Journal of Clinical InvestigationVol. 41, No. 11, 1962

THE MECHANISMOF ANTIDIURESIS ASSOCIATEDWITH THEADMINISTRATION OF HYDROCHLOROTHIAZIDETO PA-

TIENTS WITH VASOPRESSIN-RESISTANTDIABETESINSIPIDUS *

By LAURENCEE. EARLEYt AND JACK ORLOFF

(From the Laboratory of Kidney and Electrolyte Metabolism, National Heart Instititte,Bethesda, Md.)

(Submitted for publication June 5, 1962; accepted July 19, 1962)

Laragh, Heinemann, and Demartini first re-ported that the administration of chlorothiazideduring water diuresis results in an increased rateof solute excretion without significant changes inthe rate of urine flow (1, 2). This effect was in-terpreted as indicating that the drug interfereswith solute (sodium) reabsorption in the distalportions of the nephron where urinary dilutionoccurs. Similar evidence supporting the conceptthat chlorothiazide impairs sodium reabsorptionat diluting sites in the distal convolution has beenpresented elsewhere (3). Such a site of inhibi-tion of sodium reabsorption readily accounts forthe increased urinary osmolality observed whenthiazide derivatives are administered acutely.'Crawford and Kennedy, however, observed thatthe chronic administration of thiazide derivativesto animals with pituitary diabetes insipidus, andto patients with pituitary or nephrogenic diabetesinsipidus, results in a striking diminution in uri-nary volume as well as an increased urinary os-molality (5). The latter observations have been

* Presented in part before the meeting of the EasternSection of the American Federation for Clinical Re-search, Bethesda, Md., January, 1961.

t Present address: Thorndike Memorial Laboratory,Boston City Hospital, Boston, Mass.

1 According to Wesson and Anslow (4), the final urinemay be considered to be composed of two hypotheticalmoieties: solute-free water (CH20) and an isosmotic por-tion (Cosm) equal to

(urine osmolality) (volume)(plasma osmolality)

Volume= CH20 + Cosm. During water diuresis, chloro-thiazide increases solute excretion (CosM) without ap-preciably affecting urine volume. Consequently, one ob-serves a rise in urine osmolality and a fall in CH,-.From these relationships it has been concluded that thisagent interferes with solute (sodium) reabsorption inportions of the nephron where dilute urine is producedby the reabsorption of solute without water (1, 3).

repeatedly confirmed (6-13), and the thiazidederivatives have now attained a place of thera-peutic usefulness in patients with vasopressin-resistant diabetes insipidus (13).

Inhibition of solute reabsorption in the distalnephron alone does not account for the antidiureticeffect of the thiazide derivatives. As indicatedabove, such inhibition of solute reabsorption wouldmerely increase urinary osmolality without affect-ing urinary volume. Therefore, the mechanismwhereby volume is reduced must reside in someother direct or indirect action of these agents.The results of the present studies are consistentwith the view that the antidiuretic effect of hy-drochlorothiazide is a consequence of the losses ofsodium induced by the agent and is not due to anyunique property of the thiazide derivatives. Theantidiuresis is enhanced by a low sodium intake.is diminished by a high sodium intake, and mayalso be produced by mercurial diuretics, despiteapparent differences in the site and mode of ac-tion of the latter agents.

METHODS

Multiple studies were performed on four hospitalizedmale subj ects with vasopressin-resistant diabetes insipi-dus, ranging in age from seven to, seventeen years. Twowere brothers, a third had an affected brother, and allhad a history of polyuria and polydipsia dating from in-fancy. Maximal urine osmolalities after a 17- to 20-hourthirst were less than 100 mOsmper kg in three subjects,and not greater than 130 mOsmper kg in one subject(S. Z.). None of the four subjects demonstrated any in-crease in urinary concentration when dehydration wasfollowed by the administration of vasopressin. All werefree of other renal functional abnormalities. The in-takes of sodium were controlled by the addition ofweighed amounts of sodium chloride to a standard dietcontaining 9 mEq of sodium. In all instances in whichthe effects of hydrochlorothiazide were studied, the drugwas administered orally, 25 mg every 8 hours. A mini-

