal sodium diets averaged 92 ± 5 mmHg (table 3). During studies of control subjectsafter sodium depletion mean arterial bloodpressure was reduced to 84 + 4 mm Hg.

Glomerular filtration rate of the hyper-tensive patients was reduced; the inulin clear-ance (CIN) was 82 ± 28 ml/min in thosewho received the more rapid D/W infusionsand 80+20 ml in the other group. In the

240

220 U8

0a

a aa*

S . vq 0* _

ft

OA O°aAA i

0

0

a

0

U

* a

* 0

0

.

0 0

A

400 800 1200 1600 0 40 80RBF ml /min GFR ml/min

Figure 2

cpa a aO

0

0

an

0 * *:so

00 0o

120 160 0 15FILT FX %

30

The level of mean arterial blood pressure during each study is plotted against the renal bloodflow (ERBF) in left column, the glomerular filtration rate (CIN) in center column, and againstthe filtration fraction (%) in right column.

Circulation, Volume XXXVII, May 1968

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control subjects the CIN was 129 + 21 ml/minin those on regular sodium diets and 138 + 27ml/min in those who were deprived of sodium.Effective renal blood flow (ERBF) was alsodecreased in the two hypertensive groups, av-eraging 735 + 182 ml/min in the former and628 + 148 ml/min in the latter. In the controlsubjects ERBF was 1334 + 249 ml/min and1090 + 121 ml/min after sodium depletion.Among the entire group of studies of normal

and hypertensive patients there was an in-verse relationship between the height of meanblood pressure and the effective renal bloodflow (fig. 2 left). No directly inverse relation-ships between the level of blood pressure andthe glomerular filtration rate or filtration frac-tion were apparent however (fig. 2 left, cen-ter, and right).

Relationships Between Salt Excretionand Solute Load

In order to examine the possibility thatthe increased tubular salt rejection by hyper-tensive subjects might have resulted from anosmotic diuresis in these patients, various re-lationships between sodium excretion andsolute load were calculated. In the studies ofhypertensive patients and normotensive con-trol subjects there was a poor correlation be-tween the filtered solute load and the rate ofurinary sodium excretion (r = 0.493). Sim-ilarly, the correlation between the urinaryexcretion of solutes exclusive of sodium andchloride and the rate of urinary sodium ex-cretion was also poor (r - 0.083). The "non-salt" solute excretion was calculated per 100ml of glomerular filtration in both normal andhypertensive patients to correct for possi-ble differences in renal mass; this value alsodid not correlate well with the E/FNa%(r= 0.6468).Increased Sodium and Osmolar Concentrationsin Hypertensives (Table 1)During a steady state of water diuresis

urinary osmolality averaged 92 ± 12 mOsm/L in the hypertensive patients, a value sig-nificantly higher than the mean osmolality of69 + 7 mOsm/L observed in the normal sub-jects who received the same amounts of fluid(15 ml/min) (P < 0.01). Urinary osmolality

was 152 ± 70 mOsm/L in the hypertensivesubjects who received the D/W infusion at aslower rate, and was 58 ± 15 mOsm/L duringstudies of salt-depleted normal subjects.The increased urinary osmolality of the

hypertensive subject was largely due to in-creased urinary sodium and chloride concen-trations. During peak water diuresis theurinary sodium concentration (UNa) of the hy-pertensive patients averaged 38 ± 4 mEq/L,a value significantly higher than the (UNa)of 19 ± 4 mEq/L observed in control sub-jects receiving the same diet and similar D/Winfusions (15 ml/min) (P <0.01). The dataplotted in figure 1 indicate that hypertensivepatients excreted more sodium per unit vol-ume of urine even when urinary flow rateswere in the same range as those of the normalcontrols. The percentage of the urinary osmo-

lality due to salt ( UNa+ c %) averaged

43 + 14% and 52 + 11%, respectively, in thetwo groups of hypertensive patients but only22+8% in control subjects receiving regulardiets and 7 + 3% in control subjects aftersodium depletion. Thus the increased contribu-tion of sodium and chloride to urinary osmo-lality in the hypertensive patient was highlysignificant (P < 0.01).

