Reprinted from CLINICAL PHARMACOLOGY AND THERAPEUTICS, St. Louis
Vol. 1, No. 3, Pages 337-344, May-June, 1960 (Printed in the U.S.A.)

(Copyright © 1960 by The C. V. Moshy Company)

Mechanism of the antihypertensive

Effects of diuretics

Possible role of salt in hypertension

The mechanism of the antihypertensive effect of chlorothiazide does not differ from

that of such potent salt-depleting therapeutic agents as the mercurial diuretics and the rice diet.

The extracellular fluid and plasma volumes are reduced and, as a result, right heart

filling pressure, cardiac output, and blood pressure (if abnormally elevated by

some pressor stimulus) fall. Because of the reduction in plasma volume, drugs which

increase the capacity of the peripheral vasculature, such as ganglioplegic agents, synergize with

chlorothiazide. The reasons for some of the contradictory interpretations of chlorothiazide

activity are discussed and appear to be due primarily to (1) the difficulty in assessing

antihypertensive mechanisms in long-term studies and (2) confusion over the significance

of “normal” values for total exchangeable sodium in chronic experiments with

chlorothiazide. For the reasons stated, it is suggested that salt plays a permissive rather

than a primary etiological role in the genesis of essential hyptertension.

Edward D. Freis, M.D. Washington, D. C.

Veterans Administration Hospital and the Department of Medicine, Georgetown University

Hospital, Washington, D. C.

Clarification of the mechanism of the an-
tihypertensive effects of chlorothiazide and
its congeners is of considerable interest and
importance. The clinical value of chloro-
thiazide in hypertension has been demon-
strated by its effectiveness in reducing blood
pressure particularly when administered in
conjunction with other antihypertensive
agents.** The wide margin between effec-
tive and toxic doses permits simplified dos-
age schedules and insures relative freedom

 

 

Many of the studies reviewed in this paper were sup-
ported in part by United States Public Health Service
Grant H-720 (National Heart Institute), by Merck Sharp
& Dohme, and by Irwin, Neisler & Co.

from unpleasant side effects.*? The compli-
cating side action of hypokalemia appears
to be manageable with potassium supple-
mentation and the only sensitization reac-
tion of any moment has been an occasional
case of dermatitis.

Unlike other antihypertensive agents,
chlorothiazide lowers blood pressure exclu-
sively in hypertensive and not in normoten-
sive individuals.’:*" The selective antihyper-
tensive action raises the question as to
whether the drug is a specific antagonist of
the etiological factors producing hyperten-
sion.*° The present paper reviews some of
the evidence pertaining to the mechanisms

337
338 Freis

of the antihypertensive effects of chlorothia-
zide and concludes that the principal
mechanism of the antihypertensive effect
is an alteration in reactivity. The alteration
appears to be brought about by a change
in the pressure-volume relationship of the
vascular system and the blood volume
which is a consequence of the saluresis.

It has been known for some time that low
sodium diets increase the effectiveness of
various antihypertensive procedures.**7 Tt
also has been a common observation that
the diuresis associated with parenteral mer-
curials could precipitate hypotensive col-
lapse in hypertensive cardiac patients who
were taking ganglion-blocking drugs. When
it became apparent that oral chlorothiazide
approached the diuretic potency of paren-
teral mercurials it was a natural step to test
its value in the treatment of nonedematous
hypertensive patients. The results of the
preliminary trials, submitted as an abstract
to the American Heart Association in June,
1957, indicated that chlorothiazide en-
hanced the antihypertensive activity not
only of ganglion-blocking drugs but also of
hydralazine and Veratrum.® These clinical
observations lead naturally to an examina-
tion of the extent of the salt depletion pro-
duced by chlorothiazide in nonedematous
patients.

