An explanation for abnormal water retention and hypoosmolality in congestive heart failure

An Explanation Retention

for Abnormal

and Hypoosmolality

Congestive NORMAN H.

BELL, M.D.,~

Water

Heart

in

Failure*

P. SCHEDL, M.D.~ and FREDERIC C.

HAROLD

BARTTER,

M.D.,

WITH THE TECHNICAL ASSISTANCE OF ERNEST POWELL AND GEORGE SMITH, II

Bethesda, Maryland

I

T is well

established that patients with congestive heart failure and edema retain sodium and water. In such patients on average intakes of water hyponatremia may develop even when total body sodium is abnormally increased [Y-3]. Because they may fail to excrete a water load normally [45] and because anti20 MlKg.

diuretic substances have been demonstrated in their blood [6-81 and urine [9,70], it has been postulated that their inability to excrete water normally may result from overproduction or from decreased inactivation of antidiuretic hormone [6-701. Since a urine hypotonic to plasma is probably

1El

LB

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W.S.l -0

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A

I I I

I I I I

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.-NORMAL

A

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5ml/min.

4-

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FIG. 1. The effect of intravenous water loads (20 ml. per kg.) given alone and with Pitressin in a normal subject and in four patients with congestive heart failure. Note that each of the patients (1) excreted free water with the water load alone and (2) excreted a concentrated urine with the Pitressin and that (3) the interval before a diuresis of free water was comparable to that in the normal subject. * From the Clinical Endocrinology Branch, National Heart Institute, National Institutes of Health, Maryland. t Present address: Northwestern University School of Medicine, Chicago, Illinois. 1 Present address: State University of Iowa, Iowa City, Iowa. VOL.

36,

MARCH

1964

351

Bethesda,

352

Congestive Heart Failure-Bell TABLE

THE EFFECT

OF ORAL M’ATER LOADS (20 WITH

-

I

ML. PER

CONGESTIVE

Age (yr.1

IN

NORMAL

Four-Hour

% Load t

SUBJECTS

AND

IN

PATIENTS

FAILURE

CLQO as

Load’

Serum Osmolality (mOsm./kg.)

Urine *

I-

Diagnosis

and Sex

KG.)

HEART

T

Patients

et al.

%

Minimum Osmolality (mOsm. /kg.) $

Start

After Load[j

End of Study

Cardiac Patients

I E. B.

43,F

C. A. L. B. w. s. S. R.

29,M 61,M 22,M 67,M

I

I

Patent ductus arteriosus Idiopathic myocarditis Arteriosclerotic heart disease Idiopathic myocarditis Arteriosclerotic heart disease

Average

39 23 14 20 28 23 26

86 218 156 82 49 179 153

283 270 276 256 247 277 279

273 260 269 256 245 274

276

25

132

270

263

267

59 54 52 50 69 59 97 60

83 101 69 55 49 59 49 56

286 295 288 288 297 288 289 289

282 285 282 283 282 283 285

284 293 286 286 288

63

65

290

i;i 262 247 267 273

Normal Subjects

G. C.

20,M

T. T.

21,M

E. S. E. W. A. N. I. w.

20,F 16,F 34,F 65,M

.

111 100 94 84 99 96 108 84

. .

28; 283

283

287

_I_

Average

-

-

-

* Total fraction excreted during four hours after end of ingestion. t Fraction of administered load excreted in four hours X 100. i Fraction of administered load excreted as free water X 100. 5 Osmolality of most dilute urine. ]]T wo h outs after start of ingestion.

produced by removal of sodium without water in the loop of Henle [ 77,721 however, a limitation in free water excretion could result from a decrease in volume flow to the diluting segment as a result of an enhanced isosmotic proximal renal tubular reabsorption of glomerular filtrate [ 73,741. Such a “defect” has been demonstrated in patients with cirrhosis and ascites and in sodium-depleted normal subjects, and has been corrected by infusion of isotonic mannitol or salt, which increases the quantity of sodium and water available for generation of free water [741. In the present study evidence is presented that a similar mechanism may be responsible

for impaired water excretion in some patients with congestive heart failure, as has been proposed [73]. Evidence is produced to show that a similar defect may be produced in a patient with diabetes insipidus by sodium depletion and thus can occur in the absence of antidiuretic hormone. MATERIALS

