Journal of Clinical InvestigationVol. 43, No. 8, 1964

Renal Tubular Effects of Hydrocortisone and Aldosterone inNormal Hydropenic Man: Comment on Sites

of Action *

STUARTL. YUNIs,t D. DANNYBERCOVITCH,t RICHARD M. STEIN,MARVIN F. LEVITT, ANDMARVIN H. GOLDSTEIN

(From the Section, of Renal Diseases, Department of Medicine, the Mount Sinai Hospital,New York, A. Y.)

It is generally accepted that glucocorticoid andmineralocorticoid adrenal hormones influence theurinary excretion of sodium and potassium, butthe mechanism(s) and tubular site(s) of actionhave not been clearly defined. Aldosterone hasbeen reported to decrease sodium and chloride andto increase potassium and hydrogen ion excretion(1-3). With the stop-flow technique, this incre-ment in sodium and chloride reabsorption was lo-calized to the distal tubule (4. 5). \With the ob-servation that aldosterone increased urine soluteconcentration in hydropenic subjects as a basis, itwas proposed that this agent enhanced sodium re-absorption at the ascending limb of the loop ofHenle (6). However, ill these studies the influ-ence of changes in urine flow rate and composi-tion of the urine solute was not considered.When aldosterone was administered to hydratednormal subjects, an increase in the excretion ofsolute free water (CH20) was noted (7). Theauthors concluded that the primary action of thishormone was to increase sodium reabsorption inthe distal tubule. In similar experiments, reportedby others, CHOwas not elevated by aldosterone(8).

It is well established that glucocorticoids, incontrast to aldosterone and desoxycorticosteroneacetate (DOCA), correct the water clearing de-fect in Addisonian patients and adrenalectomizeddogs (9-18). The correction of this defect by

*Submitted for publication January 9, 1964; acceptedApril 23, 1964.

Supported by grant A-277 from the National Instituteof Arthritis and Metabolic Diseases, Bethesda, Md.

Presented in abstract form at the 20th Annual Meetingof the American Federation for Clinical Research, May1963. (Clin. Res. 1963, 11, 242.)

t U. S. Public Health Service postdoctoral researchfellow, National Heart Institute, Bethesda, Md.

hydrocortisone could not be attributed solely to therise in glomerular filtration rate (GFR) fre-quently produced by this agent (16-18). In ad-dition, others have recently reported that a gluco-corticoid (methyl-prednisolone) increased solutefree water reabsorption (TCH2O) in salt-depletedcirrhotics without altering GFR (19).

Under hydropenic conditions, solute concentra-tions in the medullary interstitium and collectingduct fluid have been shown to be the same in anyplane cut perpendicular to the axis of the medulla(20). Others have demonstrated that urea ishighly diffusible across the collecting duct mem-brane, producing similar concentrations of thissolute within the collecting duct and surroundingmedullary interstitial fluid (21, 22). It thereforefollows that urine nonurea solute concentration(total urine solute concentration minus urine ureaconcentration) will reflect changes in the medul-lary nonurea-solute (primarily sodium and chlo-ride) concentration (23). In addition, consider-able evidence is available to suggest that the quan-tity of salt deposited within the medulla dependsupon ascending limb sodium transport (24).With these assumptions, changes in total urinesolute and urine urea concentrations, electrolyteexcretion, and renal hemodynamics produced byhydrocortisone and aldosterone were analyzed innormal hydropenic subjects to determine the renaltubular site(s) of action of these agents.

Methods

T1lie acute effects of the intravenous administration of200 mg hydrocortisone (8 experiments) or 1.0 mg d-aldos-terone 1 (8 experiments) were studied in 14 maximally

1 The d-aldosterone was generously supplied by theCiba Pharmaceutical Company, Summit, N. J., throughDr. C. H. Sullivan, Director of Clinical Investigation.

