The Modern Management
OF HYPERTENSION

       BY
    Dr. Edward D. Freis
  Senior Medical investigator
  VA Hospital, Washington, D.C.

VETERANS ADMINISTRATION - WASHINGTON, D.C. 20420 - JANUARY 1973

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INTRODUCTION

The high prevalence of hypertension in our veteran population makes it a disease of major importance.
Through our vast facilities for delivery of quality medical care, we can make an important contribution to the
prevention of the major complications of hypertension in this country.

A number of surveys (l-3), some of them house-to-house in various sections of the country, and amongst
different socio-economic groups, have indicated that only about 50 percent of hypertensives know that they have
hypertension. Of this percentage, only half were receiving treatment at the time of the survey, and only roughly
half of them were being adequately treated, that is, their blood pressures were being well controlled. The most
recent survey amongst employees of large business concerns in Chicago found that only 11 percent of such
patients were receiving effective treatment (3).

What are the reasons for this sad state of affairs? The major reason is that the bulk of physicians have remained
unconvinced that the treatment of hypertension justifies the associated side effects, expense, and inconvenience.
There also is a highly prevalent notion that hy~rtension does not require continuous survei~~ce or control.
Patients with hypertension feel well until major complications develop. It is difficult to convince them that they
need to take daily medications which may, for a time at least, make them feel less well than they were before. It
takes the physician's time and effort to educate and motivate his patients, and his time is already heavily
committed to more acute and pressing treatment problems.

EPIDEMIOLOGY

Hypertension is one of the most ubiquitous of diseases. The National Health Survey of 1962 (4) was
representative and extensive enough to permit a fairly reliable estimate of the prevalence of hypertension in the
United States. From these data we know that there are appro~mately 23 million persons in this country (roughly
one in every 10) who have a systolic Mood pressure of 1.50 or higher, or a diastolic of 95 mm. Hg. or higher. The
physician in family practice, therefore, is constantly coming into contact with patients with hypertension. If all
of them were carefully and continuously followed, a major portion of his time would be taken up with the
treatment of patients with hypertension.

Medical tradition with respect to benign essential hypertension has been characterized by therapeutic nihilism.
The word `benign" often was taken literally. It was not conceded that ant~ypertensive drug treatlnent could
prevent the development of cardiovascular complications. Antihypertensive drugs were looked upon as only
"symptomatic" treatment, since the cause of essential hypertension remains unknown. The drugs were considered
to be nonspecific hypotensive agents. Traditional thinking in therapeutics, largely conditioned by the success of
chemothera~utic agents in the treatment of infectious diseases, has emphasized the "magic bullet" concept. Find
the cause and this will lead you to a specific cure.

Unfo~unately, the cause of essential hype~ension is likely not to reside in a single biochemical defect which
will be correctable by chemotherapy. The cause of essential hypertension is as mysterious as it ever was. In the
early stages of the disease no detectable abnormalities can be found other than the the elevated blood pressure. In
fact, Pickering has advanced a strong argument that blood pressure in the population is a continuum. When the
frequency distribution of the various blood pressure levels is plotted, a monophasic curve is formed, with a slight
skew to the right, indicating the hypertensive population. If there was a separate disease-hypertension- one
would expect to see evidence of two peaks in the distribution, the first being the normal population and the
second, or the right hand side of the dist~bution curve, representing the hy~rtensive population. Since the curve
is monophasic, Pickering feels there are no separate hypertensive and normotensive populations (5). In this sense,

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hypertension is a disorder of regulation, and the point where normality leaves off and the disease hypertension
begins, is wherever we choose to put it on the range of blood pressure values found in the general population.

Epidemiofogy of Hypertension

The consensus of Io~gitu~naI studies in population groups indicates that blood pressure rises with age (6). Miall
and Love11 (7) found that the change is related to the blood pressure level in youth, the higher the initial pressure
the greater the increase with age. These results were not corroborated, however, in the Framingham data (8),
where the tendency for the bfood pressure to rise with age was not correlated with the initiaf blood pressure level.

In cross-sectional population surveys, systolic pressure rises up to approximately age 50, and then appears to
level off (9). This tends to agree with Perera's observations that diastolic hypertension generally appears in the
thirties, and rarely does the onset begin after age 50. Blood pressure tends to be lower in females than in males,
up to age 55, and then crosses over, becoming higher than in males.

Blacks have higher systolic and diastolic blood pressures, on the average, than do whites (9,10). The prevalence
of enlarged hearts, as manifested by X-ray and electrocardiographic abnormalities, also was found to be higher in
blacks, the National Health Survey of 1962, and the death rate from hypertension, particularly in the 30 to 50
year age group, is threefold higher in blacks than in whites (11). In fact, hypertension is the leading cause of
death amongst blacks. It has been said that for every black patient who dies of sickle ceI1 disease, at least 100 die
from hypertension.

The effects of occupation and physical activity on the incidence of hypertension and of stress related to
occupation, are controversial. The results of various surveys are contradictory. There does appear to be an inverse
correlation, however, between level of education and hypertension, the lowest average blood pressures being
found in the more highly educated population groups (12).

Both cross-sectional and longitudinal surveys have consistently demonstrated a correlation between body build
and blood pressure (9,13). The heavier individuals tend to have the higher levels of blood pressures. Also, in
longitud~n~ studies, gain in weight with age was directly related to increase in blood pressure. The converse also
was true in the Framingham study (14), with lower pressures among those who lost weight Such association, of
course, does not prove cause and effect. Dahl found, contrary to popular medical opinion, that reduction of
weight had no effect on reducing the blood pressure of hypertensive patients, unless the salt intake also was
sharply restricted (15).

It has been well demonstrated, in susceptible strains of rats, that a high sodium intake will aggravate
hypertension, and produce a greatly increased incidence of cardiovascular complications (16). In man, diets very
tow in sodium (under 200 mg. per day; such a diet imposes special salt-free bread, milk, and no addition of salt in
cooking) will lower the blood pressure of hypertensive patients. However, diets less severely restricted in sodium
have not been shown to exert an antihypertensive effect. The presently popular "treatment" for mild and
moderate hypertension of telling the patient to "quit eating salt," or a limitation to 3 grams of salt daily, has no
demonstrated antihypertensive efficacy. As an investigator working in the era prior to the advent of
antihypertensive agents, I well remember that only the most rigid restriction of sodium intake had any effect on
blood pressure.

The epidemiological data on salt intake and blood pressure are controversial. In a northeast maritime province
of Japan where the salt intake appro~mates 30 gm. per day, the incidence of severe hypertension and stroke is
said to be very high (17). While Dahl found a positive correlation between sodium intake and level of blood
pressure (18), the other surveys failed to find such a relationship (19-20). While it is clear that excessive sodium
intake aggravates hyperten~on in rats, it is not established that the same relationship holds in man, except in the
presence of renal failure.

This author believes that the primary factor relating salt to hypertension is the extracellular volume, including
the plasma voiume. Sodium is important in hypertension because it is the major determinant of extracellular fluid
volume. An excess of salt in the diet can be handled by the normal human kidney, without expanding the
extracellular fluid volume. However, in renal failure, even a moderate sodium intake expands this space, and
hypertension is aggravated. Conversely, when and only when. sodium is restricted in the diet to the point of

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shrinking the ECF, will there be a significant fall in blood pressure in man. The experimental evidence supporting
this view is too lengthy to go into in this paper, but it is also consistent with our current knowledge of the
antihypertensive action of oral diuretics.

A positive correlation between cigarette smoking and level of blood pressure has not been demonstrated
(9,19,20), despite the fact that the immediate effect of smoking is often to raise blood pressure and heart rate
transiently. The same is true of psychological stresses which raise blood pressure acutely, as there is no evidence
to indicate that the frequent repetition of such stresses can raise the general level of blood pressure or cause
hypertension. Both cigarette smoking and psychic stress can be regarded as transient aggravating factors, and as
such are probably best avoided by hypertensive patients. In addition, cigarette smoking aggravates atherosclerosis,
and in combination with hypertension, greatly increases the risk of atherosclerotic complications, particularly
coronary artery disease.

An interesting positive correlation has been observed between blood glucose and blood pressure, which is
independent of the effects of age, body build, and race (21). This study confirms a clinical impression that
diabetes mellitus and hypertension are often associated.

The National Health Survey found a surprisingly high prevalence of cardiomegaly, by chest X-ray or
electrocardiogram, even with mildly elevated blood pressure (12). Long term followup of mildly hypertensive
patients revealed that 50 to 80 percent developed enlarged hearts (22). Life insurance data indicate a 50 percent
increase in mortality over a 20-year period, in male patients age 35-45 with casual systolic pressures of 140 and
diastolics of 90 mm. Hg. (23). This risk increases to 100 percent when the initial blood pressure is 145/95, and to
200 percent when the pressure is 160/l 00.

Most studies have indicated that morbidity and mortality rates are about twice as high in men as in women
(22,23). This is especially pertinent to our veteran population. While the natural history of hypertension is
extremely variable in different patients and in the two sexes, Perera has estimated from his data that the average
duration of life following the appearance of diastolic hypertension C, 89 mm. Hg.) is about 20 years.

