Reprinted from CIRTULATION
Vol. XX, No. 6 December, 1969
    Printed in U.S.A.

Relationship Between Plasma and Extracellular Fluid
Volume Depletion and the Antihypertensive
       Effect of Chlorothiazide

By ILSE M. WILSON, M.D., AND EDWARD D. FREIS, M.D.
   With the technical ass&arm? of Ma,ry J. Taylor

The importance of plasma and extracellular fluid volumes in the mechanism of the anti-
hypertensive effect of chlorothiazide is disputed. The present investigation indicates that
the lowering of blood pressure is accompanied by reductions in plasma and extracellular
fluid volumes and in body weight.  Furthermore, re-expansion of plasma volume with
salt-free dextran reverses the antihypertensive effect.  However, since gradual reaccumu-
lation of extracellular fluid occurs during 1 year of continuous treatment, the late anti-
hypertensive effects of chlorothiaxide cannot be explained by the volume-depletion
mechanism.

T HE tliscovrry of the antihypertensive
  action  of chlorothiazide'z 2 raised cer-
tain questions as to its mechanism of action.
These questions included (1) whether the
hypotensive response was caused by salt de-
pletion or by some independent factor ; (2)
if produced by salt loss, by what mechanism it
reduced blood pressure ; (3) the factors that
lead to increased reactivity to other antihy-
pertensive agents ; and (4) the reason for
the moderate antihypertensive action of the
drug when used aloue in hypertensive pa-
tients alld the absence of such activity in
normotensive subjects.`iv 4 Complete answers to
these questions cannot yet be given. This
report concerns an attempt t,o elucidate some
of thr factors involved.

MATERIALS AND METI~~D~

Twenty male hypertensive patients with no
symptoms or signs of congestive heart failure or
edema were hospitalized and placed on a stand-
ard diet containing 1.5 Gm. of salt per day plus
a supplement of 3 Gm. of salt in tablet form.
This supplied a sodium intake of approximately
75 mEq. per day. Most of these patients were

From the Veterans Administration Hospital and
t,he Cardiovascular Research Laboratory, Department
of Medicine, Georgetown University School of Medi-
cine, Washington, I>. C.

Supported in part by U. S. Public Health Service
grant H-720 (National Heart Institute) and by a
research grant from Merck, Sharp and Dohme.

under treatment with other antihypertensive agents
(table l), which were continued during the entire
period of study. A a-day period for acclimatiza-
tion to the diet was instituted in order to obtair
stabilization of body weight and electrolyte excre-
tions as well as average basal blood pressure
readings. Determinations of plasma and extra-
rellular volumes, serum electrolyte concentrations,
and serum bicarbonate were carried out on thr
morning of the fifth day. Each patient was then
given 500 mg. of chlorothiazide twice daily, and
the studies were repeated after a period of 3 to
8 (average 6) days.

Tn 11 patients carefully screened for reliability
and conscientiousness in regard to taking thei,
Itledications, studies were repeated at approxi-
mately 6-month intervals for a period of 18
months.  Seven of these patients were hospitalized
and placed on the controlled salt intake for t'
to 3 days prior to repeating the determinations.
while the remaining 4 were hospitalized for 1 day
only because of thrir inability to take time out
from work. Thus, dietary intake of salt cannot
be regarded as well controlled in the long-term
studies. At approximately 6 nlonths following
initiation of treatment the determinations of
plasma and extracellular volumes in `i patients
were repeated. Chlorothiazide therapy was then
discontinued for 1 week, after which another series
of determinations were carried out. The patients
remained hospitalized throughout this lattm
period.

Plasma volume was determined in the fasting
subject after one half hour of rest in the supine
position with the Evans blue dye method of Gibson
and Evans" adapted and modified for use in the
Coleman spectrophotometer,@s 7 3 specimens being

1.028            Circrlation, Vohne XX, December 1959


FT~I:ID VOLUME DEPLETIOS                                      1029

(`.E.     46
.J .\Vr.    4i
s.xr.    GO
r\..l.     46
.I .Er.    43
.l.HlI.    Ii0
11.K.    10
.I.%.     .5 7
A.W.    Iii
S.K.    50
.I .We    66

( `.H.