1988

THIAZIDE ANTIDIURESIS IN DIABETES INSIPIDUS

TABLE I

Relationship between dietary sodium and the antidiuretic response to hydrochlorothiazide

Control* Hydrochlorothiazide*

Dietary Urine Urine Urine Urinesodium volume concentration volume concentration

L/24 hr mOsm/kg L/24 hr mOsm/kgJ.W.

85 mEq 9.0 74 7.2 1089 mEq 5.9 63 3.6 121

R.W.85 mEq 11.1 66 7.8 109

9 mEq 6.5 57 4.4 111

D.M.85 mEq 8.6 95 6.0 13050 mEq 7.0 73 3.8 175

* Mean values for four days preceding and four days following the initiation of hydrochlorothiazide. The first dayof therapy was not included in the calculations.

mumof 3 control days preceded each period during whichthe drug was studied. Except during acute measurementsof renal clearance, all determinations on urine were per-formed on aliquots of 24-hour collections.

Sodium and potassium were determined by internalstandard flame photometry. Chloride was determinedby amperometric titration (14), and urea and ammoniaby the microdiffusion technique of Conway (15). Os-molality was measured cryoscopically (16), and inulin bythe method of Walser, Davidson, and Orloff (17).

RESULTS

Influence of dietary sodium on the antidiureticresponse to hydrachlorothiazide. Three subjectswere studied at two different levels of dietary so-dium. The means of urine volume and osmolalityfor 4 control and 4 experimental days are shownin Table I. Although hydrochlorothiazide re-sulted in a clear fall in urine volume and a rise inurine osmolality-at each level of dietary sodium,the antidiuretic effect was relatively greater whenthe patient was receiving the diet of lower sodiumcontent. Daily values for urine volume and osmo-lality of one subject at two levels of dietary sodiumare shown in Figure 1. The lower intake of so-dium chloride permitted a greater increase in urineosmolality and a relatively greater fall in urinevolume during the administration of hydrochloro-thiazide. While the patient was on an intake of 9mEq of sodium, the administration of the drugresulted in a reduction in urine volume which wasmaintained well below control days throughout theperiod of therapy (Figure 1, right side). In con-

trast, when he was on an intake of 85 mEq of so-dium (Figure 1, left side) urine volumes were notdepressed to the same extent during the adminis-tration of hydrochlorothiazide, and on same daysof therapy the volumes were as great as during thecontrol period. Despite this limited depression ofurine volume in the presence of the higher intakeof sodium, the urine osmolality remained greaterthan control values, indicating a continued effectof the drug on distal tubular solute reabsorption(3).

That the continued presence of hydrochloro-thiazide is not necessary for persistence of the anti-diuretic effect is demonstrated in Tables II andIII. In one subject on a sodium restricted diet(Table II) a single 25 mg dose of hydrochloro-

i50 - F-ZC AR ZE

URINEOSMOLALITY 100 -

0

50

UR WEVOLUMEL/24HR.

6~~~~~~~~~~~~~~~

Eq~5 NoDIET ~ q NoDIET

--1

CAYS

FIG. 1. EFFECT OF DIETARY SODIUM ON ANTIDIURETICRESPONSETO HYDROCHLOROTHIAZIDE. Studies were doneat an interval of 2 months. Days indicates consecutivedays during each study.