Patterns of Solute and Free Water ClearanceDuring Water Diuresis (Table 1)

The urinary flow rate during the rapiddextrose-water infusion averaged 19.6 + 7.8ml/min in the hypertensive patients and17.0 + 2.6 mI/mim in the control subjects. Inthe hypertensive group the osmolar clear-ance (C0,, ) of 6.2 ± 2.0 ml/min was sig-nificantly increased above that of normalsubjects, 3.7 + 0.6 ml/min (P <0.02). How-ever, there was no significant difference inthe free water clearance (CH2O) of the twogroups; Cn2o averaged 13.4 + 6.0 ml/min inthe patients with hypertension and 13.4 +2.2 ml/min in the control subjects. In bothnormal and hypertensive subjects CH20 andthe urinary flow rate (V) were directly re-lated (fig. 3); however, less free water was

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22.0 F

18.0 F

CH2 14.0ml/min

10.0 F

6.0 F2.0

30.0 r

00a

0

0l

0 *

25.0 F

20.0 tDISTAL No

REJECTION

0 4 8 12 16 20 24 28 32V ml/min

Figure 3

In studies performed during peak water diuresis(D/W at 15 ml/min) the urinary flow rate (V) isplotted against the simultaneous free water clearance(CH20). In both hypertensive and normal subjects,CH20 increased as the urinary flowv rate V rose. Lessfree water (CH20) was formed at each level of V inthe hypertensive group.

excreted per unit of urine flow in the hyper-tensive than in the normal subjects (fig. 3).Although not shown, the relationship betweenCH20 and V remained unchanged when thevalues in both groups were calculated per100 ml of glomerular filtrate.

Fractional Sodium Rejection in the Proximal(Isosmotic) and Distal (Diluting) Portionsof the Nephron

The fraction of filtered sodium rejectedfrom portions of the nephron, where reab-sorption is isosmotic (proximal tubules), hasbeen calculated for each study during peakwater diuresis (see Methods). The mean"proximal" sodium rejection observed dur-ing the rapid D/W infusions in the hyperten-sive patients averaged 17.9 ± 5.4% of thefiltered sodium load, a value that was higherthan the 11.4 + 2.6% observed in the normalgroup (P <0.05). Mean "proximal" rejectionwas not significantly reduced in the controlsubjects after sodium depletion, 9.5 + 1.8%(P < 0.2).The fraction of the "distal" sodium load

excreted during the infusions was also cal-culated for each study (see Methods). Thepercentage of the "distal sodium load" thatescaped reabsorption in the diluting segmentsof the nephron averaged 19.3 + 7.4% in theCirculation, Volume XXXVII, May 1968

15.0 F

100 t-

5.0

.0

0

0

0

00

0LaAn

1000 2000 3000 4000"DISTAL No LOAD".uEq/min

Figure 4

The amount of sodium that was delivered beyondsites of isosmotic (proximal) reabsorption was calcu-lated for each study during peak water diuresis (UNaV + PNa X C, 2 ). This "distal sodium load" is plot-ted against the percentage of the distal sodium loadexcreted in the urine-"distal rejection fraction %."At comparable levels of delivery of sodium to dilutingsegments of the nephron, the distal rejection fractionwas significantly elevated in the hypertensive patients(P <0.001).

hypertensive patients, a value signfficantlyabove the 6.8 + 1.7% found in the normalsubjects (P < 0.001). Distal sodium reab-sorption was increased by salt depletion inthe control subjects; the fraction of the distalsodium load that escaped reabsorption in thediluting segments was only 2.0 + 0.8% in thesestudies.

