Hypertension: A controllable disease

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

It is an especial pleasure for me to re-
ceive this award which honors Dr. Oscar
B. Hunter whose name and reputation is
so well known and well respected in my
home city of Washington, D. C.

My first experience with antihyperten-
sive drug treatment was in 1946, when as
a research fellow at the Evans Memorial
Hospital in Boston, I used the antimalarial
drug pentaquine to treat malignant hyper-
tension and other forms of severe hyper-
tension. Dr. Smithwick was chief of sur-
gery there at that time and I was referred
the patients whom he rejected for his
operation of lumbodorsal sympathectomy.
In doses larger than those used in the
treatment of malaria, pentaquine exhibits
sympathetic blocking activity. Although it
was fairly toxic in these doses and had a
number of disagreeable side effects in-
cluding methemoglobinemia, pentaquine

Presented as the Eighteenth Oscar B. Hunter Memorial
Award Lecture in Therapeutics at the Seventy-third Annual
meeting of the American Society for Clinical Pharmacology
and Therapeutics, March 9-10, 1972, Houston, Texas.

*Senior Medical Investigator, Veterans Administration

Hospital and Professor of Medicine, Georgetown University,
Washington, D. C.

did reduce the blood pressure effectively
in some of these patients.” It was exciting
to see that along with the reduction of
blood pressure there was clearing of hem-
orrhages, exudates, and papilledema in the
optic fundi and disappearance of the mani-
festations of malignant hypertension except
for the uremia.

At that time the accepted theory indi-
cated that hypertension was a manifesta-
tion of a generalized disease. It was not
thought that the hypertension could in
itself be the cause of end-organ damage.
Therefore, it was not considered rational
that reduction of blood pressure would
favorably affect the course of the disease.
Antihypertensive therapy was scornfully
referred to as treating the manometer
rather than the patient. A reason for under-
rating the importance of the blood pres-
sure was the very poor understanding of
the lability of blood pressure. It was as-
sumed that the blood pressure exhibited
by an anxious patient made more appre-
hensive by a visit to the physician was
representative of the blood pressure exist-
ing at all times in that individual. Thus,
there seemed to be no direct correlation

627
628 Freis

between level of blood pressure and pres-
ence of end-organ damage. In those days
I frequently heard the comment, “You
know, I have a patient who is now 80
years old. She has had a blood pressure
of 230/130 for the past 25 years and she is
still quite well and probably a good deal
happier than if she had been taking one
of your drugs.” It was not mentioned that
during the course of a hospitalization the
blood pressure of this patient fell to 130/
80 shortly after admission; the latter read-
ing probably was closer to her average
blood pressure. Also physicians tended to
forget the many other patients with per-
sistently high levels of blood pressure who
had developed complications and had
died.

Meanwhile, I kept running across other
evidence that strengthened my conviction
that it was the elevation of blood pressure
per se which caused target organ damage.
For example, severe pulmonary hyperten-
sion such as results from a widely open
ventricular septal defect was associated
with sclerosis of the pulmonary arterioles.
In Goldblatt’s hypertension, Wilson and
Pickering’*® and Wilson and Byrom?
showed that nephrosclerosis developed in
the opposite kidney exposed to the high
pressure, while the kidney with the clamp
on the renal artery was relatively protected
from such damage. I recall being told of
a patient who developed hypertensive neu-
roretinopathy in one eye and not in the
other. Later it was found that the carotid
artery was occluded on the side which
remained normal. Coarctation of the aorta
results in left ventricular hypertrophy and
dilatation but does not cause nephrosclero-
sis, Thus, both the vascular and cardiac
manifestations of hypertension seemed to
be the direct result of an elevated blood
pressure.

It was a good example of how wrong
traditional medical thinking can be and
still be well enough entrenched to resist
obvious clinical and experimental evidence
to the contrary. Medical opinion is most
dangerous when it is most respectable.

Clinical Pharmacology
and Therapeutics

The Osler tradition of therapeutic nihilism
was very popular. It was respectable to
diagnose. It was not respectable to treat
unless one knew the cause, and medical
opinion would not entertain the possibility
that the cause of hypertensive complica-
tions was the hypertension itself. Oddly
enough, it was considered respectable to
lower the elevated blood sugar in diabetes,
although the evidence now indicates that
this is not useful in preventing the vas-
cular disease associated with diabetes. It
should be noted that controlled clinical
trials were required to destroy both of
these false conceptions, one in hypertension
and the other in diabetes.