AND

METHODS

Materials and methods have been described previously [ 741. Eleven normal subjects and five patients with congestive heart failure were studied on an air-conditioned metabolic ward. Except when indicated, the normal subjects were given a daily diet containing 100 mEq. of sodium; the patients, for therapeutic AMERICAN

JOURNAL

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Congestive

Heart Failure-Bell

353

et al.

CARDIAC

UKV ‘oo u Eq/min.

50 0

uf.J$

50 0

uEq/min. HOURS

I

; 0

1 0

I 0’00

0123456 1/25/60

0 00

0 0

0

I‘;

4

3

5

6

0

l/21/60

I

2

3

5’6

4

VW60

FIG. 2. The effect of isotonic infusions (20 ml. per kg.) of dextrose, dextrose and mannitol and mannitol in a twenty-two year old patient (W. S.) with congestive heart failure. Note that total urine volume and excretion of free water (CA-O) and ootassium (UKV) increased with solute load without an increase in excretion of sodium (Ux.V) and was inversely related to the quantity of free water administered. reasons, were given diets containing 9 mEq. of sodium a day. Fluids were given ad libitum. During each study patients were kept recumbent except when allowed up to void. An interval of at least two days separated tests in a given subject. For studies with acute infusions, food and fluids were withheld after 6:00 P.M. on the night before the study. The patient was weighed at 7:30 A.M. on the day of the study and was given a water load to drink within one hour or by infusion (as 5 per cent dextrose) within one to one and a half hours. In some studies 10 mU of Pitressin@ (vasopressin aqueous, Parke Davis, lot Number 184) was infused together with the solution. Urine was collected from 7:30 to 8:30 A.M. and for periods up to one hour from 8:30 A.M. to 12:30 P.M. “Arterialized” venous blood was obtained before the water load, again one hour after the oral water load or fifteen minutes after the end of the infusion, and at 12:30 P.M. For studies with sustained infusions, food and fluids were withheld after lo:30 P.M. the night before, and the subject was given 500 ml. of fluid to drink at 7:30 A.M. on the day of the study. Five per cent dextrose or 4 per cent fructose in water was infused at the rate of 12 to 14 ml. a minute beginning at 8:00 to 9:00 A.M. Clearances were performed by allowing the patient to void, and “arterialized” venous blood was collected at the approximate midpoint of each collection period. After a sustained flow of urine had been obtained, isotonic (4 or 5 per cent) mannitol or normal saline solution was infused at the same rate. VOL.

36,

MARCH

1364

TABLE THE

EFFECT

(5

PER IN

OF CENT

PATIENTS

DEXTROSE) WITH

-

i

I

I

KG.)

,

II

WATER AND

FAILURE

Serum Osmolality (mOsm./kg.) I

Itiinimum osmolallty (mOsm./kgJ

OF

SUBJECTS

HEART

-I--

Cm0 as % LoadS

PER

NORMAL

Urine*

Patient Load*

IN

II ML.

CONGESTIVE

Four-Hour

%

(20

INFUSIONS

start

After Load11

End of Study

I

Cardiac Patients E. B. C. A.

w. s. L. 8. S. R.

Average

A. D. I. s.

49 36 42 14 64 29 20 34

29 16 18 9 43 3 2 14

71 106 107 65 49 207 194 146 ____

270 247 280 256 262 281 280 280

279 249 270 255 262 277 270 275 --_

36

17

118

268

267

-_ -

N. R. w. Y.

i Fraction of administered load excreted $ Fraction of administered load excreted 5 Osmolality of most dilute urine. /I Two hours after start of infusion. 7 4 per cent fructose infused.

in four hours as free water

X 100. X 100.

278 252 276 253 262 270 268 2757 267

354

Congestive

Heart Failure-Bell

et al.