PATHOLOGY AND PATHOGENESIS OF LESIONS

The characteristic lesions of hypertension are found in the arterioles, and the type of lesion varies with the
severity of the hypertension. When the diastolic blood pressure is persistently elevated at levels of 130 to 150
mm. Hg., or higher, fibrinoid necrosis of the media of the arterioles is seen in the kidney, spleen, pancreas, and
brain, including the retinal vessels. The subsequent softening of the wall results in passage of transudates ("cotton
wool" exudates in the optic fundi) and hemorrhage, both into the wall and through the wall. The vessel may
thrombose, particularly in the afferent arterioles of the kidney, resulting in ischemic necrosis of glomeruli. Both
focal or generalized edema of the brain may occur, leading to the neurological manifestations associated with
acute hypertensive encephalopathy.

Fibrinoid necrosis represents a reaction of the arteriolar smooth muscle to the presence of a severely elevated
blood pressure. In experimental renal vascular hypertension produced by constricting one renal artery, fibrinoid
necrosis develops in the opposite kidney which is exposed to the elevated blood pressure, whereas, in the kidney
which is perfused by the lower blood pressure because of the constriction, such lesions are not found (24).
Similar observations have been made in patients with renovascular hypertension due to disease in one of the main
renal arteries. In experimental animals and probably in patients with malignant hypertension, fibrinoid necrosis is
arrested when the blood pressure is reduced with antihypertensive agents (2,5). Thus, it is clear that fibrinoid
necrosis is the result, rather than the cause, of malignant hypertension,

Fibrinoid necrosis may be caused by prolonged vasospasm. In rats with renovascular hypertension, Byrom
viewed the meningeal arterioles through "plexiglass" windows inserted into the skull, (26). When the blood
pressure became severely elevated, Byrom observed segmental spasm of the arterioles which was so marked that
the lumina were almost entirely eliminated. When the clip on the renal artery was removed, the blood pressure
fell and the spasm was relieved. It is easy to see that if such severe spasm is long sustained, necrosis of that
segment could result.


While fibrinoid necrosis of the arterioles represents a reaction to severely elevated blood pressure, the response
to a moderate but long sustained increase in blood pressure (diastolic 95 to 130) is hyalinosis and hyperplasia of
the media of the small arteries and arterioles, and even of some medium sized arteries, such as the arcuate arteries
of the kidney. The media of the vessels become greatly thickened (hypertrophy) by hyperplasia of the smooth
muscle. An increase in hyaline also can be detected by special stains.

The thickening of the wall leads to progressive narrowing of the lumina of these small vessels. In the kidney,
which requires a high blood flow, there is a gradual but progressive loss of functioning nephrons secondary to
ischemia. This nephron loss produces a characteristic finely granular appearance of the cortical surface. This
process of nephrosclerosis is manifected in both "benign" and malignant forms. When the diastolic blood pressure
is very high, fibrinoid necrosis is predominant, and the pathological process is called malignant nephrosclerosis.
When malignant hypertension evolves from a preceding essential hypertension, or in any situation in which it is
superimposed on a chronic hypertensive process, a mixture of lesions is seen in the kidney, with both fibrinoid
necrosis in some vessels and extensive and severe hyperplasia of other arterioles, as well as small and medium size
arteries. In the renal arteriogram, the finer arborizations of the arterial circulation cannot be visualized because of
the marked narrowing of the lumina of the arcuate arteries, the contrast material appearing to stop short of the
cortex of the kidney. In so-called benign essential hypertension, with lower diastolic blood presseures, only
hyalinonis and hyperplasia are seen, which is confined to the arterioles and small arteries.

The arteries of the brain are thin walled, with minimal medial coat. Under the stress of an elevated blood
pressure, a segment of the wall may give way and develop an aneurysmal dilation. The resulting microaneurysms
are commonly found in hypertensive patients above the age of 45. They increase in number with aging, in the
presence of hypertension. The weakened wall may rupture, producing cerebral hemorrhage, or the aneurysm may
thrombose. Microaneurysms are particularly prevalent in the internal capsule, where cerebral hemorrhage or
thrombosis occurs most frequently.

The aorta and large central arteries dilate in response to the increased wall stress produced by the
hypertension. Eventually, the wall of the vessel loses its compliance and becomes a distended, stiff-walled tube.
The area most affected by this stress is the proximal aorta, probably because its wall contains more elastic than
smooth muscle tissue, and is therefore unable to resist the stress. The excessive distention of the proximal aorta
probably pinches shut the nutrient small vessels entering from the adventitia. Therefore, in severe hypertension,
necrosis of the media of the proximal aorta may occur and may be followed by a tear, resulting in dissection
along the plane of the media; a dissecting aneurysm.

It is well known that hypertension and atherosclerosis often are associated. Although they represent two
separate disease entities, it is apparent that the presence of hypertension accelerates and aggravates the
development of atherosclerosis (27). The mechanism by which this occurs has not been clarified. However, it
seems likely that the damage produced by the hypertension makes the artery more susceptible to the formation
of atherosclerotic plaques. Prolonged and excessive stretching of the wall of the large arteries produces
fragmentation of the elastic fibers and an increase in hyaline connective tissue. The mucopolysaccharide content
of the vessel wall also is said to be increased. Loss of wall compliance and the changes in wall structure may well
result in an increased susceptibility to plaque formation.

There are many "experiments of nature" which demonstrate the causal relationship between the elevation of
blood pressure, per se, and the development of atherosclerosis (27). In chronic, severe pulmonary hypertension,
such as occurs with large interventricular septal defect, atherosclerosis develops in the pulmonary arteries,
whereas, it never occurs in this system when the pulmonary blood pressure is normal. In the aorta, atherosclerosis
usually is more severe in the abdominal portion, but with coarctation of the aorta, atherosclerosis predominates
in the proximal aorta, that is, in the region of the elevated blood pressure. In the congenital anomaly in which
one coronary artery is derived from the low pressure pulmonary circulation and the other from the much higher
pressure systemic circulation, atherosclerosis is found only in the latter.

Even slight elevation of blood pressure is associated with increased atherosclerosis. Because of coronary artery
involvement, there is an increased risk of myocardial infarction and "sudden death." Data obtained from the
"Pooling Project," of the Council on Epidemiology of the American Heart Association, indicated that in the age
group between 30 and 39 years of age, individuals with a casual diastolic blood pressure of 85-94 mm. Hg. have
five times the risk of developing major coronary events, as compared to those with diastolics below 85 mm. Hg.
The difference is not so great in older age groups, or in elevations of blood pressure to the 95-104 range.

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However, above 104 mm. Hg., the risk of coronary events again increases steeply. These data indicate that even
borderline hypertension in 30 to 40-year-olds carries a serious prognostic import.

Atherosclerosis of cerebral arteries is a major cause of stroke, particularly in elderly patients with mild and
moderate hypertension. Microaneurysms probably are more important in the stroke, developing in the presence
of moderately severe to severe hypertension. The incidence of stroke increases progressively with slight elevations
of blood pressure, in all age groups. According to the Framingham Study, the incidence of stroke is more than
one and one-half times higher with diastolic blood pressure levels of 90-94, as compared to diastolic levels of
80-84 in the age range between 45 and 64 years of age, and is about three times as high with diastolic levels of
loo-104 mm. Hg.

Because of the great emphasis on coronary heart disease and stroke in recent years, it is generally overlooked
that congestive heart failure is an important cause of disability and death, and that hypertension is by far the
principle culprit in its pathogenesis. In the Framingham Study, hypertensives developed congestive heart failure
six times more frequently than normotensives. Congestive heart failure was a lethal phenomenon in this
population, with only 50 percent surviving beyond 5 years.

"CURABLE" HYPERTENSION

Entirely too much emphasis has been placed on the identification and treatment of curable forms of
hypertension. The impact of extensive diagnostic work-up of patients for curable hypertension on reducing
morbidity and mortality in the general hypertensive population has been minimal. Physicians working in large
teaching centers study a referred and selected sample of the hypertensive population, which causes them to
overestimate the actual prevalence of curable hypertension. It is important to note that secondary forms of
hypertension, including renovascular hypertension, were not observed in the Framingham population. The true
prevalence of curable hypertension in the total population of hypertensive patients probably is less than 5
percent, and may well be as small as 1 percent.

Another important consideration is that complete cure is by no means always obtained by surgical
intervention, nor is the operative morbidity and mortality negligible. In renovascular hypertension particularly, it
is not possible to predict either cure or freedom from serious postoperative complications. The most clear-cut
benefits of surgery result from repair of coarctation of the aorta, if diagnosed early enough, and from removal of
a solitary phenochromocytoma. The diagnosis of primary aldosteronism is difficult to establish, and 5-year cure
from removal of an adenoma is still not clearly defined.

The routine application of an elaborate, time consuming and expensive work-up for curable forms of
hypertension in every patient, is an example of poor medical judgement. The search for curable hypertension
should be individualized, principally to patients below age 35, those above this age who fail to respond to medical
treatment, those who have had a recent increase in the severity of their hypertension, or those who give a
suggestive history of such events as paroxysmal hypertension.

Simple routine tests for curable hypertension include the chest X-ray, to disclose notching of the ribs,
characteristic of coarctation of the aorta; serum potassium, to disclose the hypokalemia of primary aldosteronism
(being sure that the sodium intake has not been restricted and no diuretics have been used); serum glucose, both
to detect diabetes mellitus, and also because it is frequently elevated in pheochromocytoma. On the other hand,
intravenous pyelography should not be considered as a routine procedure, and should be reserved for the special
cases where a renal lesion is suspected.

Pheochromocytoma often can be suspected on the history and physical examination. There may be a history
of frequent headaches, or palpitation, or excessive sweating, blanching or flushing, which may be paroxysmal in
nature. The patients tend to be thin and rarely, if ever, are obese. They often give the appearance of being
hyperthyroid, and may have a fine tremor.