1989

-IDROCHLOROT-IAZ-DE

0i w

I

LAURENCEE. EARLEYANDJACK ORLOFF

TABLE II

Effect of a single injection of hydrochlorothiazide on urinaryvolume and concentration of Subject R. W. on a 9 mEq

sodium diet

Urine

Osmol- BodyDay Volume ality Sodium weight

L/24 hrs mEqIL mEqi kg24 hrs

1 6.71 57 3 53.52 7.90 56 5 52.93 5.82 58 4 53.54 6.59 60 2 53.4

Hydrochlorothiazide,* 25 mg iv.St6 3.96 92 9 52.97 3.00 97 1 52.58 5.33 81 0 52.89 3.39 91 1 52.5

* Esidrix.t Urine collection on day 5 incomplete; values for this day omitted.

thiazide resulted in a fall in urine volume and arise in urine osmolality that persisted throughfour days of observation. This persistent anti-diuresis was studied further in two additional sub-jects (Table III). When added sodium waseliminated from the diet prior to discontinuinghydrochlorothiazide, the antidiuresis persisted forseveral days after withdrawal of the drug. Urinevolume and osmolality promptly returned to con-trol levels when sodium chloride was added tothe diet. That this persistent antidiuresis afterwithdrawal of hydrochlorothiazide was related tothe lack of sodium intake and not to a cumulativeeffect of the drug is suggested by the observationthat in each subject, recovery from the antidiuresiswas evident on the first day and complete by thethird day after cessation of therapy with hydro-chlorothiazide when the intake of sodium was 50to 85 mEq daily. Further, the association of thecontinued antidiuresis with a depression of bodyweight and the return to control values of urinevolume, urine osmolality, and body weight uponthe addition of sodium chloride to the diet attestto a relationship between the loss of body sodium(and probable diminution in extracellular volume)and the antidiuresis. It is important to note alsothat this persistently low urine volume after with-drawal of hydrochlorothiazide could not be ac-counted for by the low intake of sodium alone,when the values observed in subjects D. M. andS. Z. after hydrochlorothiazide (Table III) werecompared to the values observed in the same sub-jects on a sodium restricted diet alone.

The foregoing observations demonstrate that thereduction in urinary volume incident to the ad-ministration of hydrochlorothiazide bears a directrelationship to the dietary intake of sodium. It isdemonstrated further that this antidiuretic effectis associated with a maintained deficit of sodiumand reduction in body weight. It appears clearthat the continued administration of hydrochloro-thiazide is not necessary for continuation of theantidiuresis if repair of the sodium deficit is pre-vented by a rigidly restricted dietary intake.

Antidiuresis after mercurial diuresis. In orderto demonstrate further that the antidiuresis is re-lated to the loss of sodium and not to a specificproperty of the thiazides, the effects of sodiumloss secondary to a mercurial diuretic were ex-amined. Two subjects maintained on a dailyintake of 9 mEq of sodium were given 40 mg ofmercury intramuscularly as mercaptomerin oneach of two consecutive days. In both subjectsdiminished urinary volumes of increased osmo-lality followed the sodium loss produced by themercurial. This response in one subject is dem-onstrated in Figure 2. As shown, the mercurialdiuretic resulted in an increased excretion of so-dium which was followed by significantly lowerurine volumes of increased osmolality. As indi-cated on the last day shown, an infusion of so-dium chloride (70 mEq) resulted in an immediateincrease in urine volume and a fall in urine os-

URINEOSMOLALITY

URINEVOLUMEL/24 HR.

No EXCRETIONmEq/24HR.

DAYS

FIG. 2. EFFECT OF SODIUM LOSS FROMMERCAPTOMERINON URINARY VOLUMEAND CONCENTRATION. Hg indicates40 mg of mercury intramuscularly as mercaptomerin on

each of 2 consecutive days. AaCI indicates an infusion of70 mEq of sodium as isotonic saline (see text).