NORMAL I URINE VOL. mVmin.

25D1

,

5%

Dexlrors

Xl

60

CARDIAC

V//////A

;

5%

1

Mannltol

&Gqazy

2Q0’ IWIqP.

150 ‘in ml/min.

too 50

UKV

I

‘OO

uEq/min. 500 1

uEq/min. U&

250 500

0

1 D

90

i2D

150

180

210

240

0

50

60

SO

120

160

160

210

W.S. l,llnO

1.11 wl/‘O

minutes FIG. 3. The effect of substitution of an isotonic solution of mannitol during sustained diuresis in a normal subject (Z. F.) and in a patient with congestive heart failure (W. S.). Note that mannitol produced a concentrated urine in the normal subject but increased the excretion of free water (C~~0) and potassium (UKV) in the patient without increasing glomerular filtration rate (Ch) or excretion of sodium (UN~V).

Serum and urinary sodium and potassium were estimated by flame photometry with an internal standard. Inulin was measured by the method of Walser, Davidson and Orloff [75]. Serum and urinary osmolality were measured by freezing point depression by the method of Bowman, Trantham and Caulfield [ 761. RESULTS

Eject of Intravenous Water Loads Given Alone and With Pitressin. In Figure 1 are shown the responses in the patients with congestive heart failure and in a normal subject to a water load (20 ml. per kg.) given intravenously alone or with Pitressin, 10 mU per I. or 10 mU per hour, a dose estimated to be comparable to the rate of production of antidiuretic hormone endogenously [ 17,781. Whereas free water was excreted by each patient given the water load alone, it was not produced in any subject until after the infusion with Pitressin had been stopped. There was little difference between the patient and the

normal subject as regards the time required after infusion of Pitressin was stopped for establishment of free water clearance. Eject of Water Loads Given Orally and Intravenously. The responses to an oral and to an intravenous water load in the patients with congestive heart failure and in the normal subjects are shown in Tables I and II. The results are essentially the same with the two routes of administration: all subjects excreted a urine hypotonic to plasma with each load. The patients excreted a volume of urine which was on the average less than one-third that excreted by the normal subjects. They excreted less than one-fourth the amount of free water excreted by the normal subjects and achieved a minimal urinary osmolality twice as great as that of the normal subjects. In both studies, the initial serum osmolality of the patients was significantly lower (p < 0.01) than that of the normal subjects. The Effect of Infusion of Unreabsorbable Solute. AMERICAN

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Congestive

Heart

REGIJLIR No MET

I ,

5uoDrrRosE

Failure-Bell

355

et al.

J )

I&

14 12 Kl VOLUME

8,

ml/min.

6 4 2. 0 IO0

Gin mVlwl.

80 60 I

“u” uEahin. .

30 15 0I

%a” I

I

020406080

I

I

I

I

I

I

I

I

I

I

I

I

‘0 I

ol770

010 I

0’

I

02040eOwio0L9nol6O~2W minutes

FIG. 4. The effect of sodium depletion on total urine volume, glomerular filtra-

tion rate (C,) and excretion of free water (C&o), potassium (UKV) and sodium (UN~V) in a patient with diabetes insipidus (S. K.). In both studies, infusions were given at a rate of 15 ml. per minute. Note that sodium depletion produced a marked fall in free water clearance which was increased with isotonic mannitol. responses of the patients with congestive heart failure and of the normal subjects to infusions of water (20 ml. per kg.) containing mannitol are shown in Tables III and IV. Whereas excretion of free water was less in the normal subjects with infusions containing unreabsorbable solute (Table III) than with those containing dextrose (Table II), that in the patients was little changed. Indeed, in contrast to one patient (W. S.) who produced some free water when isotonic mannitol was infused, the normal subjects excreted none. (Table IV.) In Figure 2 are shown the responses of a patient (W. S.) to three infusions of water (20 ml. per kg.) containing 5 per cent dextrose, 2.5 per cent mannitol and 2.5 per cent dextrose, and 5 per cent mannitol and thus all, half and no free water, respectively. Urine volume, VOL.