`I'. IT.

.I .( `,

c.ri.

.\T.l'.

ci.1:.

.I .I ).

\I.(`.

s. I+:.

RG

titi

47

5s

4ii

Mean
s. I).

+%I
+4.4
+5.0
+ ..5
+3.0
j-%2
+1.i
+1.0
- .4
+1.8
+4.0

+ .3 . 0

+J.4

+ .;i

+I.1

$4.4

+4.2

+1.-r

+ .-I

+L!.0

--II:!
-.iOl
-7s::
-132
-319
-.iAX
- 66
--t'!lG
- 55
-460
--2G.j

59s

-2. 4

::ci::

.:i

--43/10

1.1

29

-3.x

-172

+ .4

4.1;

6.4   --04/-I,j" +s.:!"
     11/7.5      4.9

xp va111e less than .OOl.

11stv1 tit 10, 15, :ttttl 20 tttitttttcs i'or cl~~tertttittitig tlyc
tlilutiott. `I'he lietttatwrit value wits detertrritwtl
frotn the avertage of 6 stittlples drawn during the
various experitnental procedures. Eighteen ntilli-
liters of 5 per cent sodium thiocyanate" were in-
jwtrd usudly at the end of the plasnia volutw
tlt'tc,t.tttitr;ttic)tis and s:tttlplrs WeI'? drawn at 2 ilttd
:i I10urs for tletcrntitxttion of thineyanate spnw
:twortlittg 1.0 tlte tttetltocl of Cranclall nnd Antler-
hl)llh :td;tptd to thr Coletnnn sl.`e~trophototttrtrr.
I~;itliosulI':ttc sp:tw was  dc~tcmtiinrd with SC::-
I:llwld srlll';rtc~ I,y tlw ltlrtllod of \valsrr." sodillttl
:lttd potit>>ittttt  \vcw dctrrttiined with a flninr


1030

WILXOS, FREIS

I CHANGE IN SCN
T2 SPACE - LITERS

. .          I
          I

    .             I
          o ?     I4

.

were analyed for total sodium, chloride, and
potassiuul, and the averap~ was taken as the con-
trol level of rxcrrtion. The cunudativa elevations
ahovv this lcq~~l tlurin~ the lirst 3 to 1 days a.fter
c~hlorothiazidt~ wvw tllvtk uwtl to cdinl:itc~ elf&w-
1ytr losst%.

The effect of restoratiott of tlifb plasma volulnc
was detennilled in 7 patients who exhibited sig-
nificant llypot~ensive responses to chlorothiazide.
Inch patient rweivcd X0 1111. of 6 prr crnt des-
tran in normal saline; and after several days the
procedure was repeated with substitution of a
sinlilar volut~~e of dextran in 5 per cent alucosr
in water. The infusion rate was approximately
25 ml. per minute. Blood pressure and heart rate
were detertninrd repeatedly before and through-
out the procedure and blood for hrnlatoerit detrr-
Anations was drawn innnrdiately preceding and
followin=; rach infusion.

           REs1iI,Ts

Following 3 to S (mean 6) days of chloro-
thiazide therapy the plasma volume showed
some reduction in all of 20 nonedematous
hypertensive patients (table 1). The loss of
plasma volume averaged 338 2 223 ml. and
varied in different patients from insignifi-
cant falls of less than `i0 ml. to rather marked
losses above 700 ml. The hematocrit reflected
the plasma volume change in an approximate
way by exhibiting slight to moderate eleva-
tion. However, there was no close quantita-
tive relationship between hematocrit and
plasma volume changes.

T.\BLE 2.-Lo.sscs nflcr CkloroHiiazide

                           Change after
      Chloro-   Urinary losses:      chlorothinzide
     thiazide cumulative negative  Thiocyanate -
     treatment  balance (mF.q.)      spice    wt.