Cushing's syndrome displays the typical physical appearance of moon facies, central obesity, kyphosis and
purplish abdominal striae, which should lead directly to the diagnosis. Primary aldosteronism has no characteristic
clinical features, aside from muscle weakness and nocturia, which often are not present. However, it can be
suspected by the presence of hypokalemia. Primary aldosteronism is still a rare disease, despite arguments to the

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contrary, and is especially rare in our male veteran population. Normokalemic aldosteronism, as a cause of
significant hypertension, or even as a valid disease entity, has not been definitively established. Therefore, if
several serum potassium determinations are in the normal range, primary aldosteronism can be considered to be
effectively ruled out, unless there is some other reason to suspect the presence of an aldosterone producing
tumor.

Since the present practice, in patients above the age of 49, is to treat renovascular hypertension conservatively
with antihypertensive drugs, a search for this condition in older patients is largely academic. It also is noteworthy
that the condition is less common in males than in females, and is almost never found in black males. A great deal
of needless laboratory investigation can be saved if patients are carefully selected for study. The rapid sequence
intravenous pyelogram is the screening procedure of choice. Delayed excretion on one side, and especially the
detection of a kidney that is more than 1 cm. smaller on one side than on the other, are the important points to
consider. If available locally, the renal scan and renogram also are useful screening procedures. The renal scan is
not very reliable in itself, often producing bizarre distributions of isotope within the kidney, but it is useful in
locating the probes for the subsequent renogram. Positioning of the probes over the exact center of the kidneys is
essential in obtaining valid renograms. Renal angiography and renal vein blood sampling for renin activity should
be performed only in the patients who are suspected of having the disease on the basis of the above screening
procedures, and in whom surgical rather than medical treatment would be indicated.

Unfortunately, medical tradition has grossly exaggerated the importance of detecting curable hypertension.
For years, physicians have beep taught that their major obligation was to rule out curable hypertension, and once
this was done, their obligation to the patient had been discharged. The devastation of human lives that has
resulted from this erroneous teaching can hardly be overestimated. The physician's responsibility only begins with
the ruling out of curable hypertension, and he must not strain unduly his own or the patient's resources in doing
so. The problem is to restore a perspective which is consonant with the relative worth of diagnostic and
therapeutic procedures that are most apt to be effective in preventing the major complications of hypertension.
The greatest cost-benefit ratio lies in the treatment, specifically in the drug treatment, of hypertension.

INDICATIONS FOR MEDICAL TREATMENT OF HYPERTENSION

The important factors which govern the degree of risk of developing cardiovascular complications of
hypertension are the height of the blood pressure, the persistence of the elevation of blood pressure, the
family history of hypertension and cardiovascular-renal complications secondary to it, and the degree of target-
organ damage (fundi, brain, heart and kidney) already present.

The Height of the Blood Pressure

All epidemiological studies indicate that mortality is directly related to the height of either the systolic or
diastolic blood pressure (IO, 22, 23). Thus, life insurance experience indicates that in men age 35-44 years, the
20-year mortality rate increases 1.4 times the normal with a diastolic blood pressure of 90, and five times the
normal with a diastolic of 100 mm. Hg. The increase in 20-year mortality in older patients with the same levels of
blood pressure, while somewhat less than in the younger group, also is very great, in comparison to the normal
population.

Many epidemiological studies are based on a reading of blood pressure taken at a single point in time.
However, the course of the blood pressure over time may be highly variable. Some will exhibit a progressive
increase, others will remain stable, while still others may revert to normal. While it is true that in a group of
patients of age 38, with a diastolic blood pressure of 100 mm. Hg., the mortality is five times the normal, we
cannot predict that any given individual in the group will have the same risk, since some live out a normal life
span. Therefore, we need additional criteria, to assess risk and need for treatment in a given patient.

A number of studies indicate that borderline or labile hypertension is associated with less cardiovascular
disease than is a persistent hypertension (28, 29). According to these studies, the risk of organic complications is
three or more times higher in patients with persistent hypertension, than in patients whose blood pressure
fluctuates above and below 90 mm. Hg. diastolic. A very elegant study was carried out by Sokolow and his
associates, in which the blood pressure was measured several times each hour throughout the waking hours, by

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the patient (29). The patient carried a tape recorder with him and wore the blood pressure apparatus beneath his
coat. This study indicated that the persistence of hypertension was highly correlated with the presence of target
organ damage, the patients with more labile pressures showing less damage.

All physicians are aware of the effect of emotions on blood pressure. The blood pressure taken in the absence
of physical, mental or emotional stress, or apprehension, is called the basal blood pressure. It is not the lowest
blood pressure that is recorded in the 24-hour period, since the latter generally occurs when the patient is asleep.
The blood pressure taken as an isolated reading, or closely spaced series of readings, by a physician or nurse, is
called the casual blood pressure. Casual blood pressure may be markedly different, or fairly close to the basal
blood pressure in different patients. The degree of discrepancy between the two is not always predictable on the
basis of the examiner's or the patient's appraisal of his emotional status. There is no reliable way of estimating
basal blood pressure, except by determining it.

Basal blood pressure may be determined by any one of three methods, all of which are somewhat
inconvenient. One method requires entering the patient into the hospital. He is not placed at bed rest, but rather
is advised to be up and about the ward. The blood pressure is recorded four or five times daily for 4 days, and the
readings of the last 2 days are averaged. Of course, the patient should not be faced with prolonged or
discomforting diagnostic or therapeutic procedures during this period.

A second method, introduced by Dr. Smirk, is to have the blood pressure recorded for the better part of one
day in a special clinic. Dr. Smirk had the blood pressure taken hourly by technicians, for an 8-hour day.
However,with the availability of automatic machines such as the "Arteriosonde@)" or similar instruments, if they
are equipped with a digital printout, they can be set to record the blood pressure every 5 minutes, with the
patient left alone in a quiet room. Under these conditions, it seems possible that a basal reading may be obtained
after 2 or 3 hours. However, the minimum time to obtain a basal reading under these conditions has not yet been
established.

The third method is to teach the patient, or a member of his family, to record the blood pressure at home. In
employed patients, recordings usually are taken twice daily, in the morning and at night. A 2-week period usually
is required. The readings taken during the last week are averaged (excluding sporadic readings greatly in excess of
the average), in order to obtain an estimate of the basal blood pressure. A blood pressure apparatus can be given
out on loan for the 2-week period. The patient and the individual taking the blood pressure at home should visit
the clinic at the end of the first week, in order to check on the reliability of the readings. A stethoscope equipped
with two sets of ear pieces (easily fabricated by using parts from a second stethoscope) is useful in conducting
such a check.

The clearest indication for treatment is the presence of target organ damage. This, however, is not so reliably
detected in the early stages of hypertension, since the changes are minimal. Normal individuals may show Grade I
changes in the optic fundi, or have LVH by voltage criteria only, in the electrocardiogram. Clinical renal
functional tests are insufficiently sensitive to pick up early mild damage to the kidney.

Hypertension, hypertensive cardiovascular complications and atherosclerotic complications, tend to run in
families. If one parent of a patient had hypertension and died of a cardiovascular event, the patient's risk of
developing cardiovascular complications in the future is great, if the hypertension is not controlled.

PATIENTS WHO SHOULD BE TREATED

The VA Cooperative Study clearly indicated that in male patients with diastolic blood pressures persistently at
a level of 105 mm. Hg. or higher, the benefits of treatment were great, and that over a 5-year period the risk of
developing morbid events was reduced by a ratio of more than 3 to 1 (30,3 1). In patient.s with persistent diastolic
blood pressures averaging between 90 and 104 mm. Hg., the benefit of treatment was considerably less, with only
slight differences favoring treatment. Furthermore, the complications of coronary artery disease were about the
same in the two groups, and coronary artery disease is by far the most common complication in patients with
diastolic blood pressures in the range of 90 to 104 mm. Hg.

On the other hand, this study indicated that serious toxic effects from the drugs used were uncommon, were
easily recognized and easily remedied, by substituting another antihypertensive for the offending drug. Therefore,
it seems justified to stretch the lower limit of diastolic blood pressure (for treatment purposes) to 100 mm. Hg.,


wherein the benefits of treatment would appear to definitely outweigh the risks. A lower limit of 100 mm. Hg. is
set with the understanding that the value represents an average value obtained during at least two clinic visits
other than the initial visit, and that an estimate of the basal blood pressure provides a reading of more than 89
mm. Hg. diastolic. Also, the assumption is made that the vast majority of patients seen in VA clinics will be
males.

In patients with diastolic blood pressures averaging between 90 and 100 mm. Hg. on repeated visits, the benefit
of treatment is still a matter of medical controversy. No doctrinaire statements can be made, because the decision
to treat such patients must rest on opinion tempered by medical judgment. If the patient is below age 45, and
there is a family history of hypertensive complications, or the presence of end-organ damage is evidenced in the
optic fundi, EKG, urine, etc., then treatment probably is indicated. If the patient has neither a positive family
history nor evidence of organic damage, little will be lost by a l-year period of observation without treatment.

Given 100 patients with a diastolic blood pressure averaging between 90 and 100 mm. Hg., some will subside
to normal over a period of a year, some will remain unchanged, and others will exhibit a progressive increase in
blood pressure. The course of hypertension is so highly variable, that in the more borderline cases a protracted
period of observation is needed to determine whether the elevation is persistent, progressive, or remittent.
However, if a patient is not treated because of the spontaneous subsidence of the hypertension, annual followup
still is indicated for a period of 3 to 5 years, to make certain that the remission is permanent.