36,

MARCH

1964

free water and potassium excretion varied directly with the quantity of mannitol given, and inversely with the volume of free water administered. EJect of Infusions of Unreabsorbable Solute or Saline During Water Diuresis. In Figure 3 are compared the effects of substitution of an isotonic solution of mannitol for one containing dextrose during a sustained diuresis in a normal subject and in a patient (W. S.) with congestive heart failure. In Table v are shown results of similar studies in four patients with congestive heart failure and in three normal subjects on an average intake of sodium. Whereas free water clearance consistently increased with substitution of unreabsorbable solute in the patients, it invariably fell in the normal subjects. Similarly, substitution of saline increased free water

356

Congestive Heart Failure-Bell TABLE

THE

EFFECT

OF

(20

INFUSIONS AND

T

IN

ML.

PATIENTS

Four-Hour

Patient

% Load $

CFi,O as % Load 1:

=I

PER

KG.)

OF

WITH

et al.

III UNREABSORBABLE

CONGESTIVE

HEART

Urine *

SOLUTE

Serum

Free Water Given, Excreted as CHzO$

Minimum Osmolality (mOsm./kg.)

IN

NORMAL

SUBJECTS

FAILURE

Osmolality

(mOsm./kg.)

Start

After Load 7

End of Study

Ratio Dextrose -~ Mannitol

l/l l/l l/l 1/l l/l

II

Cardiac Patients

E. B. w. s. L. B. C. A.

63 44 51 60 60

18 11 13 9 12

30 18 26 18 24

151 125 123 152 162

277 256 257 274 275

279 259 254 283 273

273 253 252 283 277

Average

56

13

23

143

269

270

268

288 285 285

281 293 284 281 289

287 283 283 283

285

286

~-

’

Normal Subjects

A. N. D. R. s. Y.

101 102 95 83 105

56 34 16 19 14

111 67 48 57 88

Average

97

28

74

(

85 112 186 138 202 145

’ ;;;

____

l/l l/l i/2 l/2 l/3

* Total excreted after end of infusion. t Fraction of administered load excreted in four hours X 100. $ Fraction of administered load excreted as free water X 100. 5 Fraction of free water load administered excreted X 100. /jOsmolality of most dilute urine. 7 Two hours after start of infusion. clearance in one patient (C. A.), hut decreased it in a normal subject (R. C.). Average net water retention at the end of the infusions was over five times as great in the patients as it was in the normal subjects. Glomerular filtration rates (inulin clearances) tended either not to change or to fall with the infusions of mannitol, except in one patient (E. B.) in whom there was a slight increase. In Figure 4 a similar study is shown in a patient (S. K.) with diabetes insipidus during a no treatment period. With a normal sodium intake, free water clearance varied from 11 .l to 13.0 ml. per minute. After sodium depletion, when free water clearance had fallen to range of 3.8 to 5.2 ml. per minute, it rose to one of 5.7 to 8.8 ml. per minute with an infusion of isotonic mannitol.

Effect of Infusions on Sodium and Potassium Excretion. Excretion of sodium and potassium over a four-hour period with the short-term infusion is shown in Table VI. With the shortterm infusions, potassium excretion generally increased when unreabsorbable solute was infused in the patients with congestive heart failure but not in the normal subjects. COMMENTS

Each of the patients with congestive heart failure in the present study (1) reestablished free water clearance following Pitressin-induced antidiuresis after an interval similar to that observed in normal subjects, (2) showed a limited ability to excrete both orally and intravenously administered water loads, (3) excreted some free water with each water load, and (4) AMERICAN