Patient   (days) Na Cl K      CL.)    (Kg.)

s. EC      3    "24   392   "09    --A6   -5.4
J. Bu.     4    301   489   181    -1.9   -2.T
s. 31.     4    290   560   168    -2.4   -3.3
J. Z.      3    162   135   154    -3.9   -2.2
J. T.     4    216   268    4    - .7   -2.2
E. W.     3    349   510   222    -3.4   -2.7
-
Average 3.5 25$* 392" 156.3" 2.8" 3.0"

s. I).          68   163    71      1.4    1.2

"p value less than .005.

The thiocyanate space declined by more
than 0.5 L. in all except 5 of the 20 cases
(table 1). For the group as a whole the mean
reduction was 2.1 5 1.75 L. Although the
reductions of both plasma and available fluid
spaces were significant (p < .OOl), there was
110 consistent relationship between the degree
of plasma volume and available fluid changes.

Body weight decreased in 16 of the 20
patients (mean 1.8 * 1.84 Kg.). The change
in body weight was significant at the .OOl
level. There appeared to be a rough correla-
tion between the extent of change in body
weight and in thiocyanate space (fig. 1).
The blood pressure fell in all patients, the
average change bring -%I/15 mm. Hg. The
reduction occurred during the first 48 hours
following institution of chlorothiazide. There
was no quantitative correlation between the
plasma volume and arterial pressure changes.

The cumulatiw losses of body electrolytes
(cumulative negative balance) by the end of
the third to fourth day of chlorothiazide treat-
ment averaged 25i 2 68 mEq. of sodium, 392
2 163 mEq. of chloride, and 1.56 * 71 mEq. of
potassium in 6 patients studied (table 2).
All of these patients exhibited significant re-
ductions in body weight and thiocyanate
space. The correlation between the extent of
body weight reduction and electrolyte losses
was poor in this small series. However, the
accuracy of 24hour urine collections cannot


PLUIU VOLUME I)El'LETIOA'                                      1031

Patient

Chloro-
thiazide
treatment
( mos. )

Con ttd
B.P.
(mm.Hg)

After
cbloro-
thiazide
chanae
mean B.P.*
  (%"o)

           Following dextran infusion
    In 5 gel- cent              In normal
      alueose                 saline
      chanpe                chanae
     ___-
Mean B.P.     Hematocrit    Mean 1S.P.     Hematocrit
(%)         (%)        ( % )         (76)

J.H.f       1.0     150/110      -16.2
J.C.y        .5     180/110        09 g
                            -I&.
C.S.$       3.0     150/110      -13.0
li.C.$       1.0     180/108      ---30.4
W.F.?       1.0     140/100      -11.3
N.B.$       1.0     145/95       -12.5
.1.x.t        2.0     148/96       -10.9

Mean

1.4

155/104

-16.7~

+10.0
+18.4
+10.5
+t'S.l
+14.0
j19.0
+ 8.4
._____.-
+15.4s

- 3.2
-11.4
---1'7.1
- 9.1
-1::.ti
-- 8.8
-- 5.0

- 9.0$

+ 9.0       - 5.8
+L?o.u       --120
+1o.u       -14.8
+X3.7       -14.G
+1x2       - 9.8
+17.0       ~ 6.0
           -

+15.4#     - 9.8#

S.D.                            8.8          G.!l         3.8         5.8         3.3

   *` ` Rknn" blood pressure equals (systolic + diast,olic) /2.
   j'0n no other antihypertensive drugs.

be regarded as completely reliable, even in
hospitalized patients. The changes in the
serum cottceittrations of sodium and chloride
were insignificant, but there was a small but
significant decrease in potassium (table 1).
The serum bicarbonate determined in 4 pa-
tients shomed essentially no change.

ckxtran in 5 lwr cent glucose ill water. In 7
patients a significaltt eleratioti of blood pres-
sure was observed ranging betwell 8 to 2&
mm. Hg (mean + 15.0 2 7.0 111111. Hg,
(p < .005) The percentage fall of hemato-
crit awraped 9.0 * 3.8.

