Medical Cbinics of North America
Vol. 34, No. 6. November, 19.50

THE TREATMENT OF SEVERE ESSENTIAL HYPERTENSION

EDWARD D. FREIS, M.D.* FRANK A. FINNERTY, JR., M.D.?
      AND WILLIAM B. WALSH, M.D.1

THE most important factor in deciding the type of treatment to be
used in any given patient with essential hypertension is the prognosis.
The reason for this is that specific hypotensive therapy is difficult to ad-
minister, requiring patience and persistence on the part of the physician
and patient alike. Such inconvenience does not seem necessary or even
desirable in the average case of benign essential hypertension since the
life expectancy of such patients usually is good without radical therapy.'

Thus, a patient who has an ambulatory diastolic blood pressure below
120 mm. of mercury with a further fall during sleep (sedation test) or
after several days of rest in bed, and who has normal renal function,
good cardiac reserve and grade I or II optic fundi may, on the average,
look forward to a normal or nearly normal life span. The symptoms of
such a patient should be treated in the same way as one would treat
similar symptoms in a normotensive patient; above all, he should be re-
assured concerning the relatively benign character of his hypertension.
Since such patients may carry on a trouble-free existence for many years,
it would be foolhardy to attempt to treat them with drugs which have
disturbing side effects, with diets that are inconvenient and unpalatable,
or with major surgical procedures.

The real problem occurs when the patient with benign hypertension
begins to show progression. The patient who has a diastolic pressure con-
sistently above 120 mm. of mercury which does not fall markedly during
sleep or with hospital rest and who shows advancing disease as judged by
changes in the fundi, kidneys and heart can no longer be treated ade-
quately symptomatically. Some type or types of specific hypotensive
therapy are indicated.

In the treatment of the severe case we have resorted to three specific
hypotensive procedures: (1) low sodium diets, (2) hypotensive drugs,
and (3) surgery. The low sodium diets are two: The Kempner rice diet
and the Meade-Johnson low sodium (200 mg.) diet. Drug treatment con-
sists primarily of the extracts of Veratrum viride orally administered and

From the Department of Medicine, Georgetown University Hospital and
Georgetown University School of Medicine ; and the Veterans Administration
Hospital, Washington, D. C.

* Adjunct Clinical Professor of Medicine, Georgetown University School of
Medicine; Assistant Medical Chief, Veterans Administration Hospital; Director
of the Cardiovascular Research Laboratory, Georgetown University Hospital.
t Fellow in Medicine, Georgetown University Hospital and Georgetown Uni-
versity School of Medicine.

$ Instructor in Clinical Medicine, Georgetown University School of Medicine.
                      1741


1742

FREIS, FIKNERTY, WALSH

in certain instances the sympatholytic drugs, principally the dihydro-
genated alkaloids of ergot and C-7337. Surgical therapy consists of vari-
ous types of sympathectomy including the Smithwick lumbodorsal
splanchnicectomy and, when cardiac denervation seems desirable, the
transthoracic sympathectomy. In addition, excision of pheochromo-
cytoma and repair of a coarctation of the aorta when these rare cases are
found and judged operable may be considered curative procedures.

No hypotensive procedure can be depended upon to provide consistent
responses in a group of hypertensive patients. Occasional cases will ex-
hibit a dramatic remission following one or another type of therapy or to
a combination of these with marked reduction in arterial pressure and
regression of many of the other symptoms and signs of their disease. Un-
fortunately, however, the majority will exhibit slight or insignificant
therapeutic responses. Nevertheless, treatment with these procedures, if
carried to the point of tolerance, will result in subjective and objective
benefit in a significant number of patients with sustained high diastolic
blood pressure. Therefore, in this group intensive treatment seems at
least worthy of trial.