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Congestive

Heart Failure-Bell

increased free-water excretion with mannitol, an unreahsorbable solute. In one patient (CL A.) saline solution also increased free water excretion during a sustained water diuresis. In some of the studies with mannitol, there was an increased excretion of potassium, an ion secreted in exchange for sodium by the distal tubule C7.91.Glomerular filtration rates were not abnormally low in any of the patients. The findings, then, suggest that the impairment in free water excretion in these patients resulted not from antidiuretic hormone, but from an enhanced proximal renal tubular reabsorption of glomerular filtrate, so that only limited amounts of sodium and water reached the diluting segment [73,74]. In this view, mannitol acted by carrying sodium and water to this site so that free water could be generated. There is much to support this hypothesis. First, it has been demonstrated repeatedly that physiologic doses of Pitressin induce antidiuresis in patients with congestive heart failure [4,5] and that the time period which elapses before diuresis is similar to that in normal subjects [4,5]. These results, together with the additional observations in the present study (Fig. 1) that Pitressin, when given in physiologic doses, inhibits formation of free water and that the diuresis which follows contains free water, suggest that these patients inactivate antidiuretic hormone at a normal rate [5]. At rates of solute excretion comparable to those in the present study (i.e., less than 1,100 mOsm. per minute), it has been shown that from 4 to 13 mU of Pitressin per hour are required to produce a concentrated urine in patients with diabetes insipidus [IB]. Since some free water was produced with the water loads in each of the patients in the present study (Tables I and II), it seems unlikely that antidiuretic hormone was present in amounts as great as this. Some patients with congestive heart failure show a complete inability to excrete free water when given a large free water load [6,20,27]. It is possible that in such patients sustained secretion of antidiuretic hormone plays a part, as has been proposed [&70]. It has been shown that a urine hypertonic to plasma can be produced in a water-loaded dog by compression of one renal artery while the “control” kidney excretes a dilute urine [72]. Similarly, a concentrated urine has also been produced in patients with diabetes insipidus by VOL.

36,

MARCH

1964

357

et al. ‘I‘ABLE

I‘HE

EFFECT

OF

INFUSIONS

MANNITOL

IN WITH

NORMAL

ML.

SUBJECTS

CONGESTIVE

Four-Hour

I

I”

(20

PER

HEART

Urine*

KG.)

AND

OF

IN

A

ISOTONIC

PATIENT

FAILURE

I 1 StrumOsmalalitv (mOsm./kg.)

Patient start

Cardiac Patient

w. s.

Average

/

68

/

21

i

150

1

250

,

251

(

247

88

1

0

[

328

/

286

I

283

/

286

*Total excreted after end of infusion. t Fraction of administered load excreted $ Fraction of administered load excreted 5 2 hours after start of infusion. 11Osmolality of most dilute specimen.

in four hours X 100. as free water X 100.

acute reduction of glomerular filtration [22,23]. Thus, a hypertonic urine can clearly be produced in the absence of antidiuretic hormone, presumably by restricting sodium and water from the diluting site. Since glomerular filtration rates were not abnormally low in the patients (Table IV), other mechanisms must have been responsible for the enhanced reabsorption of sodium by the proximal tubule. Finally, the observation that the “defect” described can be produced in a patient with diabetes insipidus (Fig. 4) by sodium depletion, and can be corrected by infusion of mannitol, demonstrates that the sequence of events postulated can occur without antidiuretic hormone. Under certain circumstances, the antidiuresis of patients with heart disease may be mediated by antidiuretic hormone. In some patients with mitral stenosis, mitral valvulotomy is followed by transient retention of fluid, oliguria and hyponatremia, all of a degree considerably greater than that found with other operative procedures in other patients [2$25]. Whereas ethyl alcohol, an inhibitor of antidiuretic hormone release by the neurohypophysis, was found to have no consistent effect in patients with congestive heart failure 1261, it produced a diuresis of free water in the patients with hyponatremia after mitral valvulotomy [25].

Congestive

Heart Failure--Bell

et al.

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;

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AMERICAN

JOURNAL

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Congestive TABLE

VI

EXCRETION OF ELECTROLYTES (,&Q./MIN.) FOUR-HOUR PERIOD AFTER

E. B. w. s. c. A. L. B.

1

0 0 0.7

6.8 1.2 9.9

0.6

s.2

END

Sorl-

Potas-

ium

sium

Inn

I””

0.R 0 0 7.3 2.1

Heart

11.6 5.1 27.8 22. 5 6.3

OF

L)“R,No

A

INFUSIONS

l/l l/l l/l l/l l/l

0.2

17 :5

* Ratio of mannitol to dextrose in sol~~tion.