CLINICAL PHARMACOLOGY OF THE PRINCIPAL ANTIHYPERTENSIVE AGENTS

The principal antihypertensive agents which are approved for use in this country are the thiazides and related
diuretic agents, hydralazine, reserpine, alpha methyldopa, and guanethidine. The diuretics act on the kidneys,
hydralazine directly on arteriolar smooth muscle, and reserpine, alpha methyldopa, and guanethidine on the
sympathetic nervous system.

Thiazides and Related Diuretics

The principal action of these agents is to induce salt and water loss by affecting the renal tubular transport of
sodium. Present evidence indicates that the principal site of action is distal to the proximal tubules. The urinary
excretion of potassium also is increased.

When a thiazide diuretic is given to a hypertensive, but non-edematous patient, in continuing daily doses, the
following sequence of events occurs: sodium, chloride, potassium, and water are excreted in excess for the first 2
or 3 days. The peak excretion occurs on the first day, and then gradually falls, so that after 3 or 4 days the
excretion of sodium returns to the approximate pre-treatment level, and the excess diuresis stops, despite
continued treatment (32).

Measurement of extracellular fluid volume before and after the diuresis indicates that the excess salt and water
depletion during the first 2 to 3 days of treatment represents extracellular fluid loss. Roughly l-2 liters of ECF
are excreted, and present evidence indicates that the loss is more or less maintained for as long as the patient
remains under treatment. The fluid loss is reflected in a decrease of body weight of several pounds. A portion of
the ECF depletion is represented by the plasma volume, which is reduced by approximately 10 percent (33).

The blood pressure also falls during this initial period, suggesting that it is related to the diuresis, and possibly
to the reductions in extracellular and plasma volumes. The important therapeutic implication is that a reduction
of blood pressure does not occur unless there is a diuresis. The diuretic dose may vary somewhat in different
individuals. For example, with hydrochlorothiazide, it may vary from 25 to 75 mg., but in patients with renal
failure and greatly reduced glomular filtration rate, hydrochlorothiazide is ineffective as a diuretic, even in large
doses. Therefore, in such patients, agents with greater saluretic effectiveness, such as furosemide, must be used to
obtain an antihypertensive effect. At the opposite end of the scale, some hypertensive patients, particularly
elderly patients, are quite sensitive to even small reductions in extracellular and plasma volume; tolerable doses of
hydrochlorothiazide in such individuals may be as small as 25 mg. once daily.

8


The effective dose of thiazide also will depend to some extent on the sodium intake. If a patient is adhering to
a salt-restricted diet, a smaller dose may be required, than if he is ingesting liberal amounts of salt. In general,
however, the dose of hydrochlorothiazide will be in the range of 25 to 50 mg. twice daily.

If the patient is ingesting liberal amounts of salt in the diet, and the doses of the diuretic are widely spaced,
the patient may then fluctuate back and forth between depletion and re-expansion of the ECF. In some patients
this may lead to considerable fluctuations of blood pressure from day to day. In general, patients with moderate
to severe hypertension will require continuous diuretic coverage, at least during the initial 4 to 6 months of
treatment, while patients with mild hypertension (or those with more severe forms who have been well controlled
for long periods) may be able to maintain control of the hypertension with intermittent doses. If the latter
pattern of dosage is used, however, it is important to check the blood pressure during the periods when there is
no diuretic coverage.

The principal side effects of the thiazide diuretics are hypokalemia, hyperuricemia, hyperglycemia, or
reduction in glucose tolerance, and sensitivity reactions, including skin rash and thrombocytopenic purpura.

Hypokalemia occurs in one-fourth to one-third of patients who are receiving continuous doses of thiazide
diuretics (34). The hypokalemia is rarely severe, and serum potassium levels below 2.5 milli Eq/L are unusual
during treatment with thiazides. The evidence is conflicting as to whether the hypokalemia reflects significant
intracellular depletion of potassium, or represents only a reduction of extracellular concentration. There is no
clear association between the hypokalemia and muscle weakness. Many patients complain of weakness and fatigue
during the first few months of effective treatment with most of the antihypertensive drugs, but this is associated
with bodily adjustment to the reduced blood pressure, rather than with hypokalemia, per se.

The principal risk associated with the hypokalemia resulting from thiazides is the resulting sensitization to
digitalis-induced arrhythmias. The incidence of digitalis toxicity greatly increases in the presence of even minor
reductions in serum potassium.

In addition to hypokalemia, hyperuricemia occurs in a significant percentage of hypertensive patients. In the
VA Cooperative Study the incidence of uric acid levels of 8 mg./ 100 ml. or higher, as compared to controls, was
15 percent. Thiazides inhibit the tubular secretion of uric acid. This effect is greater at low than high doses and,
in fact, thiazides are uricosuric at doses above the therapeutic level.

Despite the frequency of hyperuricemia, the incidence of gout is low, except in patients with a gouty diathesis,
or in patients with renal failure. In both of these groups of patients, acute gouty arthritis often is precipitated
soon after the patients are placed on thiazide diuretics. In other patients, it has not been demonstrated that
thiazide-induced chronic hyperuricemia leads eventually to either gouty arthritis or gouty kidney.

In patients with essentially normal renal function, probenecid in doses of 0.5 gm. twice daily will normalize
the serum uric acid level in thiazide treated patients. In patients with renal failure, a titrated dose of allopurinol
will do the same.

In view of the above considerations, I will treat all patients with a prior history of gout, but who do not have
azotemia with probenecid. If a patient with azotemia develops gout while under treatment with either thiazides
or with furosemide, I will begin both colchicine and allopurinol simultaneously. The reason for the colchicine is
both to treat the acute attack and to prevent its recurrence, which is very frequent during the first few weeks of
treatment with allopurinol. To prevent flare-up in gout, colchicine can be given in a dose of 0.5 mg. once or twice
daily. After the serum uric acid level has been stabilized at normal or near normal levels, I will discontinue the
colchicine.

Thiazides reduce glucose tolerance, and they also will raise the fasting blood sugar (FBS) in some patients. In
the VA trial, the excess prevalence of FBS values of 110 mg./lOO ml. or higher, in thiazide treated patients, was
13 percent. The available evidence suggests that thiazides will induce diabetes only in "prediabetic" individuals.

A less frequent, but related, side effect of thiazides is the induction of an acute, severe hyperglycemia without
ketosis. Fasting blood sugar values of 400 to 600 mg./lOO ml. are seen with this reaction. The condition clears
rapidly with discontinuation of the drug. It is sometimes possible to replace the original diuretic after the acute
episode has subsided, with another chemically different diuretic, such as replacement of hyclrochlorothiazide with
chlorthalidone, or vice-versa.

9


Diabetes mellitus is very common in our middle aged and elderly veteran population. The appearance of mild
diabetes in a thiazide treated patient does not necessarily mean that it was induced by the drug: nor is there any
evidence to suggest that discontinuation of the thiazide will prevent the vascular disease that is associated with
diabetes. If thiazides are necessary to obtain effective control of the blood pressure, I prefer to maintain this
treatment, and simply treat the mild diabetes with diet. This decision is based on the evidence that reduction of
blood sugar levels is of dubious effectiveness in preventing vascular disease in adult onset diabetes, whereas
effective control of blood pressure is of great value in preventing the complications of hypertension.

Less common side effects of thiazide and related diuretics are related to sensitivity reactions, and include skin
rash, particularly erythema multifomre and thrombocytopenic purpura. These reactions are rare, and often
manageable by changing the diuretic from one chemical form to an unrelated one, such as was described for the
management of the thiazide-induced acute, severe hyperglycemia.

Reserpine

Despite the fact that reserpine has been available for over 15 years, it is still the most misunderstood of all of
the antihypertensive agents. Among the prevalent and false opinions, that are frequently expressed, are that
reserpine is an ineffective antihypertensive agent, that it is too dangerous to use in man, that it is effective only in
mild hypertension.

Reserpine generally is not effective unless it is combined with a thiazide. The U.S. Public Health Service
controlled trial demonstrated that such a combination is as effective as thiazide plus alpha methyldopa in
controlling hypertension (35). However, reserpine is a doubleedged sword. It has one very serious side effect,
which is the induction of emotional depression. The experience has been, however, that such depression is much
more frequently induced in patients who attain a high level of intellectual, economic and social accomplishment,
and is unusual in patients who work primarily with their hands. Reserpine induces depression in individuals who
are apt to react to emotional stress with an anxiety depression. There is some evidence to suggest that this
response is due, in predisposed individuals, to depletion of catecholamines in the brain. However, in the great
majority of patients who depend upon a clinic, rather than a private physician for their medical care, reserpine, in
moderate doses, is a safe and often effective antihypertensive agent, when combined with a thiazide diuretic.

The reserpine-thiazide combination has some distinct advantages in clinical practice. The dosage schedules are
simple and convenient. Thus, hydrochlorothiazide-reserpine, given in the commercially available fixed-dose
combinations twice daily, is effective in the majority of patients who are responsive to any therapeutic doses of
these medications. For even greater convenience, one can use a long acting saluretic agent such as chlorthalidione
once daily, in the commercially available combination with reserpine (regroton). The less complex and the more
convenient the regimen, the more apt one is to obtain the cooperation of the patient, and the less likelihood of
confusion over doses, time of doses, etc., especially when a number of hypertensive drugs are being given in
differing doses at different times of day. The thiazide-reserpine combinations also are reasonable in cost and,
therefore, impose less of a strain on the budget of working people than do most other regimens.