DIETOTHERAPY

It is still uncertain as to whether the effectiveness of the Kempner rice
diet in essential hypertension is due entirely to its low sodium content or
whether deficiencies of other substances, especially protein, also may
play a role. The rice diet contains about 100 mg. of sodium in the usually
consumed daily portion, whereas, t'he Meade-Johnson low sodium or
so-called "Lanolac diet" provides twice this amount of sodium, The evi-
dence that the low sodium content of the rice diet determines its hypo-
tensive action is fairly good since feeding of salt restores the hyperten-
sion in bot'h animals2 and man.3 The evidence concerning the hypotensive
effect of protein restriction is conflicting. In Europe during the war,
studies during the siege of Budapest did not indicate any significant
hypotensive effect of a diet markedly deficient in protein,4 whereas re-
ports from Leningrad indicated that the famine period during the siege
resulted in definite amelioration of hypertensive diseases and a marked
exacerbation following the lifting of the siege.5

Because of this uncertainty in regard to the importance of sodium re-
striction alone and since the rice diet contains less sodium than any other
diet we have made it a practice to begin dietotherapy with a trial of two
weeks on the strict Kempner rice diet. If there is improvement in t,he
levels of arterial pressure at the end of this trial period the rice diet, be-
cause of its unpalatability, is replaced by the Meade-Johnson 200 mg.
sodium diet. However, if at the end of two weeks there is no change in
arterial pressure dietotherapy is discontinued. If the diet is rigidly ad-
hered to for more than a month, the flat taste of salt-free food becomes


SEVERE ESSENTIAL HYPERTENSION         1743

progressively less distasteful. However, during the first month the temp-
tation to use salt is so great that a check of the urine chloride concentra-
tion must be made at weekly intervals even in hospitalized patients. In
addition, patients who adhere to the diet usually lose approximately 10
pounds in body weight during the first months of treatment. It is of
great value to tell the patient that the diet already permits the maximum
amount of sodium and that any "break" in the prescribed regimen, no
matter how slight, will destroy its hypotensive effect completely.
  A crude but useful method of checking the urine for chloride may be

carried out in the office. This is done as follows: To 10 drops of urine in a
test tube add 1 drop of 20 per cent potassium chromate solution. The
fluid turns yellow. Using the cleaned urine dropper add 2.9 per cent silver
nitrate solution drop by drop until there is a distinct color change from
yellow to red brown. The number of drops of silver nitrate required to
produce the color change approximates the number of grams of chloride
per liter of urine.

When a low sodium diet is prescribed for hypertensive patients who
have severe renal impairment, repeated checks of the clinical state of the
patient as well as the blood nonprotein nitrogen are necessary since in
occasional cases the kidneys have lost the ability to conserve body sodium
and critical depletion of electrolyte may result. The administration of
salt will reverse this process. Similarly, in occasional patients who do not
have severe renal disease weakness and lethargy may develop after sev-
eral weeks or months of sodium restriction. These symptoms are re-
lieved by taking salt but the hypertension will return.

DRUG THERAPY

Compared with the brilliant successes of chemotherapy in other con-
ditions the drug treatment of essential hypertension remains disappoint-
ing. In our experience the ester alkaloids of Veratrum viride6 are the only
drugs that have any long-term value in the treatment of severe hyper-
tension. Significant reductions in arterial pressure do not occur uniformly
and, as with diet and sympathectomy, in a heterogeneous group of severe
hypertensives there are all gradations of response from dramatic hypo-
tensive reactions to no response. Although side effects, particularly
nausea and vomiting, are frequent, and collapse reactions are not rare,
permanent disability or death has not been reported when the drug is
given by the oral route. Therefore, if used with a reasonable amount of
care the drug does not seem to be dangerous despite occasional alarming
side effects. Profound hypertensive reactions with collapse may be
treated by giving 50 mg. of ephedrine intramuscularly and/or 1 mg. of
atropine sulfate intravenously.

The recent introduction of well standardized and uniform extracts


1744          PREM, FMNEBl'Y, WAL&H

such as-Anatensol* and Veriloid' t appears to offer someimprovement
over the crude drug (Vertavist) although the latter product is said to be
now completely uniform and well standardized. Since the extracts are
uniform, dosage may be given safely four times per day (after meals and
at bedtime). Such a dosage interval and the use of slow dissolving tablets
results in a fairly well sustained hypotensive effect in responsive patients.
The present status of the Veratrum alkaloids in the treatment of hyper-
tension has recently been reviewed by Wilkins.8

The effective dose in any given patient must be determined by trial.
Treatment is begun by administering 1 tablet of Anatensol or Veriloid
four times per day (after each meal and at midnight). After forty-eight
hours, if there is no fall in arterial pressure, the dosage is increased to 2
tablets per dose and, if necessary, at the end of the next forty-eight
hours to 3 tablets, four times per day. In this way dosage is quickly
increased to the effective range. The average effective dose has been
8 to 12 tablets per day but has varied widely between 4 and 40 tablets
per day. Patients must be seen daily during the initial adjustment period.
Our routine is to keep a record of the arterial pressure prior to and three
hours after each dose of tablets during the first week or two of treatment.
Attempts to regulate dosage in the initial period by checking the patient
once or twice per week in the oflice or clinic are not sufficient.