The urinary excretion of sodium was consistently lower in the patients than in the normal subjects. (Table VI.) The mechanism for the increased retention was investigated in some patients and has been reported elsewhere [27,28]. Whereas a diuresis of sodium was produced in two patients (E. S. and S. R.) with aldactone (SC 9420, Searle Co.), an aldosterone antagonist [29], no diuresis was produced in two other patients (W. S. and C. .4.) even when they received aldactone in near toxic doses. It was concluded that aldosterone may play a major role in the formation of edema in some but not all patients with congestive heart failure [28]. It was also noted that the absence of hypokalemia in such patients despite abnormally elevated urinary aldosterone values was evidence that the excessive renal tubular reabsorption of sodium must occur largely at sites proximal to the region in the distal convoluted tubules in which sodium is exchanged for potassium [28]. SUMMARY

.4ND

CONCLUSIONS

The excretion of total and free water and of sodium and potassium was studied in patients with congestive heart failure and in normal subjects on an average intake of sodium after (1) an oral water load (20 ml. per kg.); (2) intravenous water loads (20 ml. per kg.) containing 5 per cent dextrose both with and VOL. 36,

MARCH

1964

Failure-Bell

et al.

10 mU per hour; (3) an without Pitressin, intravenous water load (20 ml. per kg.) containing mannitol, an unreabsorbable solute; and (4) during sustained intravenous water loads followed by mannitol. The patients showed a limitation in free water excretion as compared to the normal subjects. Some free water was excreted with each water load, and free water excretion increased with mannitol during sustained diuresis. In some of the studies with mannitol, potassium excretion increased. Pitressin, given in physiologic doses, inhibited free water formation in the patients; diuresis returned at a normal time interval after Pitressin was stopped. A similar defect in free water clearance was produced in a patient with diabetes insipidus with sodium depletion, and was corrected with mannitol. The results suggest that exaggerated proximal renal tubular reabsorption of glomerular filtrate, and not antidiuretic hormone, may limit formation of free water in some patients with congestive heart failure; mannitol acts by carrying sodium and water to the diluting segment of the renal tubule. REFERENCES

G. F., DOBSON, E. L., ROD~EKS, C. E., JOHNSTON, M. E. and PACE, N. The measurement of total “sodium space” and total body sodium in normal individuals and in patients with cardiac edema. Circulation, 5: 915, 1952. 2. FARBER, S. J. and SOBERMAN, R. J. Total body water and total exchangeable sodium in edematous states due to cardiac, renal or hepatic disease. 1.

WARNER,

J. Clin. Inoest., 35: 779, 1956. 3. BIRKENFELD, 1~. W., LIEBMAN, J., O’MEARA,

M. P. and EDELMAN, I. S. Total exchangeable sodium, total exchangeable potassium and total body water in edematous patients with cirrhosis of the liver and congestive heart failure. .I. Clin. Iwest., 37:

687, 1958. 4.

WHITE,

A. G., KUBIN,

G. and LEITER, L. Studies in

edema. IV. Water retention and the antidiuretic hormone in hepatic and cardiac disease. J. Clin.

Invest., 32: 931, 1953. 5. HANENSON, I. B., GOLUBOFF,

B., GROSSMAN, J., WESTON, K. E. and LEITER, L. Studies on water excretion following intravenous hydration and the administration of Pitressin or nicotine in congestive heart failure. Circulation, 13: 242, 1956. 6. LEAF, A. and MAMBY, A. R. An antidiuretic mechanism not regulated by extracellular fluid tonicity. J. Clin. Invest., 31: 60, 1952. 7. STEIN, M., SCHWARTZ, R. and MIRSKY, I. A. Antidiuretic activity of plasma of patients with hepatic cirrhosis, congestive heart failure, hypertension and other clinical disorders. J. Clin. Zmest., 33: 77, 1954.