1990

THIAZIDE ANTIDIURESIS IN DIABETES INSIPIDUS

TABLE III

Effect of sodium intake on recovery from antidiuresis induced by hydrochlorothiazide

UrineSodium Body

Subject Day* intake Volume Osmolality Sodium weight

345

68

1012t13t1416182022

mEq/24 hrs505050

L/24 hr6.857.599.35

mOsm/kg-74

7868

mEq/24 hrs213759

Hydrochlorothiazide begun, 25 mg every 8 hours50 7.07 86 11750 4.29 185 7050 3.32 185 4750 3.95 181 11350 4.39 161 11250 3.41 167 55

9 3.12 182 29 4.48 166 49 3.99 167 29 3.40 155 2

kg24.825.425.1

25.224.424.323.823.823.323.823.623.424.0

23 925 927 928 929 10030 5032 5034 50

345

505050

Hydrochlorothiazide discontinued3.44 1513.52 1393.98 1204.60 1317.47 939.39 689.96 738.53 71

3.644.744.59

112 3891 4795 56

Hydrochlorothiazide begun, 25 mg every 8 hours6 50 4.04 110 808 50 2.80 174 46

10 50 3.45 171 4612t 50 2.94 164 9113t 50 2.59 165 8114 50 2.58 179 4616 9 3.11 192 418 9 3.00 174 120 9 2.36 176 122 9 2.90 173 1

9999

10050

Hydrochlorothiazide discontinued2.39 1762.68 1653.50 1532.59 1514.91 1255.87 92

25.024.523.924.023.623.323.223.223.723.7

1

10

1

28

23.823.823.923.724.024.6

* Days when therapy and observations were essentially unchanged from preceding day are omitted from table.f Aldactone, 200 mg, given orally every 8 hours for two days in each study.

molality. Although the antidiuretic response af-ter mercurial diuresis was not so marked as thatseen during the continuous administration of hy-drochlorothiazide, the losses of sodium in the twosubjects who were given mercury were 23 and 29mnEq, respectively, whereas sodium losses during

the administration of hydrochlorothiazide rangedfrom 75 to 140 mEq.

Effects of a sodium-retaining steroid. As indi-cated, the above data are consistent with the viewthat the antidiuretic effect of these diuretic agentsis in some way related to a loss of sodium from

D.M.

S.Z.

12119

206660

23.223.923.723.824.225.024.924.8

24.624.925.1

232527282930

1991

LAURENCEE. EARLEYANDJACK ORLOFF

I-at 90-J0

c, 700

z 50

8)

8

a:

It

Ji

6

4

2

r

D. M.25 mEq Na DIET

LDOCAASmgDAILY

40 M: ~~~~~~~~~~~~~.... 3a| ..4.0...... . ... . .0 ;Zj....

FIG. 3. EFFECT OF SODIUM-RETAINING STEROID ON URI-

NARY VOLUMEAND CONCENTRATION. Failure of sodium-retaining steroid to mimic antidiuresis of hydrochloro-thiazide. Consecutive days of study are shown. Openbars denote urine volume, stipled area denotes sodiumexcretion.

the body. Since sodium depletion and the at-tendant contraction of extracellular volume may

result in an increased release of aldosterone (18,19), the possibility was investigated that the anti-diuresis may be mediated through the action ofendogenous mineralocorticoid. Desoxycorticos-terone acetate (DOCA), 15 mg daily, was givenintramuscularly for 7 days to two subjects re-

ceiving a diet containing 25 mEq of sodium. In

view of the absence of sodium depletion under theconditions of this study, it was possible to examinethe uncomplicated effects of large amounts of thesteroid on urinary volume and osmolality. Theresults of one of these studies are shown in Figure3. In both subjects, DOCAresulted in a fall inthe excretion of sodium to levels below the dietaryintake, and when the steroid was discontinued, asodium diuresis ensued, indicating that a renaleffect of the steroid was achieved. Urinary vol-umes were unchanged during administration ofDOCA, and urine osmolality actually fell slightly(as much as 13 mOsmper kg below the range of

control values). Thus, the sodium-retaining ster-oid in no way reproduced the urinary changes as-sociated with the thiazide therapy.