Some patients will exhibit a satisfactory hypotensive response on such
crude adjustment, but the majority will require finer adjustment when
t'he effective dosage range is reached. Thus, it may be that in a given case
a dose of 2 tablets is ineffective while 3 tablets produces vomiting. A dose
of 2) tablets, however, will produce significant hypotension without
vomiting. Or it may be that the patient consistently will vomit after
only one of the doses, e.g., the after-breakfast dose. In such an instance
only this dose should be reduced slightly but not the others.

Since cumulation of the drug occurs during continuous administra-
tion, the dose usually must be decreased (by half-tablet amounts) after
the first weeks or months of treatment, usually because of vomiting. It
is of great importance not to reduce the dose too far since the margin
between the hypotensive dose and that causing side effects is very slight.
Adjustment of dosage of Veratrum parallels in many respects the pro-
cedure used in adjusting the dose of belladonna, that is, the dosage is
gradually increased until side effects occur and the patient maintained
at a dose slightly below that level. In short, the physician who wishes to
use Veratrum with any measure of success must work within an ex-
tremely narrow dosage range. Since the optimal dose varies widely in
different cases it must be determined in each instance by patient and

* E. R. Squibb &Sons, New York, N. Y.
i Riker Laboratories, Inc., Los Angeles, California.
$ Irwin, Neisler & Company, Decatur, Illinois.


SEVERE ESSENTIAL HYPERTEXSIOK         1745

persistent trial. It is obvious that such fine adjustment can be carried
out most successfully in the hospital, where frequent observations of
basal arterial pressure may be used as a guide to dosage.

Because of the chemical similarity between the Veratrum alkaloids
and the digitalis glycosides and since Veratrum occasionally may cause
arrhythmias such as nodal rhythm, heart block and bigeminal rhythm,
it has been suggested that the two drugs may be incompatible in thera-
peutic dosage.s In actual practice, however, this has seldom been the
case. We have given digitalis to patients who are taking Veratrum, and
have administered Veratrum to previously digitalized patients without
adverse side effects in most cases.

The percentage reduction in arterial pressure, while occasionally
dramatic, usually amounts to about 15 to 20 per cent of the mean arterial
pressure. Nevertheless, we have seen repeatedly in severe hypertension
reductions of 20 to 30 mm. of mercury in diastolic pressure result in
the reversal of a progressively malignant process. The primary aim in
treatment with this drug is not to reduce the blood pressure to normal,
since this is seldom possible, but rather to reduce a dangerously high
fixed diastolic pressure to a more benign range. In fact, as stated pre-
viously,G Veratrum is most useful in severe hypertension, particularly
in malignant hypertension which has not yet proceeded to the uremic
stage. In our experience the drug has been more effective in patients,
particularly males, with fixed high diastolic pressure than in labile or
mild hypertension.

Since there is no known way of determining in advance responsive
from nonresponsive patients, an adequate therapeutic trial of Veratrum
must be made in each case. As side reactions are so frequent following
the drug, the temptation to omit the medication is great, and since the
margin between the hypotensive and emetic doses frequently is small,
both the physician and the patient may find it less troublesome to fall
back on symptomatic treatment. On the contrary, successful therapy
even in responsive patients requires a persistent physician and a co-
operative patient. It seems apparent, therefore, that the extracts of
Veratrum are not drugs for the treatment of mild, asymptomatic hyper-
tension.

SURGICAL AND COMBINED THERAPY

For the average case requiring sympathectomy lumbodorsal splanch-
nicectomy has become the most generally used procedure. However, there
are certain patients who exhibit tachycardia as well as hypertension,
the acceleration of heart rate often being most pronounced in the erect
position. Following lumbodorsal splanchnicectomy in such cases cardiac
acceleration may be very marked and causes considerable discomfort to
the patient. In such cases and in others in whom palpitation is a prom-


1746            FREIS, FINNERTY, WALSH

inent symptom, transthoracic sympathectomy which permits inter-
ruption of the sympathetic nerves to the heart seems to be the prefer-
able procedure. Some surgeons prefer the latter operative approach
since it permits more ready visualization of the sympathetic chain. How-
ever, the operative mortality is said to be slightly higher with this op-
eration than with the lumbodorsal or Smithwick operation.