The antihypertensive effect and the side effects of reserpine are due to its action in depleting catecholamines.
The sympathetic nervous system still responds to stimulation, but somewhat more sluggishly, and the level of
basal sympathetic tone appears to be reduced. The net effect is a blunting of sympathetic tone and of
sympathetic pressor reflex responses, which combined with the central "tranquilizing" effect of reserpine,
probably accounts for the antihypertensive action of the drug.

The partial depletion of catecholamines can be accomplished fairly rapidly with large (2 to 4 mg.) doses of
reserpine parenterally, less rapidly with daily oral doses of 0.5 to 1 .O mg. orally, or slowly over a period of about
2 weeks, with daily doses of 0.2 to 0.3 mg. reserpine orally. Since there usually is no need for a rapid effect, the
latter dosage schedule is preferable and simpler, in the usual setting of outpatient practice.

Depletion of catecholamines results in reduced sympathetic control and resulting parasympathetic dominance.
In the heart, this leads to sinus bradycardia and diminished myocardial contractility. Another false concept
concerning reserpine is that the reduced contractility will precipitate cardiac failure in hypertensive patients.
There are several reasons why the reverse is true, that is, that reserpine given properly protects the patient against
congestive heart failure. The first reason is that a fall of blood pressure reduces myocardial demand for oxygen by

10


greatly decreasing the work load on the left ventricle. The second reason is that the diuretic in the combination
tablet prevents the development of fluid retention. Thus, the benefits of reduced afterload, and prevention of
fluid retention greatly outweigh the disadvantages of reduced contractility.

Because of the increased vagal tone and bradycardia, reserpine treated patients may develop ventricular ectopic
beats. This tendency is aided and abetted by the mild hypokalemia often induced by thiazides. However, the
danger of ventricular ectopic beats has been greatly overemphasized. If the physician or the patient are
concerned, one can substitute dyazide or aldactazide, thus avoiding hypokalemia, and give the reserpine
separately.

Another discomforting effect of reserpine is nasal stuffiness. This is probably due to failure of vasoconstriction
in the nasal mucosa. Nasal stuffiness generally is most troublesome at night, and some patients may require
vasoconstri~tive nose drops on retiring at night. Patients also should be told to discontinue reserpine during the
acute coryzal phase of a cold, or if they develop epistaxis.

The vagal predominance leads to some increase in the secretion of gastric acid. However, in the usual
therapeutic maintenance dose of 0.2 to 0.3 mg. daily, reserpine does not result in a significant increase in gastric
acidity. Also, in the VA Cooperative Study, the incidence of peptic ulcer was only slightly and insigni~cantly
higher in the reserpine treated, as compared to the control patients. While reserpine in large, parenterally
administered doses, detinitely increases gastric acidity, the risk with maintenance oral doses is negligible, and
except for the presence of active or bleeding ulcer, need not contraindicate the use of this drug.

In addition to its potential ability to precipitate a severe depression, reserpine more commonly induces a
so-called "tranquilizing" effect. The patient's drive for attainment may be replaced by lassitude, and ambition
gives way to a more philosophical approach toward life. In patients who have the habit of superior attainment,
~rticularly intellectual attainment, this reaction is decidedly unpleasant, and interferes with their normal way of
life. However, in less motivated patients, the mood induced by reserpine is a pleasant one. The latter is especially
true in those whose occupation and way of life requires fewer intellectual demands.

Fatigue is a related side effect, and it is often difficult to differentiate in deciding on its causation, between the
emotional change induced by reserpine, and the loss of energy that often results when the blood pressure is
lowered. If it is due to the latter, the patient should be reassured that the adjustment to a reduced blood pressure
is a slow one, but that it will occur over a period of months, and that he will then recover from his present
fatigue. If the fatigue is not so much physical as it is mental and emotional, the chances are that the patient is
complaining of the mood changes induced by reserpine, and that some other regimen may be required.

Increased relative parasympathetic activity also can result in greater large intestinal motility, and resulting
increased frequency of bowel movements. Increased gastric motility may lead to increased appetite. However,
these are usually minor problems, in comparison with the importance of controlling the blood pressure.

Although rcserpine is generally regarded as being ineffective in the treatment of severe hypertension, there are
many exceptions to this rule. In outpatient practice, it is not at all uncommon to rind that the addition of
reserpine will control the blood pressure of patients who have seemingly been refractory to large doses of alpha
methyldopa, and/or guanethidine, plus thiazides. It is possible that the refractoriness was due to non-compliance,
because of the complex dose schedules, or side effects associated with the more potent antihypertensive agents.
Nevertheless, in the outpatient setting, reserpine-thiazide, plus hydralizine if needed, often is more effective than
the more complicated and expensive regimens, even in severe hypertension. It is not possible to predict in advance
who will respond to one regimen, as opposed to another. The successful therapist should keep an open mind on
this subject, and maintain flexibility in his approach to management of the individual patient.

Alpha Methyldopa

Possibly because this is the most recent of the ant~ypertensive agents, it is the most popular amongst house
staff at many teaching hospitals. While it is a useful agent in many patients, its superior reputation for the long
term control of patients who are not in renal failure: is undeserved. Approxinlately half of the patients treated
with alpha methyldopa respond well to it, if diuretic coverage is given, in addition. The majority of such patients
Seen in clinic practice would respondas well to reserpine, plus a thiazide (35).

11


The disadvantages of alpha methyldopa are that it must be taken three or four times daily, thereby placing a
much greater demand on the compliance of the patient, that doses need to be individually adjusted, that it is
relatively expensive, and that it also is not free of toxic effects or side reactions.

The advantages of alpha methyldopa are that it usually can be given without fear of inducing a depression, it
seldom induces symptomatic orthostatic hypotension, and that occasional patients respond better to it than to
other drugs. This again points up the need for individualizing each patient.

In general, I reserve alpha methyldopa for two classes of patients. One is the group of patients with essential
hypertension who are not satisfactorily controlled on thiazide-reserpine, with or without hydralazine, and the
other is patients with renal failure.

Alpha methyldopa is excreted in the urine; in patients with renal failure it appears to accumulate in the body.
Thus, when one increases the dose during the titration procedure in patients with renal failure, one often
overshoots the mark, because of renal retention of drug. Therefore, in treating the uremic patient, it often is
necessary to reduce the dose of alpha methyldopa to a lower maintenance level, once an antihypertensive effect
has been achieved. In addition to often being effective in reducing blood pressure in uremic patients (especially if
fluid retention is controlled), alpha methyldopa does not decrease cardiac output or renal blood flow, and does
not induce oliguria in such patients.

Although there has been much discussion of the action of alpha methyldopa as a "false transmitter," this
attractive theory has not been established. The popular theory is that alpha methyldopa enters the metabolic
chain of catecholamine synthesis, and eventually deposits in-the sympathetic nerve endings as alpha methyl
norepinephrine, replacing norepinephrine in the storage sites. However, alpha methyl norepinephrine appears to
be as effective a pressor substance as epinephrine itself. In addition, there is evidence to believe that alpha
methyldopa acts centrally, rather than peripherally at the sympathetic nerve endings. At present, it is fair to say
that we do not fully understand the mode of action of alpha methyldopa.

The effective dose of alpha methyldopa must be individually determined in each patient, by a titration
procedure. The range of effective doses varies from as little as 250 mg. to 2,250 mg. per day. Treatment can be
initiated safely with a thiazide given separately, and with the beginning dose of alpha methyldopa at 250 mg.
twice daily. This can be decreased to once daily, or increased to three times daily, depending on the response.
Succeeding increases then are given as follows, as needed, and at as close to g-hour intervals as possible.

AM              PM

Bedtime

250              250               250
500              250                500
500              500               500
750              500                750
750              750                750

The higher doses are somewhat inconvenient, and increases above this level are not worthwhile. Very few patients
respond to a higher dose, who cannot be controlled by 500 mg. given three times daily. The common practice of
prescribing four times daily doses is quite difficult for the patient to adhere to over long periods. Such a dose
schedule is unrealistic, and invites poor compliance.

The most serious toxic effect reported with alpha methldopa is hemolytic anemia. Fortunately, it is quite rare,
although the induction of a positive direct Coomb's test is fairly common. A type of hypersensitization reaction
has occurred during the first 6 weeks of treatment, which is expressed as a hepatitis characterized by low-grade
fever and elevation of SCOT. This reaction seems to have become much less common in recent years, a change
which is said to be due to improvement in the preparation of the drug. It should be remembered that ingestion
of alpha methyldopa will cause a falsely positive test for catecholamines in the urine. However, since the drug
does not enter the vanylmandelic acid (VMA) route of metabolic degradation, the urinary VMA test for
pheochromocytoma will not become positive.

The common side effects of alpha methyldopa are sleepiness and dry mouth. Patients who are engaged in
sedentary occupations find the drowsiness to be particularly troublesome. They sometimes fall asleep at their

12


desk, or while watching TV. Patients who are physically active are not bothered by sleepiness. In many patients,
the side effect tends to moderate with the passage of time. If dryness of the mouth is frequent or severe, it may
be necessary to decrease the dose, or switch to another drug.

Impotence and depression have been implicated as side effects of alpha methyldopa. However, it is my
impression that the incidence is no higher than one would expect in an untreated population.

Guanethidine

This potent drug represents the big gun in the therapeutic armamentarium. It generally is reserved for the
treatment of patients with moderate to severe hypertension who fail to respond to simpler, better tolerated
regimens (36).