Effects of hydrochlorothiazide on urinary elec-trolyte composition. Beginning on the first dayof therapy, hydrochlorothiazide uniformly re-sulted in an increased excretion of sodium and,to a lesser extent, potassium. After the first dayof therapy the excretion of sodium decreased, andby the fourth to sixth day the output of sodiumas well as potassium had returned to controllevels (Table IV). These changes in electrolyteexcretion are similar to those described by otherinvestigators (20, 21). The total concentrationof electrolytes in the urine was immediately in-creased by hydrochlorothiazide and changed littleafter the second day of therapy (Figure 4); rather,the return toward control of urinary electrolyteexcretion was associated with a diminution in uri-

TABLE IV

Effects of the continuous administration of hydrochlorothiazide to subject (J. W.)on a daily intake of 9 mEqsodium

PlasmaUrine

Urea Fluid BodyDay Volume Osmolality Sodium Potassium Nitrogen Creatinine intake weight

L/24 hrs mOsm/kg mEqi mEqi mg/100 ml mg/100 ml L/24 hr kg24 hrs 24 hrs

1 5.2 60 5 44 10 0.8 7.3 38.42 6.7 61 6 50 6.2 38.93 6.4 61. 3 48 9 0.8 7.4 39.14 5.4 70 5 40 6.4 39.2

Hydrochlorothiazide, 25 mg every 8 hours5 4.9 97 57 82 6.0 38.46 3.4 118 32 59 12 0.8 5.7 38.37 4.6 122 35 91 5.1 38.38 3.8 123 17 61 5.0 38.29 2.6 120 12 44 17 0.8 3.5 37.8

10 2.5 127 5 32 3.6 37.8

LLI

2)-J0

LUJzZ3

1992

THIAZIDE ANTIDIURESIS IN DIABETES INSIPIDUS

S. Z.5OmEq Na DIET

HYDROCHLOROTHIAZ IDE

[S PIRONOLACTONE

50 L

URI NARY 40ELECTROLYTE L

30CONCENTRATION

mEq/ L 20

I1

1200

I-,115 URINEOSMOLALITY

100

4

3 URINEVOLUME

2 L/24HR.

FIG. 4. URINARY COMPOSITION DURING THE ADMINISTRATION OF HYDROCHLOROTHIAZIDE. Days are consecutive daysof study. The last day of control observations is shown. Bars indicate the sum of the individual cation and anionconcentrations. Spironolactone was given orally as Aldactone, 200 mg every 8 hours for 2 days. Note further dimi-nution in urine volume after increased loss of sodium during administration of spironolactone. Administration of hy-drochlorothiazide constant as indicated.

nary volume. In addition, the continued loss ofsodium was prevented further by a decreasing uri-nary sodium concentration associated with an in-creasing potassium (and to a lesser extent am-

monia) concentration, while total electrolyte con-

centration was essentially unchanged (Figure 4).That this means of conserving sodium (by sub-stitution in the urine of potassium) was mediatedby endogenous aldosterone is suggested by thereversal of this relationship during the two dayswhen spironolactone (Aldactone) was adminis-tered (Figure 4). The latter agent resulted indiminished concentrations of potassium and am-

monia and increased concentrations of sodium inthe urine. It is also noteworthy that spironolac-tone did not alter urinary volume, osmolality, or

total electrolyte concentration.

These data are in general agreement with thefindings of others (20, 21) and suggest that theadaptive response to the natriuresis induced byhydrochlorothiazide is manifested in at least twoways: 1) an effect of endogenous mineralocorti-coid which results in the substitution in the urineof potassium and ammonia for sodium, and 2) adiminution in total electrolyte excretion associatedwith decreased urine volume, but little change inthe total concentration of urinary solutes. As willbe discussed subsequently, the latter mechanismmay represent decreased delivery of isotonic fil-trate to the distal nephron and may account for theantidiuretic effect of these drugs.