In figure 4 the amount of sodium deliveredbeyond the sites of isosmotic (proximal) re-absorption in studies of hypertensive andnormal subjects is plotted against the per-centage of this "distal sodium load" that es-caped reabsorption in the diluting segments.In the hypertensive patients the amounts ofsodium presented to the diluting segmentsof the nephron were as large as or largerthan those in normal subjects. Nevertheless,despite comparable or increased sodium de-livery to the distal nephron, the percentageof the "distal sodium load" that escaped

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220[-

200 -

180

160 1-

a

a

a X

a**.U.0

0

: -140 F-

0

a cpa

so

1.0 3.0 5.0 7.0

E/F No%

Figure 5

9.0 11.0

Relationship of renal tubular sodium rejection to meanarterial blood pressure in hypertensive patients andnormal subjects during 5% dextrose-water infusions.In the 31 studies there was a curvilinear positive cor-

relation between the amount of filtered sodium thatescaped tubular reabsorption (E/FNa%) and the mean

arterial blood pressure.

0.8226, fig. 6). Lesser degrees of correlationwere found when glomerular filtrate rate andrenal blood flow were related to E/FNa%(r=0.6938, r =0.7298).

Relation of Renal Tubular Rejection of Sodiumto Renal Tubular Rejection of Solute andof WaterThe fraction of filtered sodium that ap-

peared in the urine during the dextrose-water infusions is plotted against the frac-tion of filtered solute that simultaneously ap-peared in the urine in figure 7 left; a linearrelationship with a correlation coefficient of0.9486 was obtained. In figure 7 right, datafrom 22 studies during peak water diuresis(D/W infusion at 15 ml/min) are plotted; therejection of filtered sodium by the renal tu-bules (E/FNa%) in these studies was directlyrelated to the fraction of filtered water simul-taneously rejected by the tubules (V/GFR%),with a correlation coefficient of 0.9057.

DiscussionThe present study indicates that hyperten-

sive patients exhibit an exaggerated natriuresisin response to an intravenous infusion of 5%

tubular reabsorption in the diluting segmentswas increased in the hypertensive patients.

Relation of Renal Tubular Rejection of Sodiumto Mean Arterial Blood Pressure and toRenal Vascular Resistance

In the 31 studies of normal and hyperten-sive subjects there was a curvilinear positivecorrelation between the mean arterial bloodpressure and the fraction of filtered sodiumexcreted in the urine (fig. 5). Renal vascularresistance (BP/ERBF) was elevated in thehypertensive patients and averaged 23.01 +

7.75 RU in those who received the rapidinfusions and 31.92 12.78 in those receivingD/W at 9 ml/min; renal vascular resistanceaveraged 7.13+±1.37 RU in control subjectson regular diets and 7.76 0.84 RU in thosewho had been deprived of sodium. The mag-

nitude of the renal vascular resistance borea direct linear relationship to the E/FNa%observed during the D/W infusions (r =

701-

601- a

501-

RENAL 40

RESISTANCER.U.

30j

20

10

-

* 0 .

a

0

0.

I I I

1.0 3.0 5.0 70 9.0 11.0E/F Na%

Figure 6

Relationship of renal tubular sodium rejection(E/FNO%) to the renal vascular resistance (meanBP/ERBF) in arbitrary resistance units, R.U. Therewas a linear positive correlation between the E/FNa%and the renal vascular resistance; r 0.8226.

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MEANB.P.mm.Hg

120 1-

100

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0

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FIVE PER CENT DEXTROSE-WATER INFUSIONS

01-

9

8

6

4

3

10a

9

8

7

6

0

0

0

.E/FNa %

a4

0

3

aU2 0

O.a4*an0

0

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2

0

0

00 0

0 0 0

ooa ol

5 10 15 20V

GFR%

25 30 35 40

Figure 7

During 5% dextrose-water infusions in hypertensive patients there was direct relationshipbetween the tubular rejection of filtered sodium (E/FNO%) and the tubular rejection of filteredsolute (E/F'osm%) r= 0.9486. In studies performed during a steady state of water diuresis(D/W at 15 ml/min), the tubular rejection, of filtered sodium was also directly related to thetubular rejection of filtered water (V/GFR%); r = 0.9057.