The limitations of guanethidine are basic to its mode of action. It produces a high degree of of sympathetic
blockade. This results in orthostatic hypotension. It often is dif~cult to control the blood pressure in the supine
position with a dose that does not produce symptomatic orthostatic hypotension. The therapist usually is obliged
to compromise at a dose which only partially reduces the blood pressure in the lying and standing positions.
However, this partial reduction is vastly better than no control of the blood pressure.

Orthostatic hypotension is greatly influenced by the extracellular fluid volume, and its influence on tissue
pressure. There is a considerable diurnal shift in the distribution of the ECF. As the day progresses, a large
percentage migrates to the lower extremities and abdomen, acting like a compression bandage and preventing
orthostatic hypotension.from occurring. At night the process is reversed. During the hours in the recumbent
position the excess fluid leaves the dependent portions of the body, and in the legs tissue pressure falls.
Consequently, on arising in the morning, tissue pressure is reduced in the lower extremities, and venous pooling
occurs on assuming the erect position. The result is diminished venous return and decreased cardiac output,
leading to orthostatic hypotension and faintness, even syncope.

Obviously, the diurnal fluctuations in orthostatic blood pressure will be reduced if the amount of migratory
ECF can be minimized. This is accomplished by giving a thiazide diuretic prior to and during titration with
~anet~dine. By depleting extracellular fluid volume, thiazides also enhance the antillypertensive effectiveness of
~anet~dine. Most antihypertensive agents induce a retention of salt and water, and this in turn causes an
increased resistance to the antihypertensive effect of the given drug. The development of drug resistance due to
this cause is prevented by an effective diuretic. This represents an additional reason why diuretics should be used
in conjunction with guanethidine, as well as with most other antihypertensive drugs.

Guanet~dine produces an effective block of sympathetic nerve endings. The parasympathetics are not affected
and, as in the case of reserpine, there are side effects indicative of parasympathetic predominance. These include
bradycardia and increased bowel motility. Oddly enough, nasal stuffiness is not evident. The effect on the bowel
is to produce strong peristaltic rushes and more frequent bowel movements. This side effect is readily controlled
with agents which inhibit the pardsympathetic system, such as atropine or lomotil. No sensitivity reactions or
direct toxic effects on body cells have been noted with guanethidine, the side effects all being a consequence of
the sympathetic blocking action of the drug.

A feature of guanethidine which makes it difficult to use is the wide range of effective dosage in different
individuals. In one patient, the effective dose may be as little as 10 mg. per day, and in another, 200 mg. Most
patients respond to a dose of 25 to 50 mg. daily, but one cannot begin with such doses, because of the few who
will develop orthostatic syncope. The action of the drug is long persisting, for at least 24 hours. Therefore, one
dose per day is sufficient. In hospitalized patients, after background treatment is begun with an effective diuretic
(in patients with renal failure this usually means furosemide or ethacrynic acid, while in others it means a
thiazide), guanethidine may be initiated in a dose of 25 mg., since the patient is never far from his bedside, and the
antihypertensive response in both the supine and erect positions can be recorded several times daily. The dose can
be increased by 12.5 mg. daily (i/2 tablet), until an orthostatic fail in blood pressure becomes evident. Finer
adjustment doses can then be made from this point, to achieve the optimal dose for that patient.

In outpatients, the titration procedure must be carried out with greater caution.The initial dose is 10 mg.
daily, which can be increased at weekly intervals to 201 35, 50, 75? 100, 150, and 200 mg., or until an

I3


antihypertensive effect is obtained. In outpatients, the "post-exercise response" of the blood pressure is a more
useful guide than simply taking the blood pressure in the erect position. At each visit, blood pressure should be
measured in the supine position, one minute after standing, and immediately after the patient exercises by
running or hopping in place until winded. The blood pressure is then measured while he is still standing erect,
following the exercise. In patients receiving effective doses, there will be a significant fall in blood pressure
following such exercise. If the post-exercise blood pressure is lowered, this is probably an indication that the
patient is near or at the maximal tolerated dose, and that substitution or addition of other antihypertensive drugs
is required.

With both inpatients and outpatients, the patient should be told about the orthostatic effects of the drug.
During the tritration period, he should be told to observe care on arising from the supine to the erect position,
particularly after awakening in the morning. The patient should sit on the side of the bed for a minute before
standing, to test for faintness. If such occurs, he should not attempt to stand, and should not take any more
guanethidine until consulting the clinic. If he tolerates the dangling position, he can stand erect, but should wait
beside the bed for a full minute before moving away. Patients frequently have fainted from orthostatic
hypotension while standing to urinate, or while shaving. During the titration procedure, I advise patients to
perform both functions in the sitting position. Quiet standing, rather than walking, is most apt to induce
orthostatic syncope, becaus, of loss of the pumping action of the leg muscles in aiding venous return.

Patients on guanethidine may develop retrograde ejaculation. This is due to failure of the sympathetics to
activate a sphincter at the urethral-vesical junction, which normally closes during ejaculation. Aside from this
change, sexual function is essentially unimpaired. However, failure to explain this side effect to male patients can
result in needless concern? and loss of the patient's cooperation.

The effort to explain and minimize these various side effects that "can" occur with guanethidine may suggest
that the drug is too troublesome to use. It should be emphasized, however, that most patients tolerate
guanethidine with minimal side effects, when dosage adjustment is carefully managed.

Some patients who have been well controlled on guanethidine for long periods may suddenly appear to
develop resistance to the drug. This may be due to poor adherence-the most common cause for drug resistance-or
it may be due to undetectable fluid accumulation. If it is due to the latter, a large dose of furosemide will result
in the reappearance of response to guanethidine. The test can be carried out by giving the patient 100 mg.
furosemide intravenously, and then observing his blood pressure hourly in the clinic for the succeeding 4 hours. If
the blood pressure falls, a larger dose or a change in diuretic may be indicated. Another reason for resistance is
drug imcompatibility. Imipramine and related compounds, for example, interfere with the penetration of
guanethidine into the sympathetic nerve endings, and so block its antihypertensive effect.

Hydralazine

The action of hydralazine is unique amongst the currently available antihypertensive agents, in that it acts
directly on arteriolar smooth muscle. Since the sympathetics are not affected by the drug, they will be activated
reflexly by the fall in blood pressure to increase heart rate and contractility. Cardiac output rises, and the
antihypertensive effect of the vasodilator is thereby partially nullified. In addition, the patient is often made
uncomfortable by the increased cardiac activity, developing palpitation and dyspnea on slight exertion. Angina
may be worsened. Therefore, hydralazine generally is given in conjunction with a sympathetic inhibiting agent,
the most common being reserpine.

A further disadvantage of hydralazine is that it may induce fluid retention. In patients with cardiac
complications, congestive heart failure may be precipitated. Therefore, all such patients should receive a diuretic
in conjunction with hydralazine and a sympathetic inhibitor. Thus, hydralazine is usually considered as a third
drug to be added to the regimen of patients who do not respond to thiazide-reserpine, thiazide-alpha methyldopa,
or thiazide-guanethidine. Thiazide and hydralazine, as a two-drug combination, may be effective and well
tolerated in some patients with mild or moderate hypertension.

Vasodilatation of cerebral vessels after hydralazine medication can cause severe headache. Like the cardiac
palpitation, headache is most prominent during the initial few days of treatment, and usually tends to abate,
thereafter. To minimize its occurrence, and that of other acute side effects, I begin with a dose of 25 mg. twice
daily, and increase to 25 mg. three times daily after several days or a week, then to 50 - 25 - 50, and finally to
50 - 50 - 50 mg. daily as the maximum dose.

14


Elevation of doses beyond 200 mg. may precipitate a hypersensitivity state resembling disseminated lupus. All
manifestations of the latter, except the renal lesion, may occur, including skin rash, arthritis, pulmonary lesions,
and the appearance of lupus cells in the blood. For this reason, high doses of hydralazine should be avoided.

Because of its vasodilating effect, hydralazine lowers peripheral vascular resistance more than any other
currently available agent. As a result, there is a greater percentile fall in diastolic than in systolic blood pressure.
The drug is particularly useful as an adjunctive medication when a partial antihypertensive effect has been
achieved, and an additional reduction in diastolic blood pressure is desired.

Other Antihypertensive Agents

In my opinion, the other currently available agents are inferior to the five drugs described above.

Pargyline (eutonyl) is a monoamine oxidase inhibitor, and has both antihypertensive and antidepressant
effects. It lowers blood pressure by sympathetic blockade, the mechanism of which is not clear. This results in an
orthostatic hypotension. The drawback to the use of pargyline is that, in common with other monoamine oxidase
inhibitors, is greatly potentiates the pressor effect of sympathomimetic amines. The latter require monoamine
oxidase for their metabolic degradation, and when this enzyme is inhibited, the ingestion of sympathomimetic
amines results in toxic concentrations in the tissues. Amphetamines, ephedrine, as well as tyramine contained in
processed cheese, pickled herring, etc., if ingested, can result in severe pressor reactions. Imipramine and its
analogues can produce vascular collapse in the presence of monoamine oxidase inhibition. There, also, are other
serious drug incompatabilities, which makes the use of pargyline a form of therapeutic brinkmanship which, in
my opinion, is unnecessary when other effective agents are available.

The ganglion blocking agents and the veratrum aklaloids have been replaced by the better tolerated newer
agents already described. The dihydrogenated alkaloids of ergot share a similar fate because, when given orally,
their antihypertensive effectiveness is poor. The same may be said for mebutamate (Capla), which appears to be
little, if any, better than a placebo.