Saluretic action in
nonedematous patients

Nonedematous, hospitalized, hypertensive
patients were placed on a constant daily
ration of 4.25 Gm. of salt per day. After the
basal daily excretion of urinary electrolytes
on this intake was determined, chlorothia-
zide was administered in a dose of 500 mg.
orally 3 times daily. During the first 3 to 4
days after the drug was given, there was an
excretion of approximately 250 mEq. of so-
dium, 400 mEq. of chloride, and 150 mEq.
of potassium over and above the basal level
of excretion.**'3? Following the initial di-
uresis the saluretic effect tapered off. Out-
put came back into balance with intake but
the deficit was not restored by a period of
positive balance. Thus, the initial losses of

Clinical Pharmacology
and Therapeutics

body stores of sodium and chloride were
maintained for at least one to 2 weeks of
continuous treatment.'! The serum concen-
trations of sodium and chloride remained
unchanged, Potassium concentration often
fell moderately and this reduction tended
to deepen as treatment was continued over
a period of months.

Plasma and extracellular
fluid depletion

The 250 mEq. of sodium lost from body
stores must come either from the cells or
interstitial fluids. Total extracellular fluid
volume, as estimated by the changes in
available thiocyanate space, decreased by
about 2 L.*"1,42 Since body weight declined
by an average amount of 1.8 kilograms it
was apparent that the extracellular fluid
loss could account for the change in body
weight without implicating the intracellular
fluid volume.*? Furthermore, since the
serum concentration of sodium was essen-
tially unchanged it could be concluded that
extracellular isotonicity to sodium was un-
altered. The net effect of chlorothiazide ad-
ministration in nonedematous patients,
therefore, is similar to that observed in
edematous individuals except that the mo-
bilizable pool of extracellular fluid is con-
siderably smaller in the former. Cellular
extraction of potassium also was apparent
since the excretion of this electrolyte was
above the amount present in 2 L. of extra-
cellular fluid.

Since the interstitial fluid spaces and the
plasma volume are in equilibrium, it was
not surprising that there was a reduction in
the latter, the reduction averaging approxi-
mately 350 ml. There also was a correspond-
ing rise in hematocrit reflecting the hemo-
concentration.**1°? Similar changes in
plasma volume have been observed by
others.+28

Relationship between decrease in
plasma volume and antihypertensive
effects of chlorothiazide

It is well known that depletion of blood
volume by even small amounts will enhance
Volume I
Number 3

the antihypertensive effects of certain
agents, particularly ganglion-blocking
agents.!" For example, in hypertensive pa-
tients treated with ganglion-blocking drugs,
withdrawal of as little as 2 to 4 per cent of
the total blood volume resulted in percepti-
ble additional decrements of arterial pres-
sure.!3 O’Donnell?? demonstrated a reduc-
tion in plasma volume in hypertensive pa-
tients treated for several weeks with Kemp-

HEMODYNAMIC COMPONENTS OF VASCULAR SYSTEM

HEART

 
   
     
      
 
   
     
 

ARTERIES

PRESSURE DEVELOPED IN THE)
POST ARTERIOLAR SYSTEM
DETERMINES RIGHT HEART
FILLING PRESSURE AND

HENCE, CARDIAC OUTPUT

  

ARTERIOLES
MAIN DETERMINANT
OF ARTERIAL

CAPILLARIES RESISTANCE

&
VENULES

HEMODYNAMIC EFFECTS

Antihypertensive effects of diuretics 339

ner’s rice and fruit diet. O’Donnell was able
to reverse the postural hypotensive effects
of the rice diet either by administering salt
or else by replenishing the plasma volume
with salt-free dextran solutions. It has also
been noted that parenteral mercurials
(which likewise are potent saluretic agents )
increase the responsiveness to antihyperten-
sive drugs; reduce blood pressure in hyper-
tensive patients’? but not in normotensive

DETERMINANTS OF RIGHT HEART FILLING PRESSURE

  

TISSUE

4 PRESSURE

PRIMARILY

BY SYMPATHETIC VOLUME

weaves 2

TOTAL VOLUME
OR CAPACITY OF
SYSTEM
DETERMINED

  

OF CHLOROTHIAZIDE

  

 
   
 

TISSUE
PRESSURE
REOUCED

  
 
  

it ? sopium

     
   
 

SHIFT OUT OF
BLOOD ARTERIOLAR
VOLUME WALLS

REOUCED

“FLACCIDITY" OF POST ARTERIOLAR VASCULATURE PROOUCEO
BY REDUCTION IN PLASMA VOLUME AND TISSUE PRESSURE.
LEAUS TO DIMINISHED RESPONSIVENESS TO CONSTRICTOR
STIMULI ANO ENHANCED RESPONSIVENESS TO DILATOR STIMULI.