Another refutation of traditional thinking
became clear to me as a greater variety
of antihypertensive drugs became avail-
able for testing. Since hypertension is
characterized by an increased peripheral
resistance, I thought it was important to
find drugs which lowered blood pressure
by dilating the peripheral arterioles. How-
ever, as we studied the hemodynamic and
clinical effects of various antihypertensive
agents we found that it did not appear to
make much difference therapeutically how
the blood pressure was reduced. For ex-
ample, we found that ganglion blocking
drugs reduced cardiac output but not
total peripheral resistance.’ Yet, ganglion
blocking drugs were as effective if not
more effective in reversing the manifesta-
tions of malignant hypertension than hy-
dralazine which was a classical example
of a peripheral vasodilator.’ It became in-
creasingly clear that the key element
therapeutically was to bring the blood
pressure down. The mechanism by which
it was reduced was not all important. It
was important, however, that the drug be
effective in lowering blood pressure and
that it be relatively free from severe side
effects.

Peripheral vasodilators, in fact, had an
inherent disadvantage. Since they did not
affect the cardiac sympathetics, the latter
were reflexly stimulated by the fall in
blood pressure through the baroreceptor
Volume 13
Number 5, Part 1

mechanism. As a result, heart rate and
myocardial contractility increased. This not
only made patients feel uncomfortable,
but also partially nullified the antihyper-
tensive effect of the vasodilator drug.

As a result of such experiences, I be-
came increasingly convinced that the most
effective way to treat hypertension was to
use combinations of drugs. Blood pressure
normally is controlled by a variety of
mechanisms. These mechanisms include
first, the inherent or autonomous tone of
the arteriolar smooth muscle; second, the
integrative activity of the sympathetic ner-
vous system acting over the entire cardio-
vascular system including not only the
arterioles but also the heart and veins;
and, third, the fluid balance of the body
is important in that an excess of extra-
cellular and plasma volume tends to raise
blood pressure while dehydration tends to
lower it.

The thiazide diuretics represented a
most important advance in antihyperten-
sive drug therapy because they were not
only antihypertensive in themselves but
by depleting extracellular volume also
greatly increased the responsiveness of the
patient to other antihypertensive agents,
thereby permitting lower and less toxic
doses of the latter drugs.* In some patients
it may be necessary to affect all of these
mechanisms using in combination, a diu-
retic, a peripheral vasodilator, and a sym-
pathetic inhibitor. The combination of
chlorothiazide, hydralazine, and reserpine
is an example of this approach.

The final proof of the effectiveness of
antihypertensive drug treatment in pre-
venting end-organ damage in benign es-
sential hypertension as well as in malig-
nant hypertension was provided by the
controlled therapeutic trial carried out
by my colleagues and me in the Veterans
Administration study.” ® Very briefly, this
study was a prospective, randomized,
double-blind trial, comparing drug and
placebo treatment in male hypertensive
patients with persistent diastolic elevations
between 90 and 129 mm Hg. The inci-

Hypertension 629

dence of hypertensive complications such
as stroke, congestive heart failure, acceler-
ated hypertension, progressive renal dam-
age, and dissecting aortic aneurysm was
greatly reduced in the drug-treated as
compared to the placebo-treated group.
Only the incidence of myocardial infarc-
tion appeared to be unaffected although
even here fatalities due to coronary artery
disease seemed to be less in the drug-
treated group.

The VA trial was of great significance
in erasing any lingering doubts concerning
the therapeutic value of antihypertensive
drug treatment. Also, although long-term,
large-scale cooperative trials in outpatients
are difficult to accomplish, the VA study
demonstrated that it is possible to use this
technique successfully to demonstrate the
value of an effective form of treatment.
To be successful, however, in my opinion
rigorous selection of adherent patients is
essential. Also, careful planning and per-
sistent effort are required to assure suc-
cess. Long-term cooperative trials are the
most difficult but they also may be the
most rewarding of all experimental pro-
cedures in medicine. They are evolving
into a powerful tool for settling important
therapeutic questions.

Before concluding, I would like to pre-
sent some current work which is related
to the general field of antihypertensive
agents. However, in this instance they are
used as experimental tools to explore the
nature of congenitally transmitted hyper-
tension. As you know, essential hyperten-
sion is a strongly inherited characteristic.
Recently, the Japanese have developed a
strain of rats in which the hypertension is
congenitally transmitted. As these rats
approach adult life they begin to develop
hypertension which becomes progressively
more elevated with the passage of time.
Blood pressures are higher in males than
females and after one year of age the
former begin to die off from the compli-
cations of hypertension. The Japanese have
called this model of essential hypertension
the spontaneous hypertensive rat (SHR).
630 Freis

When these animals became available
in this country, I became interested in de-
termining whether the progressive hyper-
tension of the SHR could be modified by
antihypertensive drug treatment. For some
time I had been impressed by an apparent
modification of the severity of hypertension
following drug treatment in patients. I had
the clinical impression that in some pa-
tients the hypertension became less severe
after a prolonged period of effective anti-
hypertensive treatment. The availability of
the SHR seemed to present an ideal op-
portunity to study this aspect of hyperten-
sion under controlled conditions.