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RENALTUBULAREFFECTS OF HYDROCORTISONEAND ALDOSTERONE

TABLE I

Summary of mean changes in hydropenia-low urine flow studies (group I)*

Initial FinalAVt AC~silit Uosin Uosm AUjosnt AUu"et AUNUSt AUNaVt AUKVt AUCIVt AGFRt

mi/mitt ml/min mOsm/kg mnOsm/kg mOsm/kg inmoles/L mOsm/kg &Eq/mWi uEq,/min JuEq/mifl mi/msllH20 H.20 H2O H20

Placebo0 +0.15 901 957 +56 +12 +44 +28 +5 -5 -2

SE±0.056 4±0.15 ±29 ±27 +15 ±11 ±10 +17 ±9 ±19 ±2.9Aldosterone

-0.25 -0.59 923 1031 +107 +70 +37 -56 -14 -89 +4SE±0.029 ±0.10 ±36 ±t32 ±10 ±8 ±8 ±12 i8 ±10 ±2.9

Hydrocortisone-0.03 +0.14 911 1051 +140 +25 +115 -14 +52 -13 +4

SE±0.055 ±0.17 ±36 ±54 ±17 ±t9 i18 ±16 ±8 ±14 ±2.8

* V = urine volume; C. = osmolar clearance; Uo.m = urine osmolality; UNUS= urine nonurea solute; GFR- glomerular filtration rate.

f The data are expressed as the change (A) between the control period (initial) and final experimental period 3' hoursafter the administration of placebo, aldosterone, and hydrocortisone.

hydropenic subjects free of cardiovascular and renal dis-ease. All studies were performed after a 14-hour fastand 11 hours after the intramuscular injection of 5 U ofvasopressin tannate in oil. Urine was collected by an in-dwelling catheter in female subjects and by spontaneousvoiding in males. Subjects remained recumbent through-out the experiments except for males who stood whilevoiding. Two studies were performed on 12 of the 14subjects. In one experiment either hydrocortisone oraldosterone was administered, and in the other a placeboinjection was given. Two subjects received hydrocor-tisone, aldosterone, and placebo on separate occasions.

Group I. Hydropenia. At 8:00 a.m. on the day of theexperiment the bladder was emptied (double air wash-outs were employed in all catheterized subjects), andpriming doses of inulin and para-aminohippurate (PAH)were administered intravenously. Thereafter, an infu-sion was started containing sufficient quantities of inulinand PAH to produce satisfactory plasma levels andaqueous vasopressin in a concentration adequate to de-liver 50 mgu per kg body weight per hour. This solutionwas delivered at a rate of 0.34 ml per minute through-out the course of the study by a Bowman infusion pump.After allowing 60 minutes for equilibration of plasma in-ulin and PAH concentrations, the bladder was emptied.The urine collected in the following 30 to 40 minutesserved as the control period. The placebo, hydrocorti-sone, or aldosterone was then administered. Urine wascollected at 40- to 60-minute intervals for the next 3ihours. Blood samples were drawn at suitable intervals.

Group II. Hydropenia-solute diuresis. A. Five sub-jects, prepared as outlined above for the group I studies,received an intravenous infusion of 10%o mannitol 31hours after the administration of placebo, hydrocortisone,or aldosterone. The mannitol solution was administeredat a rate of 10 ml per minute until urine flow increasedto 12 to 15 ml per minute. Urine was collected at 10- to15-minute intervals throughout the solute infusion. Eachsubject was studied on three occasions, at least 1 week

apart, receiving placebo, hydrocortisone, and aldosterone,respectively. The rate of osmolar clearance (Co.m) andsolute free water reabsorption (TCH2o) was ascertainedduring the solute diuresis.

B. With the protocol outlined in group II A, studieswere performed in one Addisonian patient (3 monthspostbilateral adrenalectomy) and in one patient withpanhypopituitarism. Cortisol therapy was discontinuedin the Addisonian patient 72 hours before each study.The patient with panhypopituitarism was receiving nohormonal replacement therapy. One week after a placebo

A TOTALURINE OSMOLALITY(mOsm/ kg. H20 )

I

I&6

E0,0E4c

A U UREA CONCENTRATION(mOsm/kg.H20 )

A NON-UREASOLUTECONCENTRATION(mOsm-/kg.H20)

HYDRO.