Investigational Drugs

There are several promising agents which have not yet been approved by the FDA. The most interesting is
minoxidil (Upjohn). Like hydralazine, it is a vasodilator compound, but is much more effective as an
antihypertensive agent, and has a longer duration of action, permitting twice daily doses for adequate 24-hour
coverage. Like other vasodilators, it is most effective when combined with an agent which inhibits the
sympathetic response to the heart, such as propranolol, reserpine, or guanethidine, and with a diuretic to prevent
secondary fluid retention. Chidsey and his associates (37) have reported on the use of the drug in hypertension.
My experience with it (in combination with other drugs) in patients with renal failure, and severe, resistant
hypertension, has been dramatic. Several patients previously requiring chronic hemodialysis no longer require it,
and control of blood pressure without orthostatic hypotension or other disturbing side effects has been most
impressive. Because of a cardiac lesion observed in the dog following minoxidil, the investigative use of the drug
has thus far been restricted to severe, resistant hypertension.

Bethanidine (Robins) is similar in action to guanethidine, but unlike the latter compound, it is short acting. It
is being used extensively in Europe, particularly in England. The patient taking guanethidine often shows
considerable diurnal fluctuations in blood pressure. This is due to the fluid shifts secondary to gravitational
influence, as described in the section on that drug. Blood pressures are at their lowest point soon after arising, and
become progressively elevated during the day, an effect which is only partially prevented by the use of diuretics.
Because the action of bethanidine lasts only 6 to 8 hours, a smaller dose can be given on arising, and larger doses
later in the day, to compensate for the diurnal variation in responsiveness. Bethanidine also is said to produce less
effect on large bowel motility than guanethidine.

Propranolol (inderal) is being widely used in Europe in the treatment of mild to moderate hypertension. Why
beta-blockade should be effective in reducing blood pressure is not clear, since the alpha receptors which supply
the resistance vessels are not affected by the drug. Both bethanidine and propranolol are currently being
evaluated in controlled trials by the VA Study Group on Antihypertensive Agents.

15


Diazoxide (hyper.,tat) is a parenterally effective vasodilator antihypertensive compound. It has been given in
doses of 300 mg. intravenously, for the treatment of hypertensive crisis. This agent also produces hyperglycemia
and sodium retention, the latter being controllable by the concurrent use of a diuretic. Experience with the agent
has been favorable, as it is easy to administer as a single bolus injection, its action is prompt, and it does not
produce vascular collapse.

Amiloride (Merck) is a potassium sparing diuretic which some investigators believe is more effective, or better
tolerated, than the currently available triamterene and spironolactone.

PROGRAMS OF TREATMENT AND PRACTICAL DETAILS OF MANAGEMENT

Thiazide diuretics are the mainstay of treatment for all hypertensive patients, except those with renal failure,
who cannot respond to these agents, and require the more potent diuretics. Thiazides control the hypertension in
a large proportion of patients. In the others, thiazides will enhance the antihypertensive effectiveness of other
drugs, which will be added later as needed. Therefore, in mild and moderate hypertension, it is customary to
begin treatment with a thiazide, alone (38).

After 2 weeks of observation (weekly visits), if the hypertension is not controlled, the therapist may add either
reserpine, alpha methyldopa, or hydralazine, depending on the type of patient one is dealing with. For most
patients, reserpine is the drug of choice, in a dose of 0.25 mg. twice daily for 2 weeks. If this .;gimen produces
satisfactory control, the daily dose of reserpine should be reduced to 0.2 to 0.3 mg. daily, and a fixed-dose
combination can be substituted, such as hydrochlorothiazide-reserpine twice daily, or chlorthalidone-reserpine
(regroton) once daily.

If the patient has depressive tendencies, or responds poorly to reserpine, one can substitute alpha methyldopa,
but maintain the thiazide diuretic. When sedation is troublesome with both reserpine and alpha methyldopa,
which may be the case in some patients, the combination of a thiazide and hydralazine may be effective. This
regimen is more likely to be successful in elderly patients, in whom baroreceptor reflexes are somewhat dulled
due to aging, and in whom reflex increase in heart rate and contractility are reduced. The danger of inducing or
increasing angina with this regimen in elderly patients has been over-emphasized. In fact, angina may be reduced
in some patients.

The three-drug combination of a thiazide, reserpine, and hydralazine was used with great effectiveness in the
VA Cooperative Study. It should be tried, however, only when the two-drug combinations of either
thiazide-reserpine or thiazide-hydralazine have proven to be insufficiently effective. The three-drug combination
is available in a single tablet as "Ser-ap-Es." The concentration of hydrochlorothiazide in this combination,
however, is only 15 mg., which may be below the optimal level for many patients. In the VA trial, thiazide and
reserpine (hydrochlorothiazide 50 mg. plus reserpine 0.1 mg.) were given in a fured-dose combination, and
hydralazine was then added as an independent tablet.

Hydralazine also may be added as a third drug in patients receiving thiazide-alpha methyldopa or
thiazide-guanethidine. It is unfortunate that hydralazine has been used primarily by some physicians in patients
with renal impairment, because of the action of the drug in increasing renal blood flow. In my experience,
hydralazine is least effective as an antihypertensive agent in patients with renal failure. Physicians who so limit
the application of the drug, gain a distorted impression of its effectiveness.

Combination Therapy In Severe Hypertension Without Renal Failure

Many patients with severe hypertension, who do not have renal failure, will respond quite well to the
three-drug regimen of thiazide-reserpine and hydralazine. A trial of this regimen is worthwhile because it requires
little titration of doses, and usually is well tolerated.

Other regimens that may be tried in severe hypertension are thiazide plus alpha methyldopa, or thiazide plus
guanethidine. After titrating the dose to the optimal level, hydralazine may be added, if adequate control of
blood pressure has not been obtained.

16


Treatment of Hypertension In The Presence Of Renal Failure

Patients with renal failure are resistant to long term treatment. It is difficult to maintain a reduction of ECF in
such patients, and this represents an important factor in causing the drug resistance. If the patients are on a
chronic hemodialysis program, their ECF will fluctuate markedly, falling after dialysis and rising between
dialyses. Thus, they will be quite responsive immediately following dialysis and quite resistant immediately before
the next dialysis. Patients who are receiving guanethidine may develop severe orthostatic hypotension,
postdialysis, and severe hypertension, pre-dialysis.

The mainstays of background treatment in patients with renal failure are severe sodium restriction in the diet,
and furosemide or ethacrynic acid. The doses of the latter must be large, sometimes as high as 200 to 400 mg.
furosemide daily, preferably given as a single dose, to incite a diuresis in the damaged kidneys. Such intensive
diuretic therapy results in further nitrogen retention and is, therefore, objected to by some nephrologists. The rise
in BUN, however, reflects a hemodynamic alteration in the kidney, rather than further kidney damage. If the
blood pressure is not lowered, further damage to the kidneys will result. Therefore, if an effective diuresis is
needed to control the blood pressure, the rise in BUN is a small price to pay for such a benefit.

Patients who are treated this intensively must be watched for evidence of salt depletion. Rarely, one may
encounter a patient who loses excessive salt through the kidneys, and becomes dehydrated and weak. This may be
seen in patients with polycystic kidneys. More often, sodium depletion occurs when there is excessive sodium loss
through the gastrointestinal tract. Excessive diarrhea or vomiting, or use of nasogastric suction, should alert the
therapist to temporarily discontinue the diuretic, and to observe the patient for signs of sodium depletion.

In addition to paying particular attention to control of the ECF in patients with renal failure, one must always
weigh the need for additional antihypertensive drugs. Of the available agents, alpha methyldopa is generally the
most effective.

Guanethidine also is frequently used, because of its effectiveness in reducing blood pressure. Because the
orthostatic hypotension associated with guanethidine is so responsive to the volume of ECF, particular attention
must be paid to maintaining a more or less constant reduction of the latter. Otherwise, the patients may fluctuate
between disabling orthostatic hypotension and complete loss of antihypertensive response.

As stated in the section on new drugs, minoxidil, in combination with furosemide and either reserpine, alpha
methyldopa and guanethidine, has been outstandingly successful in managing the patient with severe
hypertension and renal failure. Minoxidil should be added to the existing antihypertensive drug regimen in doses
of 2.5 mg. twice daily, increasing to IO mg. b.i.d., as needed.

THE PROBLEM OF COMPLIANCE

The greatest roadblock to the successful long-term treatment of hypertension is compliance. No matter how
expert the physician may be in administering the antihypertensive agents, his efforts will fail if the patient does
not cooperate. The most frequent cause for drug resistance is failure of the patient to adhere to the prescribed
regimen. Almost invariably, patients will deny this fact, and experience has shown that they often are able to
convince the therapist that they are complying. Physician judgment has been shown by pill counts and use of
marker substances to be a poor guide as to whether patients are complying.

It is important that the physician understands the reasons for non-compliance. Studies that have been done on
this important subject indicate the following:

1. The patient failed to understand directions.

2. The regimen was overly complicated.

3. The patient did not understand the nature of his illness and the need for continued treatment.

4. The patient was seen by too many different therapists. (Often the case in outpatient clinics).

17


5. The patient was made to feel like a second class citizen, because of prolonged waiting to be seen,
prolonged waiting to receive his medications at the pharmacy, and by the busy, impersonal atmosphere of an
overcrowded clinic.