Acute Ikstoratiou of Plnsnaa Volume

thiazide

The effect of re-expansion of plasma    Whereas the reductions in plasma volume,
rolume on blood pressure was determined in   thiocyanate space, and body weight mere
7 patients who had been under continuous   significant during short-term therap)- with
treatment with chlorothiazide for periods   chlorothiazide~ this was not t,he ease follow-
railging from 2 weeks to 3 months (mean   ing long-term treatment. In 11 patients mhen
1.4 months). These patients had exhibited   these parameters were measured at the elrtl
reductions of " meau " (systolic + diastolic) /2   of 6 months, old>- the rcdnctiotl in thio-
blood pressure averaging 17.0 c `1.0 mm. Hg   vyauate spacae rcmainec1 si&?cant (table 4).
(table 3). The administration of G per cent   At the end of 1 year the change irt thiocyanatc
dcxtralt in isotonic salirie in 6 of these pa-   space was no longer significant at the .05
tients resulted in an immediate elevation of   level. Despite this trend, hoverer, the blood
blood pressure averaging 15.0 * 6.0 mm. Hg.   pressure changes, although not as marked at
The mean percentage fall in the hematocrit   the end of 1 year as in the early stages of
was 9.8 2 3.3 during the dextran infusion.     therapy, still showed significant rcduet,ions.

Tn order to determine whether sodium ion    In 9 patients after 1 to 3 months (average
was important in the reversal of the anti-   l.S months) the rxtraeellular flnid volume
hypertensive effect the infusions were re-   was estimated by means of 2 indicators (table
peated after several days with 6 per cent   5). thioqwrate and radiosulfate simultane-


WILSON, FREIH

           TABLE 4.-Changes Initially after Xc and l'weke Months                 ---
                                                       ~~~-  .
                 __..
         Plasma volume             Blood pressure           Thiocyanate space       Hody weight
            (ml.)                (mm. Hg)                  CL.)              (Ka.)
                                                    _____..~~ -~
                      -~-
Patient  1 wk.    6 mo.   12 mo.     1 wk.      6 mo.       12 mo.   1 wk.   6 mo. 12 mo. 1 wk.   6 mo.   12 mn.
                                                                      -~__
J .We.  -265   - 22  +165  --ao/-1s  -3o/--15    O/--8   -5.8   -3.9 - .i -4.6   -1.1  -2.8

J.Wr.  --Xl   - 49  --112  -26/-16  -2?/-20  -~ 7/O    - .9   -2.2 - .2 - .9   -6.0  -6.1

C.8 / .   -741   -201  -225  -14/-20  -2o/-20  -3oi'--30  -4.0   -3.2 --I.? -1.4   -8.0  --4.9

N.M.  -783   + 74  f132  -17/--F  -2o/-19  --35/-14  -2.4  ---2.4 $1.2 -3.3   + 2  -1.0

T.11.  -598   +110  -168  -4o/-2.5  -3o/-20  -w-10  -2.4   - .4 - .i -3.0   +7.7  f(i.7
s.13.   -596  + 58  - 19  --05/-E  -N-20  -20/--o::  -4.6  -4.7 + .9 -5.1   -6.3  +5.i
J .(:.   -363   -3'3  -402  -2()/-2"  --.30/f-20   30/-5   - .5  - .5 -.I +.r!   + .9  +4.9
J.R1.  -319   -248  -534  -3o/-20  -28/-15  -10/o    + .1  -2.1 -2.1 +".o  +4.4  +1.9
J .Bn.  -568   -164  -336  -E-l0  -E--PO  -lo/-l5  -1.9   - .8 - .6 -2.7   + .8  -1.4
C.P.   -177   - 51  - 51  -so/-30  -3o/-20  -u/-20  -2.1   -1.1 -1.5 -2.3   -4.3  ---7.0
H.K.  - 66   - 75  - 56  --8o/-20  --2oj--20  --`o/-15  - .5   - .9 - .7 -1.2   - .I  + .L
                                                                      ~~
31ean  -452"  - 80  -1557 --37/m*  -24/x9"  -n3/13*  --?.3$  -2.01 - .6 ".o$  -1 .o  - .4

s. I).   "s::     128    212  11.6/6.8   5.5/t!     10.5/" d. 4     I .8    1.5 .9 2. I     4.6    4.7
                     ~-___~~
     *p value less tlmn .OOl.
    tp r:llne leas than .05.
    $p vn111c less thm .Ol.