The effectiveness of combined therapy in severe hypertension may
necessitate a revision in the criteria for the choice of candidates for
surgical sympathectomy. Cases in the past believed to be too far ad-
vanced to be suitable for surgery at present may be benefited when
medical therapy is used following operation. Indeed, as judged by our
as yet limited experience, the only patients that would be excluded from
operation are (1) those with far advanced renal disease verging on uremia
and (2) elderly patients whose life expectancy is not sufficiently long
to warrant operation. The principal indication for operation in our ex-
perience are patients who fail to respond or have lost their response to
medical treatment alone.

It is apparent from this brief review of the specific hypotensive treat-
ments available at present that none are simple or easily carried out
procedures. Nor is it possible as yet to predict in advance with any great
degree of success whether the given patient will respond to any or all
of t#hese treat,ments. For these reasons we have reserved such procedures
for the treatment of severe hypertension only (diastolic blood pressure
persistently above 120 mm. Hg).

It is true that in many instances of severe diastolic hypertension the
long-term results with any of the above mentioned treatments used
alone have been only fair. Not infrequently reductions in arterial pres-
sure occur especially after surgical and drug therapy, which do not
persist. However, me have also observed that the results of treatment
with drugs, diet or sympathectomy are more dramatic, more persistent
and effect a greater percentage of patients if these forms of treatment
are combined.

A second encouraging factor is that in severe hypertension clinical
improvement frequently will occur after only moderate reductions in
diastolic pressure. Thus, it is not uncommon to see regression of papill-
edema, hemorrhages and exudates in the optic fundi and great improve-
ment in cardiac reserve with a reduction of diastolic pressure previously
maintained persistently at 140 and above to one maintained between
110 and 130 mm. of mercury. Apparently in many cases of this type it
is only necessary to reduce diastolic blood pressure from the severe to
the benign range.

The following case histories will serve to illustrate the manner in
which the various forms of treatment may be combined in order to re-
vert patients from severe to benign hypertension and to maintain them
in the less severe range.


SEVERE ESSENTIAL HYPERTENSION         1747

CASE I. Severe Essential Hypertension In Young Negro Male Treated with Ex-
tract of Vera&urn Viride and Later with Low Sodium Diet Added. E. C., a 34 year
old Negro taxi driver, came to the hospital because of severe occipital headaches
of six months' duration and progressively blurred vision of one month's duration.
Physical examination disclosed a blood pressure of 250/150 and grade III optic
fundi with large exudates but no papilledema. There was no significant cardiac
enlargement. The urine contained a trace of albumin with occasional cells and
hyaline casts and concentrated to 1.023. Phenolsulfonphthalein excretion was
15 per cent in twenty-five minutes and 35 per cent at the end of an hour.

VERILOID MG.PER DAY             [     200MG.SODiUM DIET      1
`i[ miwmf-
       f                                     I
           2         6  2    3    4    5     6    7    a     9
            WEEKS                    MONTHS

Fig. 228. Chart, of arterial pressure and treatment of patient E. C., Negro males
aged 34. Patient discharged from hospital between second and third week of
treatment. See text for further details.

After two weeks in the hospital at bed rest, the blood pressure fell to 190/120
(Fig. 228). At this point Veriloid: an extract of Veratrum viride, was given and
the dosage increased from 2 mg. four times per day (after meals and at mid-
night) to 3 mg. four times per day. When the latter dosage was given the blood
pressure fell abruptly to 145/90 and remained at this level. After several days
the patient was discharged and returned to work, reporting daily for blood pres-
sure measurements. The blood pressure remained reduced despite return to
activity. The headaches had disappeared and complete reabsorption of exudates
was observed in the fundi.

Without the patient's knowledge a placebo was substituted and within three
days the blood pressure had risen to 190/120 and the headache had recurred.
On resuming the medication, the arterial pressure again fell to 145/95 and re-
mained at this level for a total of two months. However, at the end of that period
he developed several episodes of severe nausea and vomiting requiring slight
reduction in dosage and consequent moderate return of arterial pressure to


1748           FREIS, FINNERTY, WALSH

160/110. Therefore, the 200 mg. Meade-Johnson diet was given in addition, and
after two weeks the blood pressure had fallen to 140/95 and has remained ap-
proximately',`at this level for the past five months. When placebo was again
substituted for the Veriloid there was partial elevation of the arterial pressure
to 195/125 with a prompt fall on resuming medication. Frequent checks of the
chloride concentration in the urine indicate that he is maintaining the diet and
he has lost 20 pounds in weight. He is entirely asymptomatic, actively employed
and has no restrictions on his physical activities. The present dosage of Veriloid
is 3, 2,3 and 3 mg. daily without side effects.