AV( ml. /min.)

FIG. 1. MEANCHANGESIN URINE OSMOLALITY, URINEUREA, AND NONUREA-SOLUTECONCENTRATIONS31 HOURSAFTER THE ADMINISTRATION OF PLACEBO, HYDROCORTISONE,ANDALDOSTERONEPLOTTED AGAINST THE CHANGEIN URINEFLOWRATE (V) PRODUCEDBY THESE AGENTS.

1 669

YUNIS, BERCOVITCH, STEIN, LEVITT, AND GOLDSTEIN

TABLE IITwo typical experiments-group I

Time V Cosm UOsm UIrea tUNUS UI Na N UK UKV ICCl iV CIn*

mill ?nll'inn mnllmiii in~sm/kg inmoles,'l. mnOsmkg mEq 'l, ,uFq, /nii ?Fq, ,I. uEqiYnii mnq;Eql, pAEq miii mnimH20 H20

Subject G. S. Placebo studyControl 0.40 1.40 1,035 290 745 184 74 204 82 249 100 87

0 Placebo injection58 0.45 1.56 1,029 274 755 190 86 198 89 240 108 89

124 0.42 1.52 1,074 288 786 200 84 192 81 255 107 93180 0.44 1.59 1,068 276 792 213 94 204 90 267 117 92208 0.41 1.49 1,073 281 792 230 94 195 80 257 105 90

Subject G. S. Hydrocortisone studyControl 0.28 1.01 1,100 369 731 131 37 197 55 237 66 96

0 Hydrocortisone, 200 mg iv60 0.31 1.18 1,150 362 788 148 46 229 71 263 82 100

126 0.27 1.06 1,177 368 809 129 35 256 69 229 62 98188 0.32 1.29 1,210 372 838 135 43 258 83 247 79 99217 0.28 1.15 1,231 379 852 125 35 274 77 206 58 100

Subject J. F. Placebo studyControl 0.82 2.12 737 156 581 182 149 133 109 148 121 108

0 Placebo injection60 0.73 1.97 764 174 590 174 127 173 126 135 99 105

118 0.73 2.03 785 175 610 209 153 143 104 142 104 108182 0.67 1.91 801 193 608 209 140 152 102 137 92 97214 0.68 1.97 810 193 617 215 146 152 103 134 91 101

Subject J. F. Aldosterone studyControl 0.70 1.87 762 234 528 122 85 187 1 31 145 102 89

0 Aldosterone 1.0 mg ixv64 0.62 1.75 801 263 538 99 61 229 142 140 87 91

125 0.54 1.61 847 288 559 104 56 235 127 153 83 94180 0.50 1.51 859 305 554 110 55 237 109 140 70 90209 0.47 1.44 870 319 551 120 56 233 110 129 61 96

* C1. = inulin clearance. Other abbreviations, as in Table I.

study, a repeat study was performed with hydrocorti-sone.

All urine and blood specimens were analyzed for os-molality and for sodium, potassium, chloride, urea, inu-lin, and PAH concentrations. Osmolalities were deter-mined with a Fiske osmometer. Other determinationswere performed by methods previously described fromthis laboratory (25). GFR and effective renal plasmaflow (RPF) were measured as the clearance of inulinand PAH, respectively. Osmolar clearance and solutefree water reabsorption were calculated from the fol-lowing formulas: osmolar clearance (Cosm) =[urine os-molality (U.sm) X urine volume (V) ]/plasma osmolality(Posm), and solute free water reabsorption (T'H2o) =Cosm-V.

Results

Group I. Hydropenia (Tables I and II; Fig-ures 1 and 2). The effects of placebo, hydrocorti-

sone, and aldosterone are expressed as the change(A) between the control and the final experi-mental period, approximately 31 hours after theinjection.