dextrose and water. This finding confirmsa report by Ek,29 who in 1955 reported in-creased sodium excretion by hypertensivepatients in response to infusions of 5% D/W,but differs from observations of Hollander'35and Steinmetz and associates,36 who did notobserve increased natriuresis in hypertensivepatients during infusions of 3.5% and 2.5%glucose in water. As will be discussed subse-quently, differences in the degree of extra-cellular fluid expansion produced by theinfusions* and in the renal hemodynamics

*Undoubtedly both intracellular and extracellularfluid compartments increased as glucose present inthe 5% D/W was metabolized by the body. However,since the infusions were rapid, the rate of glucoseintake probably exceeded the rate of its metabolismas suggested by an occasional trace of glycosuria.Hence a greater expansion of the extracellular fluidcompartment was probably present throughout thestudies.Circulation, Volume XXXVII, May 1968

of the patients studied may account for thediscrepancy between the various reports.The increased urinary sodium excretion ex-

hibited by the hypertensive patients in thepresent studies did not result from larger in-creases in the filtered load of sodium in re-

sponse to 5% D/W because (1) mean serum

sodium concentration of the hypertensive pa-

tients during diuresis was not significantlyelevated above that of the control subjects,and (2) mean glomerular filtration rate was

lower in patients with increased blood pres-

sure. Since the fraction of filtered sodiumexcreted by the hypertensive subjects was

significantly increased above that of the con-

trol subjects, the data indicate that renaltubular sodium reabsorption was reduced inthe patients with arterial hypertension duringthe D/W infusions.

In the study of Ek,29 the possibility thatincreased natriuresis in patients with hyper-tension resulted from a concomitant glucose

E/FNo% 5 _

vrt IE

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osmotic diuresis was not rigidly excluded. Itseems most unlikely that an osmotic diuresisaccounted for the impaired renal tubularsodium reabsorption observed in hypertensivepatients in the present studies for severalreasons: (1) there was a poor correlationbetween the filtered osmotic load and therejection fraction of sodium, (2) increasedtubular rejection of filtered sodium was ap-parent in individual hypertensive subjectswho exhibited rates of glomerular filtrationthat equaled or exceeded those of individualcontrol subjects (table 1), (3) the percentageof the urinary osmolality due to sodium andchloride was increased more than twofoldabove normal in the hypertensive patients,and (4) there was a poor correlation betweenthe excretion rate of solutes other than so-dium and chloride and the urinary sodiumoutput.

It also seems unlikely that an osmotic diu-resis of functioning residual nephrons ac-counts for the increased E/FNa% of hyper-tensive patients during D/W loading, eventhough such a mechanism may explain inpart the increased sodium rejection observedin uremic patients7: First, none of the hyper-tensive patients subjected to D/W infusionhad a blood urea nitrogen greater than 25mg%; with only a few exceptions they ex-hibited only moderate reductions of glomer-ular filtration. Second, during an osmoticdiuresis of residual nephrons, a linear cor-relation would be anticipated between theexcretion of solutes other than sodium andchloride calculated per 100 ml of glomerularfiltration and the fraction of filtered sodiumthat escaped reabsorption; the absence ofsuch a correlation in the present study tendsto make this mechanism an unlikely causefor increased salt rejection by the hyperten-sive patients.From an analysis of the patterns of solute

and free water clearance that accompanytubular salt rejection during water diuresis,one may ascertain whether impaired tubularsodium transport occurred in portions of thenephron where reabsorption is isosmotic(proximal tubules) or in more distal portions

of the nephron where osmotically free wateris generated by the selective reabsorption ofsodium (loops of Henle, distal tubules).The finding that the "proximal" sodium