Fig. 1. Schema of proposed concept of the mechanism of the antihypertensive effect of chloro-
thiazide. Other factors influencing right heart filling pressures and cardiac output, such as
myocardial “contractility,” pulmonary and systemic peripheral resistance, etc., have been
omitted only because they do not pertain to the concept developed in this review. This is not
to deny their importance in other circumstances.
340 Fre's

subjects!®; and diminish plasma and extra-
cellular fluid volumes in nonedematous in-
dividuals.’®" These observations pointed
the way for further experiments with chlo-
rothiazide,

If depletion of plasma volume was im-
portant in the antihypertensive effect of
chlorothiazide, then restoration of the
plasma volume should reverse the process.
This was indeed the case. Hypertensive pa-
tients under hospital control conditions and
a constant daily intake of salt exhibited
reductions in basal arterial pressure with
chlorothiazide alone which averaged ap-
proximately 15 per cent less than the pre-

» systolic + diastolic

treatment “mean — 3 °)

blood pressure.'# When 500 ml. of 6 per
cent dextran was infused intravenously over
a 15 minute period, the blood pressure rose
to approach the pretreatment level.1°™ Ad-
ministration of salt was not important in
this response as comparable elevations were
seen when the dextran was administered
either in isotonic saline solution or in 5 per
cent glucose in water.''3* These observa-
tions have been confirmed recently by Dol-
lery and co-workers.*

The relationship between the vascular
capacity and the contained blood volume
seems to be important in this antihyperten-
sive effect. Crosley and his associates? have
shown and we!! have confirmed that the
hypotensive response to chlorothiazide is
associated with a decrease in right heart
pressures and in cardiac output as estimated
by the Fick principle. Crosley found, in ad-
dition, that if the lower extremities were
elevated in order to increase the venous
return, the cardiac output rose. Dustan and
her co-workers® using the dye method found
a decrease in cardiac output after chloro-
thiazide. This was reversed by infusion of
salt-free dextran.

These observations permit the formula-
tion of a concept of the mechanism of the
antihypertensive effects of chlorothiazide
and other salt-depleting agents. It is con-
venient to postulate a labile reserve of total
extracellular fluid and plasma volume which

Clinical Pharmacology
and Therapeutics

are in equilibrium. The amount is approxi-
mately 2 L. in nonedematous individuals
who have free access to salt in the diet.
This reserve of extracellular fluid can be
mobilized by severe salt restriction, by po-
tent saluretic agents, or by any event pro-
ducing dehydration. (It may be noted that
drastic purgation, a popular method of
treating acute forms of hypertension in by-
gone days, produces the same effect). The
resulting decrease in plasma volume and
probably also of tissue pressure impairs the
venous return of blood to the heart with a
consequent fall in cardiac output and,
hence, arterial pressure. Ganglion-blocking
drugs also decrease venous filling pressures
and cardiac output, but they affect the
other member of the relationship between
vascular capacity and blood volume. After
blocking drugs, the blood volume remains
unchanged but the peripheral vascular ca-
pacity increases thereby reducing right
heart filling pressures.?® These interrelation-
ships explain the synergism between the
hypotensive effects of chlorothiazide and
the ganglion-blocking agents.

Effects of chlorothiazide on
blood pressure responsiveness

In discussion of the changes produced by
chlorothiazide on the effects of pressor and
depressor agents, it is preferable to use the
terms “blood pressure responsiveness” or
simply “reactivity” to “vascular reactivity.”
The latter phrase implies a change in con-
tractility of the smooth muscle of vascular
walls, an interpretation that cannot be as-
sumed on the basis of present evidence.