Our first experiment was with an excess
of salt.! The drinking water was replaced
with one per cent salt solution. Excess salt
administration was begun when the rats
were 3 months old and continued for a
period of 5 months. Blood pressure mea-
sured in the tail by the plethysmographic
method indicated a steeper rise of blood
pressure in the salt-treated animals, and
after 4 months several already had died
of malignant hypertension.

In our next experiments we treated the
SHR with antihypertensive drugs. Pre-
liminary experiments indicated that a mix-
ture of chlorothiazide, reserpine, and
hydralazine dissolved in the drinking water
was extremely effective in reducing the
blood pressure and did not seem to ad-
versely affect the well-being of the ani-
mals,

Beginning at 3 months of age, we ran-
domly selected from the same litters a
group of the SHR which were treated
and another group of controls who re-
mained untreated. At 3 months of age the
systolic blood pressures of the 2 groups
were similar, averaging about 130 mm. Hg
in each group. Treatment with antihyper-
tensive agents was continued for 6 months
and then was abruptly discontinued. Dur-
ing the treatment period the blood pres-
sure fell and at the end of the 6 months
averaged 92 mm. Hg. By contrast the
blood pressure of the control group rose
gradually to a level of 160 mm. Hg at the
end of the 6 month period.

Clinical Pharmacology
and Therapeutics

At that time, when the rats were 9
months of age, treatment was stopped and
the blood pressure of the treated animals
rose abruptly but not to the level of the
controls. Rather it rose to the same level
as had existed when the treatment was
started 6 months previously. Following
this rapid elevation, the blood pressure
rose gradually over the succeeding 4
months at the same rate and to the same
level as the controls exhibited when they
were progressing from 3 to 7 months of
age. Thus, at 13 months of age (4 months
after discontinuing drugs) the blood pres-
sure of the previously treated rats was ap-
proximately 150 mm. Hg which is the
same as the blood pressure of about 150
mm. Hg exhibited by the controls when
they were 7 months of age.

These results could not be ascribed to
poor condition of the treated animals.
Both groups gained weight at the same
rate throughout the experiment and the
treated rats were active, alert, and in ap-
parently excellent health throughout.

What is the significance of these ex-
periments?

First, they indicate that the hypertension
is not dependent upon any biological
changes associated with aging per se.
When the treatment was stopped the blood
pressure did not rise to the level of the
controls, which would have been the case
if the hypertension was an age-dependent
process. Rather it rose to the level that
had existed prior to treatment, 6 months
previously, when the rats were 3 months
of age. Six months in the life of a SHR is
equivalent to about 20 years in the life of
man, and during this period the rats had
progressed from young adulthood to mid-
dle age. This form of hypertension, there-
fore, appears to be a_ time-dependent
rather than age-dependent process. Over
time the blood pressure builds gradually
on the previous base somewhat in the
fashion that coral builds upon itself by
gradual increments to form a reef.

Second, while the hypertension is ge-
netically determined the rate of blood pres-
sure increase is greatly influenced by en-
Volume 13
Number 5, Part 1

vironment. An excess of salt will acceler-
ate the process dramatically. On the other
hand, progression of the hypertension can
be completely arrested for the duration
of antihypertensive drug treatment. There-
fore, the course of the disease can be in-
fluenced by modifying environmental fac-
tors. Thus, both genetic and environmental
factors are important in determining the
severity of this form of hypertension.

The animals were sacrified when they
were 13 months of age. At this time the
average blood pressure of the control SHR
had reached 185 mm. Hg. Many of these
control animals exhibited end-organ dam-
age in the heart, kidneys, and mesenteric
arteries. The left ventricle was hyper-
trophied and showed small infarcts with
areas of myocardial necrosis and fibrous tis-
sue replacement. The kidneys showed ne-
phrosclerotic changes, focal pyelonephritis,
and in some cases fibrinoid necrosis of
arteries and arterioles. The mesenteric
arteries exhibited segmental areas of
fibrinoid necrosis and extensive infiltration
of the wall with inflammatory cells and
fibroblasts. This resulted in a nodular or
beaded appearance of the arteries resem-
bling periarteritis nodosa.

In striking contrast none of these patho-
logical changes were seen in the treated
animals. At the time of sacrifice, the blood
pressure of these animals averaged only
150 mm. Hg and apparently this was not
high enough to result in end-organ dam-
age. Thus, in these SHR, as well as in
experimentally induced hypertension,® *° it
is apparent that the pathological changes
are the result of the hypertension and can
be entirely prevented by effective antihy-
pertensive therapy.