rejection fraction was increased in hyperten-sive patients (P <0.05) suggests that someof the increased sodium rejection inducedby a D/W infusion in the hypertensive groupmay have occurred in the proximal tubules.This interpretation is consistent with the re-port of Metzger and associates,37 who foundthat CH20/GFR per unit Cosm/GFR wasincreased in hypertensive patients duringoral water loads. In animal studies extra-cellular volume expansion by infusion ofsaline or Ringer's solution has been demon-strated to depress proximal tubular reabsorp-tion in rats'3' 38, 39 and dogs40 by a mech-anism independent of glomerular filtrationrate, plasma protein concentration, aldoste-rone activity, or antidiuretic hormone.4' Thatextracellular fluid (ECF) expansion with di-lute dextrose solutions can produce a similareffect on proximal salt reabsorption in animalsis supported by observations of Martino andEarley42; these investigators noted depressedfractional reabsorption of sodium in the prox-imal tubules of dogs with diuretic-inducedblockade of distal tubular sodium reabsorp-tion during rapid infusions of distilled wateror dilute solutions of glucose.To assess accurately sodium reabsorption

in "distal" segments of the nephron it isnecessary to consider both the delivery ofsodium to the diluting sites and also theintrinsic characteristics of sodium reabsorp-tion in these areas.43 Since little water escapesfrom the distal segments at high rates ofwater diuresis, the urinary flow rate, V, wastaken as an approximation of the amount ofsodium-containing fluid reaching the dilutingsegments, and CH20 was taken as an approxi-mation of selective sodium reabsorption inthese areas.* As delivery of sodium-containing

*Although C,1,20 actually represents the amount offree water generated in the ascending limb anddistal tubules minus any back diffusion of water thatoccurs in the distal tubule and collecting duct, it is

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fluid to the diluting segments increased inboth the normals and hypertensives, C1920also increased (fig. 3). Thus during the D/Wload a complete inhibition of distal sodiumreabsorption was not apparent in either groupof subjects, nor was a transfer maximum fordistal sodium transport demonstrated overthe range of distal delivery achieved in thesestudies.However, fractional sodium reabsorption in

diluting segments of the nephron was de-pressed in the hypertensives during the D/Winfusions. Nineteen per cent of the "distalsodium load" of the hypertensive patientswas excreted in the urine whereas only 7%of the "distal sodium load" escaped reab-sorption in the normal subjects on regulardiets, and only 2% in normals after sodiumdepletion. The difference between hyperten-sive and normal subjects in fractional rejec-tion of the sodium delivered to the distalnephron was highly significant (P < 0.001)and was proportionally greater than theincrease in "proximal" rejection found inhypertensive patients during the same in-fusions.

Micropuncture studies in normal rats3 38, 39and dogs40 have indicated that the markeddepression of fractional sodium reabsorptionthat occurs in the proximal tubules duringECF volume expansion with saline is ac-companied by a much smaller change insodium excretion, because there occurs simul-taneously an increased reabsorption of sodiumin the distal nephron, particularly in theloops of Henle. The present finding that thefractional "distal" sodium reabsorption wasreduced 12% below normal in hypertensivepatients during 5% D/W infusion suggeststhat reduced distal tubular sodium transportmay explain to a major extent why hyperten-sive patients excrete more sodium than nor-mal subjects in response to infusions thatexpand extracellular fluid volume.

uinlikely that back diffusion of water was significantlydiminished in hypertensive patients with increasedurinary flow rates, since (Uos, ) was increased, notdecreased, in those patients.

Circulation, Volume XXXVII, May 1968

Other data also indicate that urinary dilu-tion was altered in the hypertensive patientsduring the (15 ml/min) D/W infusions: (1)mean Uosm and UNa were higher in the hyper-tensive than in the normal subjects; (2)mean CH20/GFR per Cosm/GFR was lowerin the hypertensive patients; (3) slightlyless CH120 was formed by hypertensive pa-tients at any given urinary flow rate (fig. 3);and (4) at comparable levels of "distal so-dium load," the hypertensive patients ex-hibited greater "distal" tubular sodium rejec-tion (fig. 4) and were unable to lower UO,mand UNa to the levels attained by normalsubjects.Whether the altered urinary dilution and