As previously mentioned, only hyperten-
sive patients exhibit a reduction in basal
blood pressure after chlorothiazide alone.
Normotensive subjects with basal diastolic
levels of 85 mm. Hg or less do not exhibit a
significant change in blood pressure follow-
ing the drug.’ On the basis of this and other
evidence, Wilkins, Hollander, and Cho-
banian®° postulated that chlorothiazide and
mercurials have a specific antagonistic effect
on the etiological factors operative in pro-
Volume 1
Number 3

ducing hypertension. They proposed that
chlorothiazide inhibits the production of
renin. Obviously chlorothiazide might pro-
vide a pharmacologic tool of some impor-
tance in exploring the nature of the differ-
ence between hypertensive and normoten-
sive individuals.

As a preliminary to this investigation it
was necessary to determine whether chlo-
rothiazide produced a similar depletion of
extracellular fluid space and plasma volume
in normotensive subjects as in hypertensive
patients. Following chlorothiazide in nor-
motensive subjects who were studied under
identical hospital conditions, there was an
average loss of 285 mEq. of sodium over
and above the level of intake during the
first few days of therapy.45 The mean de-
crease in body weight in these patients also
was 2.0 kilograms. This was identical with
the weight loss observed in the hypertensive
patients. A significant decline in plasma vol-
ume was indicated in the normotensive sub-
jects by the fact that the mean hematocrit
values rose from 44.2 to 48.3 per cent. Thus,
chlorothiazide did not appear to exert a dif-
ferent effect on sodium excretion or fluid
volume compartments in normotensive and
hypertensive patients.

Although chlorothiazide did not reduce
the basal level of blood pressure in normal
individuals, it was soon found that their
blood pressure responsiveness was altered.
The pressor response to agents such as nor-
epinephrine was significantly reduced?'-2*
and the depressor response to depressor
agents such as trimethaphan was. signifi-
cantly increased.” The average clevation of

systolic + diastolic
~~ —-—-—— | blood pres-

“mean”
9

sure following a given level of infusion of
norepinephrine was approximately 15 per
cent less after, as compared to before, chlo-
rothiazide.4*" It is interesting that this is
quantitatively similar to the average fall in
basal blood pressure in hypertensive pa-
tients. Reduction in blood pressure respon-
siveness to pressor agents has also been ob-
served in dogs after chlorothiazide! and
other diuretic agents.”

Antihypertensive effects of diuretics 341

In order to estimate the importance of
plasma volume depletion, salt-free dextran
was infused in the chlorothiazide-treated,
normotensive subjects. After restoration of
plasma volume, the blood pressure respon-
siveness of these normotensive subjects re-
turned in some cases completely to the con-
trol value. Thus, the change in reactivity
induced by chlorothiazide seemed to be de-
pendent in large measure on plasma volume
depletion.

This observation may explain the differ-
ing effects of chlorothiazide on the basal
blood pressure of hypertensive and normo-
tensive subjects. If the fall in plasma vol-
ume (and possibly tissue pressure) dimin-
ishes reactivity to any pressor stimulus, then
chlorothiazide also would diminish the re-
sponse to the unknown pressor agent or
agents which produce essential hyperten-
sion. Thus, chlorothiazide or any salt-de-
pleting agent reduces blood pressure only
when some abnormal hypertensive stimulus
is operative. In this respect, its action is
nonspecific. Pressor responses of all types
are dampened and diminished but not spe-
cifically antagonized in the metabolic sense
that Wilkins and Hollander*® proposed.

It is significant that the basal blood pres-
sure was reduced by chlorothiazide in hy-
pertensive patients with diastolic levels as
low as 90 mm. Hg."! Such results do not
support Pickering’s”® thesis that hyperten-
sive patients with only moderate elevations
of arterial pressure represent merely the
higher ranges of normal blood pressure in
the total population. The difference in the
response of the basal blood pressure to chlo-
rothiazide when it is above or below 90 mm.
Hg suggests that we are dealing with two
distinct populations.