      Duration        Thioeyanate s~aee            SWabeled sulfate space      Thiocyanate     $y;
      treatment            CL.)                      (L.)              change      ehanae
Patient   ( mos. )     Control   After dup.   Chanae -   Control   After drug   Change     (5%)       (76)

J.W.
N.&L
A.J.
T.II.
R.E.
.I .Bu.
.I .14r.
(1.P.
IT. Ii.

2
3
`,

1
1
6, ,-
-..,
1
1
1

"5.4
19.8
24.0
25.6
24.5
19.11
00 1
--.
18.9
17.1

23.2
17.4
21.;
25.0
"1.1
1X."
18.9
1 ti.3
16.8

i, 0
--.-
-2.4
-2.3
--- .(i
-3.4
-1.X
--3.5
---2.6
- 2

19.9
14.1
17.7
19.6
18.3
14.1
lS.li
15.8
13.2

15 7
t .
13.6
Ii.3
19.6
1 (i.0
13.2
15.8
14.1
12.4

-4.2
-0.5
~- .4
-0
-2.3
-1.2
-2.8
-1.7
- .8

-1 1 .r,
-12
--I 0
0

-14
-11
-I6
-14
-2

Rlean      1 xi     21.8     19.9     -2.1.5     lG.8     15.3     -1.5     -1 (,.3X     - -9.at

RI).                              I.1                      I .:1        5         7.3

*p wrloe less than .OOl.
tp value less than .05.

ously, as ill1 additional cehec*k 011 t,lle validity
of the change demonstrated with thiocyalmte
alone. Considerably more variation was ob-
served with radioslilfate as the indicator.
ITowevrr, the averagr vhangc for the group
as a whole was similar with either thiocyanate
or P-labeled sulfate and the reduction in
estimated extracellular space was still sig-
nificant with either method.

Chlorothiazide was withdrawn for a l-week

period in 8 patients after 3 to 7 (average
.5.4) mont,hs of contiuous treatment in order
to evaluate the changes that might occur fol-
lowilig tliwontitiuation of long-term therapy
(table 6). There was a prompt elevation of
plasma volume averaging 241 -C 100 ml., a
rise in blood pressure (mean 23/15 * 8/9
mm. Hg), and a gain in body weight aver-
aging 1.6 * 1.3 Kg. All these changes mere
signific'ant. at the .01 level or less. The in-


FLUID VOLUME DEPLETION

T.IBT,E 6.-Changes Following Disconlint~ation of ChZorothGazide

              Plasma volume           Blood pressure          Thiocyanate space      Body weight
      Duration       (ml.)               (mm. Hg)               CL.1            (Kg.)
  tryat~e,nt Af;e; Repeat Ga$x    .4fkr    Repeat    Gain or    After Repeat Gain or
Patient m .      . control         chlor.    control    1OSS     chlor. control   1OSS  after Repeat "a&or
                                                                 chlor. control

J.We.
J.Wr.
C.S.
T.H.
S.E.
J.C.
J.Rr.
H.K.

4    3720  3827  +107
7    3717  4106  +389
i    3537  3871  f"34
7    3943  4152  +209
7    3183  3525  +349
5    3340  3663  +323
3    3200  3350  +150
3    2931  3106  +175

170/l 00  f00/190  +30/-00
151/103  180/130  +29/27
I P8/87   150/110  +2?/?3
153/l 00  160/110  + 7/19
160/170  180/l 25  +"0/15
170/100  n00/110  +30/10
140/100  165/100  +25/o
130/90   150/110  +00/20

33.   06.9
56.4  25.4
19.6  20.7
54.7  25.6
"4.2  25.6
02.8  23.0
18.9  SP.4
16.4  17.2

+2.1
-1 .o
+1.1
+ .g
+1.4
+ 2
+3.5
+ .8

S.i..?   85.3
1n3.3 I04
73.0   74.3
90    94.3
71.5   70 d. 7
95.4   99.5
80.3   83.0
7n    70.7

  0
+ .i
+1.3
+2.3
+1.2
+4.1
+2.7
+ .7

Average 5.4  3446 3700 +241* 150/99  173/144 +?3"/15?  21.5 23.4 +1.1   83.8  85.2 +l.Sf

S.D.                    100.4               7.8,`8.8              1.4              1.3

*p value less than .OOl.
tp value less than .05.

crease in thiocyanate space averaged 1.1 `-
1.4 L. The latter change was of questionable
significance (p < .06).