the reduced fractional "distal" sodium reab-sorption demonstrated in hypertensive pa-tients during the D/W infusions occurred inthe loop of Henle or in the "corticaY' dilutingsegment43 or in both sites cannot be ascer-tained from the present studies. However,reductions in urinary concentrating abilityin dehydrated hypertensive patients havebeen reported by other investigators.'7 4' 45Moreover, Buckalew, Ramirez, and Gold-berg46 have recently found a reduced TCH1,,per unit Cos01 during the natriuresis inducedby hypertonic saline in antidiuretic hyperten-sive patients. Together with the present find-ings the accumulated observations suggestthat at least some of the impaired urinarydilution and 'distal" sodium rejection ob-served in hypertensive patients during ECFvolume expansion results from a defect insodium reabsorption in the ascending limbof the loop of Henle.The curvilinear positive correlation be-

tween the level of mean arterial blood pres-sure and tubular sodium rejection observedin the normal and hypertensive subjects dur-ing the D/W infusions (fig. 5) suggests thatrenal arterial pressure is in some way in-volved in the mechanism for increased sodiumrejection by the latter group. Rough correla-tions between the magnitude of natriuresisand the height of blood pressure have beenreported in several studies of hypertensivepatients receiving saline loads.'8 20.21 25 In

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addition, a variety of renal perfusion studieshave indicated that increases of renal arterialblood pressure may increase urinary salt andwater excretion without affecting glomerularfiltration rate.47A9 In stop-flow studies of

Tobian and associates50 the "distal" nephron

was the site of impaired sodium reabsorptionin rat kidneys that were perfused with bloodat elevated pressures.

Although depressed glomerular filtrationrate and renal blood flow were to some ex-

tent correlated with increased E/FNa% in thepresent studies, these correlations were lesssignificant than the linear positive relation-ship between the degree of tubular sodiumrejection and the calculated renal vascularresistance (fig. 6). This finding is similar tothe direct correlation between salt rejectionand renal vascular resistance noted by Cottier,Weller, and Hoobler24 in a group of hyperten-sive patients given saline infusions. Renal vas-

cular resistance is a numerical expression ofthe intensity of hypertensive renovasculardisease; these observations therefore suggestthat alterations of renal pressure and vascularresistance in the kidneys of hypertensive pa-

tients may determine the increased salt re-

jection exhibited by these patients duringsaline, mannitol, or 5% D/W infusions.

It has been suggested that proximal tubularsodium reabsorption is regulated by a natri-uretic hormone of extrarenal'0 or intrarenalorigin.51 Whether greater amounts of a pos-

tulated natriuretic hormone are elicited byvolume expansion in patients with increasedblood pressure and increased vascular resis-

tance, or whether normal amounts of thissubstance elicit greater natriuresis in hyper-tensive patients because of abnormalities ofrenal hemodyamics are questions that awaitfurther study.

Alternatively, physical factors may influencetubular sodium transport. Earley and associ-ates,5' 12 have provided evidence to sup-

port the hypothesis that transmission ofarterial blood pressure along the renal vas-

culature may act to inhibit tubular sodiumtransport, possibly by altering renal interstitialvolume. In the present studies during water

diuresis the rejection fraction of sodium wasdirectly related not only to the rejectionfraction of total solute (E/FFosm%) but alsoto that of filtered water (V/GFR%). Sucha balance between the fractional excretionof sodium and water is not characteristic ofthe action of any known hormone and sug-gests that the changes in sodium and wateroutput were mediated by physical factors.Mechanisms whereby the combination of in-creased blood pressure and increased renalvascular resistance could produce proportion-ate changes in the tubular rejection of filteredsodium, solute, and water during ECF ex-pansion in hypertensive man remain specula-tive at this time. It is conceivable howeverthat (1) medullary washout secondary to apressure induced increase in medullary bloodflow52; (2) increased passive back diffusionof reabsorbed sodium and water due to al-tered pressure and resistance in peritubularcapillaries,12 13, 53 or (3) a pressure-induceddistortion of the normal relationship betweenthe quantity of glomerular filtrate and tubularvolume, with a consequent increased linearvelocity of tubular flow,54 could contributeto a hemodynamically mediated natriuresisin these patients.