Total urine solute concentration (Urn), urineflow rate (V), and solute clearance (CCosm) (TableI; Figure 1). After the placebo injection (14 ex-periments), Uosm rose an average of 56 mOsmperkg H2O without a mean change in V. In 8 hy-drocortisone studies Uosm increased a mean of 140mOsmper kg H2O associated with a mean de-crease in V of 0.03 ml per minute. Co.m rose 0.15ml per minute after placebo and 0.14 ml per min-ute after hydrocortisone. Although there wasno significant alteration in V or Cosm between theplacebo and hydrocortisone groups, the differencein the increment in Uom was significant (p <

1670

RENALTUBULAREFFECTS OF HYDROCORTISONEAND ALDOSTERONE

0.01). After the administration of aldosterone(8 experiments) Uosm rose a mean of 107 mOsmper kg H20, which was significantly greater thanthat noted in the placebo studies (p < 0.05).This increase in Uo.m was associated with a meanfall in V of 0.25 ml per minute and a mean fallin Co.m of 0.59 per minute. The decrements inurine flow and solute clearance were also sig-nificant when compared to the placebo group(p <0.01).

Urine urea (UUrea) and nonurea solute (NUS)concentrations (Table I; Figure 1). Ulrea in-creased in all three groups, the change averaging12, 25, and 70 mmoles per L for placebo, hydro-cortisone, and aldosterone, respectively. The in-crement in UUrea noted with aldosterone was sig-nificantly higher than that observed in the placebogroup (p < 0.01), whereas the change producedby hydrocortisone was not significant. UrinaryNUS concentration also rose in all three groups.Hydrocortisone produced an increase in NUSconcentration (115 mOsmper kg H2O), whichwas significantly greater than the increase notedin the placebo group (p < 0.01). The rise inNUS concentration noted with aldosterone (37mOsmper kg H2O) did not differ significantlyfrom that seen in the placebo group (44 mOsmper kg H2O).

Electrolyte excretion (Table I; Figure 2). Inthe placebo studies, sodium excretion increasedprogressively over the 31 hour experimental pe-riod (mean A, 28 fLEq per minute), and potassiumexcretion increased initially and then returnedtoward control levels (mean A, + 5 ptEq per min-ute). After hydrocortisone administration, po-tassium excretion rose progressively for approxi-mately 2 hours and then stabilized, the incrementaveraging 52 ,uEq per minute after 31 hours.Sodium excretion fell a mean of 14 ,uEq per min-ute during the course of the experiments. Incontrast to hydrocortisone, aldosterone produceda prompt and marked fall in sodium excretionthat averaged 56,uEq per minute at the end of theexperimental period. During this same period,potassium excretion diminished a mean of 14 pEqper minute. Chloride excretion fell 5, 13, and89 uEq per minute in the placebo, hydrocortisone,and aldosterone studies, respectively.

+60 r+40 -

v +20-AUNaG OHjuEq/min. - 20

-40-60+60+40-

UIK V +20 -

juEq/min. 0

_-20+20 -

01-AUCI V -20j-puEq/min. - 40

-60 -

-80-+60 -

+401-,UK V +20[

+ ^

AUNOVpuEq/min.

I PLACEBO 0 HYDRO [ ALDOS

.. M.H M

I I I

-20-40

-60_-of%

La1J

HUH~~~H---60 120 180TIME IN MINUTES

210

FIG. 2. MEAN CHANGES IN ELECTROLYTE EXCRETIONPRODUCED BY PLACEBO, HYDROCORTISONE, AND ALDOS-TERONE.

Glomerular filtration rate (GFR) and renalplasma flow (RPF) (Table I). In all threegroups the mean change in GFRvaried less than4%o. These alterations were not statistically sig-nificant and are within the expected experimentalerror. In the individual experiments there wasno correlation between changes in GFR and themagnitude of the alteration in Uosm or urinaryNUS.

RPF rose 27 ml per minute, 26 ml per minute,and 30 ml per minute in the placebo, hydrocorti-sone, and aldosterone groups, respectively. Therewas no significant difference between the groups.

Group II A. Hydropenia-solute diuresis (Fig-ure 3). Over a comparable range of osmolarclearance, the TCHI0/CO.m curves were almost iden-tical in the placebo and aldosteroiie groups. Af-ter the administration of hydrocortisone, theTCH20/COSm curve was consistently higher thanthose noted in the placebo and aldosterone groups.