CASE II. Severe Hypertension Treated at First with Vera&urn and Diet, Later
by Sympathectomy in Addition. A 42 year old former salesman was hospitalized
two and a half years ago because of increasing elevation of diastolic blood pres-
sure. Sympathectomy was not done at that time because of impaired renal func-
tion and persistent elevation of diastolic pressure at 140 mm. of mercury despite
sedation and hospital bed rest. There was a good response to crude Veratrum
viride (Vertavis) with fall in blood pressure to 180/110. The patient returned to
work but after several months the blood pressure rose to 200,020. He then was
given the 200 mg. low sodium diet in addition to Veratrum but with no further
fall in blood pressure. Ten months ago the arterial pressure rose to 230/130
despite Veriloid and low sodium diet and all attempts to increase Veratrum re-
sulted in repeated nausea and vomiting. Therefore, a lumbodorsal splanchnicec-
tomy was performed eight months ago. During convalescence from this operation
all medical treatment had been discontinued; within a month the patient devel-
oped hypertensive encephalopathy with marked elevation of blood pressure to
250/160 mm. of mercury, papilledema, and hemorrhages and exudates in the
optic fundi. Salt-free diet and Anatensol (Veratrum extract) were begun im-
mediately with good response. At present the patient is asymptomatic, back at
work, and the average blood pressure is 180/110 mm. of mercury. The only side
effect from Anatensol is occasional vomiting occurring about once per month.

This case is typical of other severe hypertensives in which high levels
of diastolic blood pressure returned despite combined drug and diet
treatment. Sympathectomy by itself was of less value than medical
treatment. However, following operation the patient again responded
well to drug and diet therapy.

A similar response has been noted so frequently in patients who have
been treated with drugs and diet before and after sympathectomy
that we decided to make a specia1 study of this phenomenon. A previous
study had indicated that the fall in blood pressure after an intravenous
injection of 400 mg. of tetraethylammonium in reactive patients was
significantly greater when these patients were taking sodium poor diets
than prior to such diets. lo We have given Veratrum, C-7337, and di-
hydroergocornine both alone and in various combinations. In responsive
subjects the combined hypotensive effects of the drugs were additive.
It also was apparent that in many cases the hypotensive action of non-
toxic doses of Veratrum viride extracts was greater after sympathectomy


SEVERE ESSEIVTL~t IIP PERTERSION        1749

than before and frequently also was more marked after the low sodium
diet than prior to its administration."

A PROGRAM FOR THE TREATMENT OF MALIGNANT HYPERTENSION

During the past eight months we have treated seven classical cases
of the malignant phase of essential hypertension. Two patients who
entered the hospital in severe uremia died several days after admission.
-411 of the remaining five patients have shown regression of papilledema
and a partial to complete remission of the malignant phase despite the
fact that four of these patients have marked impairment of renal func-
tion. It is admitted that the period,of follow-up has been too brief to
pass final judgment on the efficacy of treatment. However, sufficiently
impressive short-term results have been obtained to encourage us to
publish this regimen of treatment so that it may be evaluated by others.

The patient is hospitalized and given the Kempner rice diet. The
blood nonprotein nitrogen and urine chloride concentration are de-
termined every other day to be certain that critical salt depletion does
not occur. If the urine chloride concentration does not fall to extremely
low levels after a week of such treatment and the nonprotein nitrogen
rises, treatment with restricted diets is abandoned.

In addition to dietotherapy the patient is given Anatensol or Veriloid
in increasing doses as outlined above until side effects such as nausea
and vomiting or severe hypotension occur following which the dosage
is reduced to levels slightly below such toxic amounts. In addition, the
mixed dihydrogenated alkaloids of ergot (C. C. K. 179) are administered
intramuscularly in doses of 0.3 mg. twice per day. Since tolerance de-
velops to sympatholytic agents, after a week Priscolinc or C-7337 is
given in doses of 50 mg. four times per day by mouth. The following
week the dihydrogenated alkaloids of ergot are again substituted and
this rotation between Priscoline and these alkaloids continued in order
to forestall the development of tolerance.