References1. MILLS, I. H., DE WARDENER, H. E., HAYTER,

C. J., AND CLAPHAM, W. F.: Studies on theafferent mechanism of the sodium diuresiswhich follows the administration of intravenoussaline in the dog. Clin Sci 21: 259, 1961.

2. LEVINSKY, N. G., AND LALONE, R. C.: Mechanismof sodium diuresis after saline infusion in thedog. J Clin Invest 42: 1261, 1963.

3. BLYTHE, W. B., AND WELT, L. G.: Dissociationbetween filtered load of sodium and its rateof excretion in the urine. J Clin Invest 42:1491, 1963.

4. RECTOR, F. C., JR., VAN GIESEN, G., KIIL, F., ANDSELDIN, D. W.: Influence of expansion ofextracellular volume on tubular reabsorptionof sodium independent of changes in glomeru-lar filtration rate and aldosterone activity.J Clin Invest 43: 341, 1964.

5. EARLEY, L. E., AND FRIEDLER, R. M.: Observa-tions on the mechanism of decreased tubularreabsorption of sodium and water during salineloading. J Clin Invest 43: 1928, 1964.

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6. STEIN, R. M., BERCOVITCH, D. D., AND LEVITT1,M. D.: Dual effects of saline loading on renaltubular sodium reabsorption in the dog. AmerJ Physiol 207: 826, 1964.

7. BRICKER, N. S.: Control of sodium excretionwith normal and reduced nephron populations:Pre-eminence of third factor. Amer J Med43: 313, 1967.

8. JOHNSTON, C. I., AND DAVIS, J. O.: Evidencefrom cross circulation studies for a humoralmechanism in the natriuresis of saline loading.Proc Soc Exp Biol Med 121: 1058, 1966.

9. LIcHARDUS, B., AND PEARCE, J. W.: Evidencefor a humoral natriuretic factor released byblood volume expansion. Nature (London)209: 407, 1966.

10. MARTINEZ-MALDONADO, M., KURTZMAN, N. A.,RECTOR, F. C., JR., AND SELDIN, D.: Evidencefor a hormonal inhibitor of proximal tubularreabsorption. (Abstr.) J Clin Invest 46: 1091,1967.

1 1. EARLEY, L. E., AND FRIEDLER, R. M.: Effects ofcombined renal vasodilatation and pressor

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12. EARLEY, L. E., MARTINO, J. A., AND FRIEDLER,R. M.: Factors affecting sodium reabsorptionby the proximal tubule as determined duringblockade of distal sodium reabsorption. J ClinInvest 45: 1668, 1966.

13. RECTOR, F. C., JR., SELLMAN, J. D., MARTINEZ-MALDONADO, M., AND SELDIN, D. W.: Mecha-nism of suppression of proximal tubular re-

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14. FARNSWORTH, E. B.: Renal reabsorption ofchloride and phosphate in normal subjects andin patients with essential hypertension. J ClinInvest 35: 897, 1946.

15. GREEN, D. M., WEDELL, H. G., WALD, M. H.,AND LEARNED, B.: Relation of water andsodium excretion to blood pressure in humansubjects. Circulation 6: 919, 1952.

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19. GREEN, D. M., JOHNSON, A. C., BRIDGES, W. C.,AND LEHMAN, J. N.: Stages of salt ex-

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PAUL J. CANNONHypertensive Patients and Its Relation to Renal Hemodynamics

Man: Evidence for Increased Proximal and Distal Tubular Sodium Rejection by Effects of Five Per Cent Dextrose-Water Infusions in Normal and Hypertensive

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1968 American Heart Association, Inc. All rights reserved.

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