As compared to pretreatment values it was
of interest that following discontinuation of
the drug plasma volume increased 120 t 18
ml. and thiocyanate space rose to 0.5 -I 0.3 L.
above the original, untrrated level. These
slight ovrrshoots werr not accompanied by
parallel behavior of the blood pressure, t.he
latter rcmainillg -4/6 f 7/7 mm. Hg below
the pretreatment level.

The cha.nges in serum electrolyte concen-
trations and in serum bicarbonate were dc-
termined after 1 year of chlorothiazidr
treatment in 11 patients (table 7). Serum
sodium concentrations were essentially nn-
changed.  Serum chloride levels decreascad
slightly in most patients bnt increased slightly
in 2, the average change being 3.4 -I- 6.8 mEq.
There was a significant decline in serum po-
tassium concentrations. The rn(`an reduction
was 1.1 f 0.6 mEq. (p .OOl). The serum bi-
c.arbonatP remained unchanged.

DISCUSSION

In the present observations the reduction
of blood pressure paralleled the saluresis and
did not precede or follow it. The saluretic
effect was essentially complete in 48 hours.
The quest,ion arises as to the source of the

sodium depletion, specifically as to whether
it represented reductions in int,racellular
stores or came from the extracellular fluid.
The maintenance of normal serum sodium
levels indicated that the drug did not ex-
tract sodium from the ext,racellular water.
Rowever, the extent of the depletion of ex-
tracellular fluid volume indicated that the
majority if not all of the sodium removed
could be accounted for by an excaretion of
isotonic, extracellular fluid. This is in keep-
ing with the observations on other saluretic
agents such as mercurials, which produce pri-
marily  a rednction of ext,racellular fluid
volllIlle.l"

Since the plasma volnnw is in equilibrium
with the interstitial fluids, it also shared in
the general redurtion of extracellular fluid
space. However, the relationship between
change in extraeellular and plasma volumes
is only approximate. I3 Because of the failure
to find any evidence for significant cellular
losses of sodium, the question arose whether
the antihypertensive effect was related simply
to the decrease in total circulating blood
volume and to a reduction in tissue pressure
secondary to t,he extracellular fluid loss.
Such an interpretation is supported by the
observation of Crosley and his associateslJ
that right heart pressures and cardiac output
are reduced by chlorothiazide. Preliminary


1034                                    WILSOK, FR,EIS

TABIZ T.-Changes Following One Year of
   Treatment with Chlorothiazide

-

Patient

Na

Change in mEq.
Cl        K

CO?

J.Wc.      -3     -4     - .8     -1.
J .Wr.      --1     -I?      - .3     -1.6
C.S.         0     -9     - .6     -2.0
S.M.       -1     -9     - .6    +4.8
T.TI.      $2     -11     -1.1     +x1
S.E.         0     -8     -1.5    +3.`3
J.C.       -4     -1      - .4    +s.o
.J.Uu.       -5    +g     -1.2     -3.0
J.Rr.      -1     -3     - .4     -1.0
C.P.       -4    +5      -2.1     -4.0
1I.K.        0     -5     -1.0     +1.0
~___
Mean      -1.5    - 4.4"   - .93t    + .,o

S.D.         `, r
           -.J      6.8       .6       2.9

*p vahe less than .05.
tp value less than .OOl.

results ill this laboratory tend to confirm
these observations. Dustan aud her co-mork-
crslZ also found a reduction iu cardiac out-
put following chlorothiazide.