Other effects of hydrochlorothiazside. Duringthe period of therapy with hydrochlorothiazidebody weight decreased by 0.8 to 1.5 kg. The most

1993

LAURENCEE. EARLEYANDJACK ORLOFF

TABLE V

Clearances of inulin before and during therapy with hydrochlorothiazide*

Control Hydrochlorothiazide

Inulin Urine Urine Inulin Urine Urine Day ofSubject clearance concentration volume clearance concentration volume therapy

ml/min mOsm/kg L/24 hrs mi/min mOsm/kg L/24 hrsD.M.t a) 80 68t 9.35 80 103 4.23 12

85 83 8978 83 87

b) 75 58 8.46 87 107 5.09 688 58 86 9878 59

R.W. 113 73 103 108t 6.91 5123 70 13.41 102120 67 104

118 80 7.38 17120 87118 87

J.W. 97 55 9.51 76 1131 5.74 490 59 7983 55 75

89 109 5.04 1582 10588 100

* Control studies done on day preceding initiation of hydrochlorothiazide. Inulin clearances and osmolality weredetermined from consecutive periods of collection not exceeding 30 minutes. Urine volume is given for the day clearanceswere measured.

t Two separate studies with hydrochlorothiazide shown for this subject.$ 24-hour urine osmolality on day of clearance.

rapid period of weight loss was during the firstdays of therapy, when there was an excess excre-tion of sodium and a progressive diminution inurinary volume. There was a rapid return to con-trol of body weight when the antidiuresis was ter-minated by cessation of the drug, or by the addi-tion of sodium to the diet. The voluntary dailyintake of fluid changed qualitatively with thechanges in urinary volume. Plasma osmolality fellduring the periods of administration of hydrochlo-rothiazide by mean values ranging from 3 to 10mOsmper kg, and there were associated modestdepressions in serum sodium concentrations(mean values 133 to 139 mEqper L). These de-pressions of serum osmolality and serum sodiumoccurred during the first few days of therapy andremained largely unchanged thereafter. Serumpotassium concentrations, however, showed a pro-gressive decline throughout the periods of therapywith hydrochlorothiazide, with values falling aslow as 2.6 mEqper L. The low values for serumpotassium were returned to normal during the twodays that spironolactone was administered to twosubjects.

At no time were abnormal serum concentrationsof protein, urea nitrogen, or creatinine noted(Table IV). There was never clinical evidenceof dehydration, weakness, or other discomfort dur-ing the periods of administration of hydrochloro-thiazide.

Values for the clearance of inulin in three sub-jects are given in Table V. Although the clear-ance of inulin during therapy with hydrochloro-thiazide was depressed in two of the measurementsin two subjects, this was not a consistent findingin six determinations in the three subjects shown.

Hydrochlorothiazide has been administered totwo subjects for a period of six to twelve months.The drug has been given daily as a single 25- or50-mg dose in conjunction with daily potassiumsupplements and a diet of restricted sodium chlo-ride content. This has resulted in a significantdecrease in urine volumes as judged by less fre-quent urination and less enuresis. There havebeen no apparent side effects and serum urea nitro-gen and creatinine have remained within normallimits. A continued deficit of potassium has beensuggested by serum concentrations of low normal

1994

THIAZIDE ANTIDIURESIS IN DIABETES INSIPIDUS

values (3.0 to 3.5 mEq per L), but frank hypo-kalemia has been avoided by a daily supplement of30 to 60 mEqof potassium as potassium chloride.

DISCUSSION

The present report of an inverse relationshipbetween the dietary intake of sodium and the anti-diuretic response to hydrochlorothiazide in pa-tients with diabetes insipidus is in keeping with thefindings of Cutler, Kleeman, Dowling, and Max-well (7) and Havard and Wood (9, 12), who re-ported that a high intake of sodium either abolishedor limited the antidiuresis associated with ad-ministration of this drug.