1671

YUNIS, tERCOVITCH, STEIN, LEVITT, AND GOLDSTEIN

GROUPII A

2 4 6 8 10 12C OSM(ml./min.)

GROUPII B

SUBJECT E.T.ADDISONIAN

*-- PLACEBO(MEANG.F.R. 47ml./min.)0- HYDRO. (MEAN G.F.R.50ml./min)

0

0

-------- ----

0/~~~~~~0:,'.W+2 +6 +10 +14

C OSM(mi./min.)

TCH2o(ml. /min.)

+45+5

14 16 18

SUBJECT P.P.PANHYPOPITUITARISM

PLACEBO(MEANG.FR. 1Olml. /min.) - -*HYDRO.(MEANG.F.R. 102mi./min.) -o

+2++2

+1 /,"+18 +2 +6 +10 +14

C OSM(mi./min.)FIG. 3. (Upper) EFFECT OF PLACEBO, HYDROCORTISONE,AND ALDOSTERONEON

FREE WATERREABSORPTION (TCH2o) DURING A MANNITOL DIURESIS IN FIVE NORMAL

SUBJECTS. All TCH2o values are grouped about successive 2-ml increments inCosm and represent the mean values for each group. (Lower) EFFECT OF PLACEBO

AND HYDROCORTISONEON TCH2o DURING A MANNITOL DIURESIS IN TWOADRENAL-IN-

SUFFICIENT SUBJECTS.

GFR and RPF were comparable during thesolute diuresis in all groups.

Group II B. Adrenal insufficiency-hydropenia-solute diuresis (Figure 3). Hydrocortisoneacutely increased TcHO in both patients withadrenal insufficiency. The magnitude of the rise(1.3 ml per minute and 1.9 ml per minute) inthese subjects with depressed TCHO/CO.m curves

exceeded that produced by hydrocortisone admin-istration in the normal subjects. The change in

GFR produced by hydrocortisone in these twosubjects was not different from that noted in thegroup II A studies.

Discussion

With the assumption that urinary NUS con-

centration reflects medullary salt concentration,the rise in NUS concentration produced by hy-drocortisone suggests that this agent increases

7

6

_'~ 5

._4-

4"0ONz3

2 -

0

0>',.' *- - -. PLACEBO(MEAN G.F.R.IOOmi./min.)By.& a.a ALDOSTERONE(MEAN G.F.R. 102ml./min.)

-o OHYDROCORTISONE(MEAN G.F.R. 103 ml./min.)

+18

i672

+4t+4

+3++3

RENAL TUBULAREFFECTS OF HYDROCORTISONEAND ALDOSTERONE

salt concentration within the medulla. The aug-mented salt concentration might result from an in-creased rate of sodium transport at the ascendinglimb or from a decrease in effective medullaryblood flow (decreased "medullary wash-out").There is no available evidence to suggest that hy-drocortisone diminishes medullary blood flow.In fact, the clearance of PAH, although not neces-sarily a direct index of medullary blood flow,tended to rise in the studies presented here. Itappears, therefore, that the increment in medul-lary NUSconcentration can best be explained asa consequence of increased sodium transport atthe ascending limb of the loop of Henle. SinceTCH2O represents an index of ascending limb so-dium transport (26-28), the increment in thisparameter produced by hydrocortisone is con-sistent with the proposed action of this agent.

An increase in sodium transport at the loopcould result indirectly from an enhanced sodiumsupply or from a direct hormonal effect on theactive sodium transport mechanism located at thissite. If there were an increase in supply, it doesnot appear to have been mediated by a measurablerise in GFR. No significant alteration in GFRwas evident in our studies or in those reported byothers (19, 29). In fact, hydrocortisone has beenshown to produce a prompt rise in GFR only inglucocorticoid or salt-depleted subjects with re-duced filtration rates (16-18, 29). When hydro-cortisone was administered to these subjects un-der hydrated conditions, an abrupt increase inGFRand CH2O occurred. The increase in CH2O,however, could not be explained solely by therise in GFR (16-18). Since CH2O is formedprimarily at the ascending limb, the hydrated stud-ies may also be explained by the proposal thathydrocortisone increases ascending limb sodiumtransport, apart from its effect on GFR. Theincrements in TCH9O noted in normal and Addi-sonian subjects after hydrocortisone (Figure 3)are compatible with this view.