Definite subjective and objective improvement begins to occur usually
within a week or two weeks. As the patient improves he will regain ap-
petite and the 200 mg. low sodium diet is'substitut,ed for the Kempner
regimen. Treatment with the sympatholytic drugs also may be discon-
tinued at this time. In three of our cases the total duration of hospitaliza-
tion was only three weeks.

It may be argued that such "shotgun" therapy does not permit the
evaluation of any single therapeutic procedure. However, in view of
the serious nature of the illness in these patients we did not feel justified
in withholding any treatment which might be beneficial. Further, the
effectiveness of each of the drugs may be evaluated at any time by sub-
stituting a placebo while the contribution of the diet may be estimated
by administering enteric coatecl tablets of sodium chloride,


1750

FREIS , FINIWRTY , WALSH

SUMMARY

The prognosis in stable benign hypertension usually is good, so that
only reassurance and symptomatic therapy are required. It is the pa-
tient with sustained high diastolic blood pressure who presents the great
problem in treatment.

Although no therapy has consistently produced lowering of arterial
pressure and clinical improvement, sympathectomy, diets extremely low
in sodium, and Veratrum extracts have produced moderate improve-
ment in a certain percentage of severe hypertensives. These various
forms of therapy do not provide a satisfactory solution to the problem
of treatment in the majority of patients but they are the best of the
available procedures and seem worthy of trial in properly selected pa-
tients as a means of prolonging their useful lives.

Recent data suggest that by combining these treatments the per-
centage of good results may be increased appreciably. However, in pre-
scribing a diet, the physician must make certain that sodium is being
avoided, while in prescribing the Veratrum alkaloids he must use equal
care and persistence in regulating dosage. Provided that the patient is
cooperative, such care and persistence not infrequently will be rewarded.

REFERENCES

1. Blood, D. W. and Perera, G. A.: Hypertensive Vascular Disease. Duration of
   Life in a Selected Series. Am. J. Med. 4:83, 1948.
2. Grollman, A. and Harrison, T. R. : Effect of Rigid Sodium Restriction on Blood
   Pressure and Survival of Hypertensive Rats. Proc. Sot. Exper. Biol. &
   Med., 60:52,1945.

3. Chapman, C. B. and Gibbons, T. B.: The Diet and Hypertension. A Review.
   Medicine 29:29, 1950.

4. KohBri-Kuchttrik, J. : The Effect of a War-Imposed Protein Free Diet on the
   Blood Pressure Level in Essential Hypertension. Am. J. M. SC. 219:27,
    1950.

5. Brozek, J., Chapman, C. B. and Keys, A.: Drastic Food Restriction. J.A.M.A.
   197:1569,1948.

6a. Freis, E. D. and Stanton, J. R.: A Clinical Evaluation of Veratrum Viride in
   The Treatment of Essential Hypertension. Am. Heart J. 56:723,1948.
6b. Freis, E. D., Stanton, J. R. and Moister, F. C.: Assay in Man of the Chemical
   Fractions of Veratrum Viride, and Identification of the Pure Alkaloids
   Germitrine and Germidine as Potent Hypotensive Principles Derived
   from the Drug. J. Pharmacol & Exper. Therap. 98:166, 1950.
7. Wilkins, R. W., Stanton, J. R. and Freis, E. D.: Essential Hypertension.
   Therapeutic Trial of Veriloid, a New Extract of Veratrum Viride. Proc.
   Sot. Exper. Biol. & Med. 72:302, 1949.

8. Wilkins, R. W. : Veratrum Viride and Essential Hypertension. New England
   J. Med. 2..$2:535, 1950.

9. Meilman, E. and Krayer, 0.: Clinical Studies on Veratrum Alkaloids. I. The
   Action of Protoveratrine and Veratridine in Hypertension. Circulation
   1: 204, 1950.

10. Stead, W. W., Reiser, M. F., Rapoport, S. and Ferris, E. B.: The Effect of
   Sodium Chloride Depletion on Blood Pressure and Tetraethylammonium
   Chloride Responses in Hypertension. J. Clin. Investigation, 27:766, 1948.
11. Freis, E. D. and Finnerty, F. A., Jr.: Unpublished observations.