It has been recognized for some time that a di-rect relationship exists between the dietary intakeof sodium and the magnitude of an induced waterdiuresis (22). Such observations have been ex-tended to demonstrate that increased rates of ex-cretion of many solutes result in augmentation ofwater diuresis (23). Since during water diuresis(absence of antidiuretic hormone) the distal con-volution (24), and probably the collecting duct(25), are virtually impermeable to water, it wouldappear reasonable that large changes in volumewould not occur within the distal nephron, andchanges in urine volume during water diuresismust, to a major degree, reflect changes in theamount of filtrate escaping reabsorption in theproximal segment of the nephron. Therefore,since dilute urine is produced by the reabsorptionof solute without water (in the absence of anti-diuretic hormone) in the distal portions of thenephron (24), the volume of dilute urine excretedwould be conditioned by the volume of filtrate de-livered to the distal segments.

The mechanisms governing the extent to whichthe glomerular filtrate is reabsorbed in the proxi-mal nephron are unknown. The influence of die-tary sodium on sodium excretion (26) and in turnthe influence of sodium excretion on urine volumeduring water diuresis (as discussed above) sug-gest, however, that some effect of total body so-dium (such as extracellular fluid volume) bears adirect relationship to the volume of filtrate escap-ing proximal tubular reabsorption.

On the basis of the present observations it issuggested that when thiazide derivatives are ad-ministered to patients with diabetes insipidus, the

immediate effect is an increased excretion of elec-trolyte without an increase in urinary volume, re-sulting from the action of these agents on solutereabsorption in the distal nephron. As electrolytelosses continue, an additional stimulus (possiblymediated through sodium loss and contraction ofthe extracellular volume) results in diminisheddelivery of filtrate to the distal nephron (and, inturn, diminished final urine volume). This couldbe accomplished either by small decreases in therate of glomerular filtration, or by an absolute in-crease in proximal tubular reabsorption. Thissequence of events is evident during the first 24to 48 hours of therapy with hydrochlorothiazide.Such changes appear to take place in the absenceof clinically apparent depletion of sodium and maymerely be an exaggerated manifestation of a nor-mal mechanism whereby sodium excretion is inpart regulated. That these changes are not medi-ated by aldosterone is suggested by the presentobservations demonstrating the failure of an al-dosterone antagonist to block the antidiuretic ef-fect of hydrochlorothiazide and the failure ofDOCA to mimic the antidiuretic effect of thethiazide or mercurial diuretic.

Further evidence suggesting diminished de-livery of filtrate to the distal nephron during theantidiuresis of sodium depletion is afforded by theobservation of persistent antidiuresis after with-drawal of hydrochlorothiazide and prior to so-dium repletion. Such findings may be interpretedas indicating that a sufficiently low flow existsthrough the distal nephron so that the proportionof water which moves out of the tubular lumen issufficient to preclude the excretion of urine ofminimal osmolality.2

Also consistent with this premise is the mannerin which electrolyte balance was achieved duringthe administration of hydrochlorothiazide. Al-

2Even in the complete absence of antidiuretic hor-mone or its effect, it is unlikely that the distal nephronis completely impermeable to water, and small net trans-fers of water may occur along the concentration (water)gradient from tubular lumen into the interstitium (27).With high rates of urine flow during water diuresis thisnet loss of water is probably insignificant in terms ofaltering the final urine volume or concentration. Asflow through the distal nephron diminishes, however, thisloss of water may reach proportions sufficient to increaseurine osmolality in the absence of antidiuretic hormone(28).

1995

LAURENCEE. EARLEYANDJACK ORLOFF

though sodium conservation was effected to alarge measure by replacement in the urine withpotassium and ammonia, total electrolyte balancewas approached by a reduction in total cation ex-cretion as urine volume decreased, while littlechange occurred in the total concentration of elec-trolytes (Figure 4). If this diminution in totalelectrolyte excretion represented decreased de-livery of filtrate to the distal nephron, then thelosses of electrolyte induced by hydrochlorothia-zide would diminish as less substrate (sodium)reached the distal sites where the agent acts(1-3).