The rise in potassium excretion produced byhydrocortisone confirms the conclusion that thisagent increases the sodium/potassium exchangeprocess (2, 3, 16, 30) located in the late distal tu-bule and collecting duct (31, 32). Since the in-crement in potassium excretion was associatedwith a fall in sodium excretion, this alteration in

potassium excretion apparently was due primarilyto a direct hormonal effect. However, the datasuggest that potassium excretion may, in part,have been enhanced by an increased supply of isos-motic fluid to the late distal tubule and collectingduct. The failure for urine flow to fall in theface of a more concentrated medulla is consistentwith an increased water supply to the collectingduct. In addition, the increment in the combinedrate of sodium and potassium excretion (Figure2) implies that there was a coincident increase insodium supply to these distal sites.

In summary, it has been suggested that hydro-cortisone acutely enhances sodium transport atthe ascending limb without a decrease (and pos-sibly a modest increase) in sodium and watersupply to more distal sites. This combination offindings is explicable only if the rate of isosmoticfluid escaping proximal tubular reabsorption hasbeen augmented. This increment in loop sodiumsupply can result only from a hydrocortisone-in-duced inhibition of proximal tubular sodium reab-sorption or an increase in GFRproduced by thishormone, or both. If this increase in loop solutesupply is due to a rise in GFRrather than to aproximal tubular block, the alteration is too smallto be measured by our present techniques. Inaddition to its proximal effect, hydrocortisoneapparently directly enhances sodium/potassiumexchange in the late distal tubule and collectingduct. It is tempting to ascribe to hydrocortisonea similar direct hormonal effect on the rate of so-dium transport at the ascending limb. Other in-vestigators have suggested that methylprednisoloneexerts such a direct hormonal action at this site(19). Although our data do not contradict thisinterpretation, the increase in ascending limb so-dium transport may be explained entirely by anincreased sodium supply to the loop of Henle.

The administration of aldosterone did not ap-pear to alter renal hemodynamics. In constrast tohydrocortisone, aldosterone produced a distinctfall in sodium and chloride excretion, solute clear-ance, and urine flow rate without a significantchange in urinary NUS concentration. Appar-ently aldosterone enhances sodium and chloridereabsorption without effecting medullary salt con-centration. Other physiologic stimuli producinga fall in sodium excretion have been shown to re-

1673

YUNIS, BERCOVITCH, STEIN, LEVITT, AND GOLDSTEIN

duce urinary NUSconcentration in both man anddog (25, 27, 33). It was suggested that thesestimuli decreased sodium supply to the loop ofHenle. The failure of aldosterone to alter uri-nary NUS concentration implies that this agentdid not exert its action primarily in the proximaltubule or ascending limb. Thus, it is suggestedthat aldosterone enhances sodium and chloridereabsorption in the distal convoluted tubule. Thisproposed distal site of action of aldosterone isconsistent with the failure of this agent to effectTc,2o formation, another parameter reflectingloop sodium transport during a mannitol diuresis.Moreover, the observation that aldosterone re-duces Uosm in hydrated subjects is also explicableby this proposal (7). Finally, experiments utiliz-ing the stop-flow technique have indicated thataldosterone influences a distal sodium absorptivemechanism (4, 5).

An alternative explanation to a singular tubu-lar site of action is an aldosterone-induced increasein sodium reabsorption throughout the nephron.Such an action would demand a delicate balancebetween decreased loop sodium supply (increasedproximal reabsorption) and an enhanced rate ofsodium transport at the ascending limb. Thisbalance of effects would have to be precisely ad-justable to progressively changing loop sodiumsupply and altered tubular fluid sodium concen-trations to explain the failure of aldosterone toinfluence Tc1H20 during increasing mannitol diu-resis. For these reasons, an effect of aldosteronethroughout the tubule appears unlikely.