Antihypertensive effect of
chlorothiazide after
long-term treatment

Much of the difference of opinion con-
cerning the mechanism of the antihyperten-
sive effect of chlorothiazide is based on the
difference in results obtained in short-term
and long-term experiments. After several
342 Freis

months of continuous daily treatment the
depletion of total extracellular and plasma
volume tends to disappear and after 6
mouths or one year no significant difference
from control values can be found.?* The
reason for this is not clear, For want of a
better explanation we have ascribed this
to the development of tolerance. In most in-
stances, however, the blood pressure con-
tinues to be depressed. This has been the
most cogent argument for a specific antihy-
pertensive effect of chlorothiazide distinct
from its saluretic action.*?8 It implies, how-
ever, that the drug reduces blood pressure
by one mechanism initially and by an en-
tirely different mechanism at a later date.

Another explanation which fits with ob-
servations made on the long-term effects of
other antihypertensive agents™* is that the
severity of the hypertension decreases after
long-term control at lower levels of blood
pressure. The reason for this modification of
the hypertensive process is not known al-
though there is evidence that the barore-
ceptor mechanisms can he reset if blood
pressure is maintained at a different level
for weeks or months.2* Thus, in order to
prove that chlorothiazide still is exerting an
antihypertensive effect after long-term
treatment, the drug should be withdrawn
for some time in order to determine whether
the blood pressure will rise to the pretreat-
ment level. In any event, it is difficult to
assess the long-term hypotensive mecha-
nisms of antihypertensive agents.

Another discrepancy in the interpretation
of the antihypertensive action of chlorothia-
zide can be traced to a confusion between
the estimation of total extracellular fluid
space and total exchangeable sodium. The
latter provides an estimate of both extra-
cellular and intracellular sodium which can
be exchanged with isotopically labeled so-
dium over a defined period of time, usually
24 hours. The space so measured is consid-
erably larger than the extracellular fluid vol-
ume and includes most of the sodium in the
body except that which is fixed in bone. In
addition, chlorothiazide produces a continu-
ous potassium loss and if the dietary intake

Clinical Pharmacology
and Therapeutics

of this ion is not ample, a gradual deple-
tion of potassium will occur. Under these
circumstances sodium will move into the
cells to make up the potassium deficit. Thus,
in the studies of Hollander!’ and Winer*
where total exchangeable sodium was esti-
mated, sporadic results might be expected
especially since the experimental measure-
ments were made in outpatients after sev-
eral weeks or months of treatment. For ex-
ample, if potassium intake was poor in a
given patient, the total extracellular space
and plasma volume could be reduced but
the value for total exchangeable sodium
would be normal because of accumulation
of exchangeable sodium in the cells. In ad-
dition it is impossible to be certain with out-
patients that the prescribed medications are
being taken faithfully. It is not too surpris-
ing, therefore, that these authors failed to
observe a significant correlation between
total exchangeable sodium and antihyper-
tensive effect.

Much has been written on the signifi-
cance of sodium in the genesis of essential
hypertension. Most of the valid human evi-
dence on which this supposition is based has
to do with antihypertensive effects of salt-
depleting procedures. Salt in this situation
appears to have no specific etiological sig-
nificance, however. Its action rather is per-
missive in that by allowing “normal” expan-
sion of plasma and total extracellular fluid
volumes the unknown pressor factors in hy-
pertension can operate more effectively than
when these fluid spaces are contracted.

It is entirely possible, of course, that the
sodium ion may play an important role in
smooth muscle contractility and by this
means exert an additional influence in hy-
pertension. However, the data available on
this subject are so conflicting that as yet no
guiding concepts can be defined.!® What-
ever the role of sodium in vascular reac-
tivity and in hypertension may turn out to
be, we cannot neglect the simple relation-
ship of this ion to the maintenance of nor-
mal plasma and extracellular fluid volumes
and the importance of these to blood pres-
sure responsiveness.
Volume 1
Number 3

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Clinical Pharmacology
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