Congestive Heart Failure--Bell 8. BUCHBORN,E. Vassopressin und edementstehung. Deutsche med. Wchnschr., 48: 235, 1958. 9. BERCU, B. A., ROKAN, S. N. and MASSIE, E. Antidiuretic action of the urine of patients in cardiac failure. Circulation, 2: 409, 1950. 10. Docmos, M. and DREIFUS, L. S. Antidiurrtic hormone studies in patients presenting edema. Am. J. M. SC., 222: 538, 1951. 11. BERLINEK, R. W., LEVINSXY, N. G., DAVIDSON, D. G. and EDEN, M. Dilution and concentration of the urine and the action of antidiuretic hormone. Am. J. Med., 24: 730, 1958. 12. BERLINER,R. W. and DAVIDSON,D. G. Production of hypertonic urine in the absence of pituitary antidiuretic hormone. J. Clin. Inurst., 36: 1416, 1957. 13. ORLOFF, J., WALSER, M., KENNEDY, T. J., JR. and BARTTER, F. C. Hyponatremia. Circulation, 19: 284, 1959. 14. SCHEDL, H. P. and BARTTER, F. C. An explanation for and experimental correction of the abnormal water diuresis in cirrhosis. J. Clin. Invest., 39: 248, 1960. 15. WALSER, M., DAVIDSON,D. G. and ORLOFF, J. The renal clearance of alkali-stable inulin. J. Clin. Invest., 34: 1520, 1955. 16. BOWMAN,R. L., TRANTHAM, H. V. and CAULFIELD, P. A. An instrument and method for rapid, dependable determination of freezing-point depression. J. Lab. & Clin. Med., 43: 310, 1954. 17. LAUSON,H. D. The problem of estimating the rate of secretion of antidiuretic hormone in man. Am. J. Med., 11: 135, 1951. 18. DEWARDENER, H. E. and DEL GRECO, F. The influence of solute excretion rate on the production of a hypotonic urine in man. Clin. SC., 14: 715, 1955.

et aE.

19. DAVIDSON.D. G., LEVINSKY,N. G. and BERLINER, R. W. Maintenance of potassium excretion despite reduction of glomerular filtration during sodium diuresis. J. Clin. Znoest., 37: 548, 1958. 20. TAKASU, T., LASKER, N. and SHALHOUB, R. J. Mechanisms of hyponatremia in chronic congestive heart failure. Ann. Int. Med., 55: 368, 1961. 21. BELL, N. H. and BARTTER, F. C. Unpublished observations. 22. KLEEMAN, C. R., MAXWELL, M. H. and ROCKNEY, R. Production of hypertonic urine in humans in the probable absence of antidiuretic hormone. Proc. Sot. Exper. Biol. tY Med., 96: 189, 1957. 23. BARTTER, F. C. Unpublished observations. 24. GOODYER, A. V. N. and GLENN, W. W. L. Observations on hyponatremia following mitral valvulotomy. Circulation, 11: 584, 1955. 25. D’ANGELO, G. J., MURDAUGH, H. V. and SEALY, W. C. The nature and treatment of the postcommissurotomy hyponatremic syndrome. Surg. Gynec. &3 Obst., 106: 87, 1958. 26. LAMDIN, E., KLEEMAN, C. R., RUBINI, M. and EPSTEIN,F. H. Studies on alcohol diuresis. III. The response to ethyl alcohol in certain disease states characterized by impaired water tolerance. J. Clin. Invest., 35: 386, 1956. 27. THOMAS,J. P. and BARTTER, F. C. Relation between diuretic agents and aldosterone in cardiac and cirrhotic patients with sodium retention. Brit. M. J., 1: 1134, 1961. 28. BARTTER, F. C., GANN, D. S. and THOMAS, .I.P. On the mechanism of sodium retention in cardiac and hepatic disease. In: The Human Adrenal Cortex, p. 294. Glasgow, 1960. E. 8; S. Livingston, Ltd. 29. BELL, N. H. and BARTTER, F. C. Unpublished observations.

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