The rise in Uurea associated with the almost in-versely proportional fall in V noted in the presentstudies (Table II) indicates that the aldosterone-enhanced absorption of water occurred at a seg-ment relatively impermeable to urea despite thepresence of antidiuretic hormone (ADH).Others have suggested previously that the distaltubule possesses such a low order of permeabilityto urea (24, 34). More recently, in micropunc-ture studies a concentration gradient for ureawas demonstrated in the distal convoluted tubule(35, 36). Thus, the observed changes in UUreaand V are also compatible with the proposal thataldosterone enhances salt and water reabsorptionin the distal tubule. This action of aldosteronewould decrease flow rate and increase urea con-centration of the isosmotic fluid entering the col-

lecting duct. The higher tubular fluid urea con-centration would favor the passage of urea fromcollecting duct into the medulla. Since the col-lecting duct membrane is highly permeable tourea, this solute would equilibrate between col-lecting duct fluid and medullary interstitium.When equilibrium has been established, medullaryurea and total urine solute concentration will beincreased without any alterations in NUS con-centration.

It would be anticipated that the aldosterone-induced increment in sodium and chloride reab-sorption would decrease sodium available for so-dium/potassium exchange. However, after aninitial decrease, potassium excretion remained un-changed as sodium excretion continued to fall(Figure 2). Apparently aldosterone increases therate of sodium/potassium exchange despite a pro-gressive decrease in sodium available for exchange.These data are consistent with the reports ofothers that aldosterone has a direct hormonal ac-tion on the sodium/potassium exchange mecha-nismi in addition to increasing sodium and chloridereabsorption in the distal convoluted tubule (3, 7,37, 38).

The aldosterone studies revealed that as urineflow rate decreased, total urine solute concentra-tion increased while NUS concentration and pre-sumiably medullary salt concentration remained un-changed. Others investigators have also notedthis divergence of urine osmolality and NUSconcentration (39, 40). This increase in urineconcentration without an increment in medullarysalt concentration may result from the relativeimpermeability of the distal convoluted tubule tourea. Thus, an increase in distal abstraction ofwater will increase urine solute concentrationwithout an effect on the countercurrent multipliersystem. The importance of distal tubule imper-meability to urea in the determination of urinesolute concentration under conditions of low flowdemands the separation of urea and nonurea-solute when studying the concentration mechanismunder these conditions.

Summary1) Changes in urine solute concentration, urine

urea concentration, electrolyte excretion, and re-nal hemodynamics produced in normal hydro-penic subjects by the intravenous administration

1674

RENALTUBULAREFFECTS OF HYDROCORTISONEAND ALDOSTERONE

of hydrocortisone and aldosterone were comparedto those produced by a placebo injection adminis-tered under the same experimental conditions.

2) Hydrocortisone produced a significant in-crease in urine osmolality without any alterationin urine flow rate, solute clearance, and urine ureaconcentration. Aldosterone also increased urinesolute concentration but with a significant de-crease in urine flow rate and solute clearance. Incontrast to hydrocortisone, the increment in urinesolute concentration produced by aldosterone wasentirely accounted for by the increase in urineurea concentration.

3) Neither hydrocortisone nor aldosterone in-fluenced renal hemodynamics. Hydrocortisoneincreased potassium excretion and decreased so-dium excretion to a lesser extent. Aldosteroneproduced a significant reduction in sodium andchloride excretion with only a minor decrease inpotassium excretion.

4) Hydrocortisone increased Te'lCo formationin both normal and adrenal-insufficient subjects.This parameter was not affected by aldosterone.

5) These data indicate that hydrocortisone en-hances sodium supply and transport at the ascend-ing limb. In contrast, aldosterone appears to en-hance directly sodium and chloride reabsorption inthe distal convoluted tubule. Both agents alsodirectly augment the sodium/potassium exchangemechanism in the late distal tubule and collectingduct.

Acknowledgment

We gratefully acknowledge the valuable technical as-sistance of Mrs. Edith Neubert and Miss Sarah Chipoco.

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