If the antihypertensive effects of chloro-
thiazide mere due to a change in intracellular
sodium coucentratiou producing a decrease
either in arteriolar tow or a dehydration
Of "waterlogged " arterioleqi" the hemodg-
llamic ctI'ects should be reflected iu a reduc-
tion of total peripheral resistance rather
thaii a fall iii cardiac filliiig pressures ant1
output. The latter fiutlings, however, are
readily c~xplainetl by the dwrcasrs in plasma
atrtl extrac~rlluliir fluid volumes. It is of in-
tcrrst that the normotcnsive individual com-
pensates so that the basal blood pressure is
Ilot lowered, whereas this compensation seems
to be deficieut in hypertensive patients."* 4
Whether such failure of homeostasis is due
to a decreased responsiveness of the barore-
ccptors or to other factors cannot be deter-
mined on the basis of present evidence.

The importance of the plasma volume
change in the mechanism of the antihyper-
tensive effect was indicated by the fact that
restoration of plasma volume either with or
without any replenishment of sodium re-
stored the blood pressure to essentially pre-

treatrnent~ levels. The lack of a yuantitativc
relationship between t,he decrease in plasma
volume and the fall of blood pressure can
be explained on the basis of variations in
the activity of compensatory mechanisms in-
cluding the baroreceptor reflexes, and in-
trinsic vascular distensibility in different
individuals. This variability was further
enhanced by the fact that some of the patients
mere taking ganglion-blocking drugs and
others were not.

These cotmlusions on the importance of
oligemia iu the mechanism of the antihyper-
tensive action of chlorothiazide confirm our
initial find&$ and are similar to those ex-
pressed by Dustan, Tapia, and associates.`", ii
They propose that the oligemia enhances
rasomotor "tone" which in turn makes the
patient more responsive to ganglion-blocking
agents. However, the observation that the
hypertensive patient often shows some reduc-
tion of blood pressure with chlorothiazide alone
whereas the normotensive subject does not33 4
suggests that the compensatory mechanisms
for plasma volume depletion often are in-
adeyuate in hypertension. Also, the decreased
responsiveness to norepinephrine following
chlorothiazide'", lQ in normot,ensive subjects
is imt readily explained on the basis of iti-
creased vasomotor tone alone, and suggests
that reactivity is dependent to sorne extent
ou the degree of filling of the vascular system.

The fa,ilure to obsrrvc a significant reduc-
tion of plasma volume after 6 to 12 months
of treatment reflects either tolrrancc to the
saluretic effects of the drug or the establish-
ment of compensatory mechanisms for res-
toration of homeostasis. Compensatory mech-
anisms become active after the first 48 hours
of treatment when the output of sodium
comes back into balance with the intake.
However, in the first month of treatment the
depletion achieved during the initial salure-
sis is maiutained and only gradually, there-
after, is the plasma volume deficit made up.

Other investigators have postulated that
chlorothiazide may have antihypertensive
effects additional to its saluretic action.* This


FLUID VOLUME DEPLETIOJJ

1035

is based on the observation that the blood
pressure remaius below pretreatment levels
after the body weight has beeli restored. It
should be pointed out, however, that disap-
pearance of acute drug effects without return
to pretreatment levels of blood pressure is
not unique for chlorothiazide. For example,
the acute heniodynamic effects of hydralazine,
characterized by taehycardia and palpitation
reflecting ail increase ill cardiac: output, geu-
erally disappear with long-term treatment.
Similarly, the manifestations of ganglioiiic
blockade such as impaired visual accommoda-
tion, dry mouth, and postural hypotension
often diminish with loiig-continued therapy
even though basal arterial pressure remains
below the pret,reatment lcvcl. The observations
of Perry and SchroederzO indicate that vigor-
ous treatment to obtain a continuous and pro-
longed reduction of arterial pressure, often
modifies the severity of the hypertension, so
that less intensive or no further treatment
is required. Thus, after long-term therapy
many factors, such as tolerance, compensa-
tory reactions, and modification of the basal
level of blood pressure, come into play to
obscure t,he initial relationship between drug
action and antihypertensive effect. It does
not seem possible to draw valid conclusions
concerning the antihypertensive activity of
a drug at this late stage, especially if the
effects of drug withdrawal are not deter-
mined.