In the past, it has been considered es-
sential in the understanding and treatment
of any disease that we determine first
the nature of the primary pathogenetic
mechanisms. In infectious diseases, for ex-
ample, the approach has been to identify
an organism and, by Koch’s postulates,
prove that it is the cause of the disease.
Once the organism. has been isolated, bio-
chemical agents can be found which will

Hypertension 631

kill or arrest the multiplication of the caus-
ative microorganisms. Such a classical ap-
proach has been applied unsuccessfully to
hypertension and to other disorders for
many years. In hypertension the primary
pathogenetic mechanism has been sought
in the kidney, in the adrenals, and in the
autonomic nervous system. While these ex-
tensive efforts on the part of many indi-
viduals have given us a better understand-
ing of the physiological control of blood
pressure and have been helpful in under-
standing some unusual froms of hyperten-
sion, they have not revealed the cause of
essential hypertension nor have they been
particularly helpful in the treatment of the
majority of patients.

The results I have summarized today
indicate that considerable progress also
can be made if we set for ourselves a
somewhat less ambitious goal. When the
ultimate cause of a disease is obscure and
there are no immediate prospects of dis-
covering such a cause, we still can profit
by devoting considerable effort to investi-
gating, understanding, and controlling the
consequences of the disease. In essential
hypertension, the ultimate cause or causes
remain unknown but the pathological con-
sequences are the result of the elevation
of blood pressure. Efforts at controlling
the latter have paid off dramatically while
basic research into ultimate cause is still
largely frustrated.

A similar approach can be used in other
important diseases, such as atherosclerosis.
The cause of the basic lesion in athero-
sclerosis is poorly understood. Probably
there is a basic injury to the vascular wall
that we do not understand and cannot
control. Yet, there also is considerable evi-
dence that the severity and rate of devel-
opment of atherosclerosis is related to the
serum cholesterol concentration and to
the level of blood pressure. Much more can
be done to clarify the effects of these ad-
verse influences and to test the effectiveness
of modifying them in arresting the develop-
ment of atherosclerosis. I have little pa-
tience with the purists who seek vainly for
the needle in the hay stack looking exclu-
632 Freis

sively for ultimate causes. This is scientific
snobbery. The primary responsibilities of
medicine are to cure the sick and to pre-
vent disease. In medical research we must
work with the most promising leads we
have and by so doing important progress
will be made. I am not against the attempt
to fulfill Koch’s postulates as a useful step
in finding effective treatment in all dis-
eases, but it seems foolish to rigidly and
exclusively adhere to such a purist’s ap-
proach when more promising avenues of
therapeutic investigation which are equally
valid may be lying readily at hand.

References

1, Barsanti, J. A., Pillsbury, R. C., III, and Freis,
E. D.: Enhanced salt toxicity in the spon-
taneously hypertensive rat, Proc. Soc. Exp.
Biol. Med. 136:565-568, 1971.

2. Freis, E. D., and Wilkins, R. W.: Effect of
pentaquine in patients with hypertension, Proc.
Soc. Exp. Biol. Med. 64: 455-458, 1947.

3. Freis, E. D., Ros, J. C., Partenope, E. A., et
al.: The hemodynamic effects of hypotensive
drugs in man. JJI. Hexamethonium, J. Clin.
Invest. 32:1285-1298, 1953.

Clinical Pharmacology
and Therapeutics

4, ¥Freis, E. D.: Mechanism of the antihyper-
tensive effects of diuretics. Possible role of
salt in hypertension, Ciin. PHanMaco., THER.
1;:337-344, 1960.

5. Johnson, R. L., Freis, E. D., and Schnaper,
H. W.: Clinical evaluation of 1-hydrazin-
ophthalazine (D-5968) in hypertension with
special reference to alternating treatment with
hexamethonium, Circulation 5:833-841, 1952.

6. Okamato, K.: Spontaneous hypertension in
rats, Int. Rev. Exp. Pathol. 7:227-270, 1969.

7. Veterans administration Cooperative Study
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treatment on morbidity in hypertension: Re-
sults in patients with diastolic blood pressures
averaging 115 through 129 mm. Hg, J. A. M. A.
202:1028-1034, 1937.

8. Veterans administration Cooperative Study
Group on Antihypertensive Agents: Effects of
treatment on morbidity in hypertension: Re-
sults in patients with diastolic blood pressure
averaging 90 through 114 mm. Hg, J. A. M. A.
213:1143-1152, 1970.

9. Wilson C., and Byrom, F. B.: Renal changes
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10, Wilson, C., and Pickering, G. W.: Acute

>

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hypertension, Clin. Sci, 3:343-355, 1938.