An alternative explanation for the antidiuresisof hydrochlorothiazide administration is that thethiazide derivatives increase the permeability towater of the distal nephron in a fashion similar toantidiuretic hormone. This would appear unlikelyfor several reasons. The antidiuresis is not de-pendent upon the continued presence of hydro-chlorothiazide, and a qualitatively similar antidiu-resis followed losses of sodium from mercapto-merin. In addition, urine osmolalities neverreached values as great as that of plasma-a re-sponse which should be anticipated with only smallamounts of antidiuretic hormone (27). Further,in vitro experiments with a vasopressin-sensitivemembrane have failed to demonstrate any vaso-pressin-like quality of chlorothiazide on net wa-ter movement along an osmotic gradient (29).

The antidiuretic effect of the mercurial reportedherein is in contrast to the report of Crawford,Kennedy, and Hill, who observed no antidiuresisduring the duration of a "trial period of twenty-four to forty-eight hours" on mersalyl (13).Since mercurial diuretics appear to interfere withthe isotonic reabsorption of sodium (30-32), how-ever, these agents would produce an increasedfinal urine volume, and an antidiuretic effect wouldonly be expected during the period following themercurial diuresis and prior to a repletion of thelosses of sodium.

It has been suggested that the thiazide deriva-tives are in some way antagonistic to the renalaction of mineralocorticoids (33). The findingin the present studies of a clear effect of spirono-lactone, despite the presence of hydrochlorothia-zide, suggests a distinct renal action of endogenousmineralocorticoid in the presence of a thiazide

derivative. Also, Kahn has recently observed theexpected effect of chlorothiazide on electrolyteexcretion in adrenalectomized animals (34).

Although the reduction in urinary volume isanalogous to that which would be expected fromdietary restriction of sodium, the combination ofhydrochlorothiazide with a limited intake of so-dium offers a means of reducing body sodium andurinary volume to an even greater extent than bydiet alone, and as previously suggested (13), theseagents may have an important place in the man-agement of patients with vasopressin-resistantdiabetes insipidus. Since the depletion of body so-dium should be self-limited owing to the diminisheddelivery of filtrate to the sites where these agentsare active, the primary hazard would appear tobe excessive urinary losses of potassium andhypokalemia.

SUMMARY

The antidiuretic properties of hydrochlorothia-zide were studied in four subjects with congenitalvasopressin-resistant diabetes insipidus. Evidenceis presented which suggests that the antidiuresisresults from mild sodium depletion and is not dueto a unique property of the thiazide derivatives.A mechanism is discussed whereby reduction inbody sodium may lead to intrarenal alterationsresulting in a reduced volume of urine of higherosmolality. Data are presented which suggestthat the natriuretic effect of hydrochlorothiazidemay be overcome by the endogenous release ofaldosterone and by diminishing the delivery offiltrate to the distal sites where this agent isactive.

It is concluded that when employed in conjunc-tion with supplemental potassium and a restricteddietary intake of sodium, hydrochlorothiazide isof value in reducing the urine output of patientswith vasopressin-resistant diabetes insipidus.

REFERENCES

1. Laragh, J. H., Heinemann, H. O., and Demartini,F. E. Effect of chlorothiazide on electrolyte trans-port in man. Its use in the treatment of edema ofcongestive heart failure, nephrosis and cirrhosis.J. Amer. med. Ass. 1958, 166, 145.

2. Heinemann, H. O., Demartini, F. E., and Laragh,J. H. The effect of chlorothiazide on renal ex-cretion of electrolytes and free water. Amer. J.Med. 1959, 26, 853.

1996

THIAZIDE ANTIDIURESIS IN DIABETES INSIPIDUS

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