SIJMMARY AND CONCLUSIONS

Plasma and extracellular fluid volumes,
serum  electrolyte  concentrations,  arterial
pressure, body weight, and electrolyte excre-
tions were determined in hypertensive pa-
Cents treated with chlorothiazide.

Plasma aud extracellular fluid volumes
tlccreased promptly during the early phases
of treatmcirt. This was accompanied by a re-
tlnctioll of :I ierial pressure and body weight.
Sodium losses could be accounted for on the
basis of extracellular fluid volume depletion.
Restoration of plasma volume either with or
without partial replenishment of sodium
reversed the antihypertensive effect of chloro-

thiazide. Withdrawal of chlorothiazide after
3 to i months of treatment was followed by
an elevation of plasnia volume usually to
levels slightly above the control. Blood pres-
sure rose to levels slightly below the control.

Significant reductiolis of plasma volume
and body weight were not found after 6
months and of extracellular fluid volume after
12 months of therapy even though the blood
pressure remained reduced. However, the
latter may not be a valid criterion of drug
activity following long-term modification of
the blood pressure level. The only significant
change in serum electrolyte concentration
was a reductiou in serum potassium. Serum
bicarbonate levels were not altered.

On the basis of this and other evidence
tliscussed it is suggested that the decrease in
plasma volume is an important, factor pro-
ducing the init,ial antihypertensive effect. Re-
duction in tissue pressure secondary to extra-
cellular fluid volume depletion also could
contribute to this response.

SUMMARIO IN TNTERLINGUA

Le volumines de1 plasma e de1 liquid0
extracellular, le coinentrationes de1 electro-
lytos in le sero. le tension arterial, le peso
corporee, e le cscretion tlr rlectrolytos esseva
tleterminat,e in patientes hypertensive sub-
tractamento con chlorothiuzido.

I,e volumines de plasma e de liquido extra-
cellular descendeva promptemeilto durante Ir
phases initial de1 tractamento. Isto esseva
accompaniate per un reduction de1 tension
arterial e de1 peso corporee. L.c perditas de
natrium esseva explicabile super le base de1
tlepletion de1 volumine de liquido extracellu-
lar.  Tie restauration de1 plasma, tailto coil
coma etiam sin le restitution partial de nat-
riurn reverteva le effect0 antihypertensive dc
chlorothiazide. Tie privation de chlorothiazido
post 3 a 7 menses de tractamento esseva so-
quite per un elevation de1 volumine de1 plas-
rna, usualmente usque a uivellos levenientc
supra le nivellos de controlo. T,e tension de1
sanguine montava usque a iGvellos levenieute
infra le nivellos dc c:ont.rolo.


1036

Signifkati\-c rrductioncs dcl volumitie de1
plasma e del pcho corporee 11011 esseva coil-
st.atatc ~iosf 6 liieilses dc therapia, c! similc-
ttlentc HIIIIC sigllificativc reductiones de1 vol-
imine clel licjiiido extracellular esseva cou-
statatc post 12 mcllsea de thcrapia ben que
lc tcusiou de sauguiue remaneva reducite.
Tatneu, iste ultime facto es possibilemente
iltralitle vo111e criteria de1 activitate de1 droga
post LIII proloiigate modificatiou de1 nivello
tlel teiisioii de sanguine. Le sol sigiiificative
alteration iu lc concentration de electrolytes
in le sero css(`va 1111 reduction de1 content0 de
Icalilun. I :(A tlivellos dc bicarbouato in le sero
Lieu esseva alterate.

Super 1~1 base de iste e altere observationes
tliwutite in lc presente reporto, le these es
fotmulatc~ q11c le reduction de1 volumiue de1
Illitslllil OS 1111 inlportaute factor in le produc-
t ioii tlvl cfY~vA0 aiitihypertemive iuitial. Le
rcvliwt~ioil (1~1 prcssioii de1 histos quc sequc
In dr[llrtiou de1 volmnille cle liquid0 exkacel-
llllar (1s etiam possibilemeute uu contributor
it illc WSpOlls~.

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