6.  Failure to care for intercurrent or associated illness.

Clinics for the long-term care of hypertensives must be specially organized and conducted with a view toward
gaining improved compliance. Scheduling should be by appointment, in terms of exact time schedules. Waiting
time should be minimal. If the patient appears at the scheduled time? he should be seen immediately.
Arrangements must be made with the pharmacist to supply refills of drugs, without need for the patient to wait
beyond a 1 O-minute period.

Since most of our VA clinics will use clinic assistants to see the patients on routine followup, the patient will
be able to identify with a single therapist. It is important that the clinic assistant establish good rapport with the
patient and evince an interest in him, not only as a patient, but also as a person, A feeling of mutual respect and
trust should be developed between the therapist and patient. The clinic assistant should have time to listen to the
patient's problems, both real and imagined, and should have at least a basic understanding of psychotherapy. This
does not mean that the clinic assistant should offei psychotherapeutic advice, or become too emotionally
involved in the patient's problems, but he or she should be a good listener.

Every patient who comes under long-term observation or treatment should have an indoctrination in the
nature of hypertension, the relationship of hypertension to complications, and the rationale of preventive
treatment. This may take the form of movies-such as the excellent movie of the American Heart Association
called "What Goes Up," or of slide talks, pamphlets, or personal talks with the patient by the therapist. Such
indoctrination should be repeated in modified form, from time to time, particularly during the first year of
followup. Group discussion sessions also may be helpful. In such sessions, patients meet to talk about their
reactions to treatment, what they understand the treatment is for, and problems they have encountered. It is
important that the therapist determine whether the patient actually understands, and has not misinterpreted what
has been said to him.

Patients expect care for all of their illnesses. They recognize the clinic as their health center. If they are turned
away with the excuse that the clinic only will take care of their hypertension, their confidence and trust in the
clinic will be seriously compromised.

The recording of the blood pressure in the home by the patient, or a member of his family, often is helpful to
the patient in gaining a better insight into the action of the drug treatment. He will find out for himself that when
the drugs are omitted the blood pressure will go up, and that moderate side effects may have to be tolerated in
order to control the blood pressure. Another advantage is that the patient becomes a more active participant in
the therapeutic process. Home blood pressure recordings should be reserved for the patients who are difficult
treatment problems, and the equipment need not be loaned out for more than monthly periods.

Failure to comply also is due too frequently to side effects. Either the patient is embarrassed to discuss the
side effect (as sometimes happens in the case of impotence), or he wants to please the therapist by making a good
report. Some patients find it easier not to discuss reduction or omission of certain drugs, rather than to admit
they did this because of side effects. They fear that the therapist will insist on their taking the drug, in any event.

It should be made clear to the patient at the outset of treatment that a variety of drugs are available, and that
if one regimen is troublesome, another can be substituted. The therapist should evince an interest in determining
whether the patient has had any side effects since he was last seen, and should attempt to draw out a history of
real or imagined reactions to the drugs. It they are real, the regimen should be modified. If they are not drug
related, the patient should be encouraged to try again, at the same time being given assurance that the reaction
complained of was drug related.  .

It can be seen that gaining, and maintenance of, the compliance of the patient requires great skill, knowledge,
tact, and a change in our present organization of outpatient clinics.

18


RECOMMENDED CRITERIA FOR TREATMENT

Average diastolic at disappearance (3 successive visits) over 104 mm Hg Treat all patients

Average diastolic at disappearance (3 successive visits) 90-104 mm Hg

Score 1 point for each of following:

Age below 50
Male sex
Black
All diastolics 95+
Target organ damage (fundi, ECG etc.)
Parent with major hypertensive complication

Average of Diastolics                     Treat if Sum of Scores is

loo-104
95-99
90-94

1 or more
2 or more
3 or more

CONCLUSION

Hypertension is currently the most important of the chronic cardiovascular disorders of man, because it is the
one common cardiovascular disease in which treatment has been shown to be effective. An improvement in the
quality of life and increase in life span is now possible of achievement for millions of Americans so afflicted.
However, these benefits are not being delivered to the public effectively. The establishment of the VA
Hypertension Clinics can serve as models for others to follow, in meeting this important problem.

19


REFERENCES

(1) Wilber, J.A.: Survey of hypertension in Bladwin County, Georgia. In the Epidemiology of Hypertension.
Edited by Stamler, J., Stamler, R., and Pullman, T.N., 1967, New York, Grune & Stratton, Inc.

(2) Stamler, J.: Hypertension in gas company employees. Communication from the author.

(3) Schoenberger, J.A.: Hypertension in bank employees in Chicago. JAMA. In Press.
(4) National Center for Health Statistics: Blood pressure of adults by age and sex, United States, 1960-62.
Washington, D.C., U.S. Department of Health, Education, and Welfare, Vital and Health Statistics Series
  11, No. 4, U.S. Government Printing Office, 1964.

(5) Pickering, G.: Hypertension: causes, consequences, and management. London, J & A Churchill, 1970.

(6) Johnson, B.C., Epstein, F.H., Kjelsberg, M.O.: Distributions and familial studies of blood pressure and
serum cholesterol levels in a total community. Tecumseh, Michigan, J. Chronic Dis. 18: 147, 1965.

(7) Miall, W.E., and Lovell, H.G.: Relation between change of blood pressure and age. Br. Med. J. 2:660, 1967.

(8) Feinleib, M., Gordon, T., Kannel, W.B., and Garrison, R.J.: Relationship between blood pressure and age.
The Framingham Study. Paper presented at the 10th annual conference on cardiovascular disease
  epidemiology. New Orleans, 1970.

(9) Borhani, N.O., and Barkman, T.S.: The Alameda County blood pressure study. Berkeley, State of
  California Department of Public Health, 1968.

(10) McDonough, J.R., Garrison, G.E., and James, C.G.: Blood pressure and hypertensive disease among Negroes
  and whites in Evans County, Georgia. The Epidemiology of Hypertension. Edited by Stamler, J., Stamler,
  R., and Pullman, T.N., New York, Grune & Stratton, Inc., pp. 167-185, 1967.

(11) Vital Statistics of the United States, 1959, Section 6. Mortality Statistics, U.S. Department of HEW, Public
  Health Service. National Center for ,Health Statistics.

(12) National Center for Health Statistics: Hypertension and hypertensive heart disease in adults. U.S. 1960-62.
  Washington, D.C., U.S. Dept. of HEW Vital and Health Statistics Series 11, No. 13, U.S. Government
  Printing Office, 1966.

(13) Ibid, Series 11, No. 34.

(14) Kannel, W.B., Brand, N., et al: The relation of adiposity to blood pressure and development of
  hypertension: The Framingham Study.Ann. Intern. Med. 67:48, 1967.

(15) Dahl, L.K., Silver, L., and Christie, R.W.: The role of salt in the fall of blood pressure accompanying
  reduction in obesity.iV. En@. J. Med. 258: 1186, 1958.

(16) Meneely, G.R., Tucker, R.G., Darby, W.J., and Auerbach, S.H.: Chronic sodium chloride toxicity in the
  albino rat. II. Occurrence by hypertension and a syncrome of edema and renal failure. J. Exp. Med. 98:7 1,
   1953.

(17) Sazaki, N.: The relationship of salt intake to hypertension in the Japanese. Geriatrics, 19:735, 1964.

(18) Dahl, L.K.: Salt and hypertension. Am. J. Clin. Nutr. 25:231, 1972.

(19) Evans, J.G., and Rose, G.: Hypertension. Br. Med. Bull. 27:37, 1971.

(20) Dawber, T.R., Kannel, W.B., Kagan, A., et al: Environmental factors in hypertension. Edited by Stamler, J.,
  Stamler, R., and Pullman, T.N. New York, Grune & Stratton, Inc., pp. 255-282, 1967.

20


(21)

(22)

(23)

(24)

(25)

(26)

(27)

(28)

(29)


(30)



(31)


(32)

Florey, C., du, V., and Acheson, R.M.: Blood pressure as it relates to physique, blood glucose and serum
cholesterol. Same series as reference 4, Series 1 I, No. 34.

Bechgaard, P.: The natural history of benign hypertension. One thousand patients followed from 26 to 32
years. (Same reference as 20) pp. 357-363.

Lew, E.A.: Blood pressure and mortality. Life insurance experience. Ibid. pp. 392-396.

Wilson, C. and Byrom, F.B.: Renal changes in malignant hypertension. Lancer, 1:36, 1939.

Freis, E.D., Ragan, D., Pillsbury, H., and Mathews, M.: Alteration of the course of hypertension in the
spontaneously hypertensive rat. Circ. Rex In Press.

Byrom, F.B.: Pathogenesis of hypertensive encephalopathy and relation to malignant phase of
hypertension: experimental evidence from hypertensive rat. Lancet, 2:201, 1954.

Freis, E.D.: Hypertension and atherosclerosis. AM. J. Med. 46:735, 1969.

Sokolow, M., et al: Relationship between level of blood pressure measured casually and by portable
recorders and severity of complications in essential hypertension. Circulation, 34:279,1966.

Smirk, F.H., Veale, A. M. O., and Alstad, K.S.: Basal and supplemental blood pressure in relation to life
expectancy and hypertension symptomatology. N.Z. Med. J. 53:711,1959.

Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effect of treatment on
morbidity and mortality. Results in patients with diastolic blood pressures averaging 115 through 129 mm.
Hg. JAMA, 202: 1028,1967.

Ibid. II. Results in patients with diastolic blood pressures averaging 90 through 114 mm. Hg. JAMA,
213:1143, 1970.

Freis, E.D.: Mechanism of antihypertensive effects of diuretics: possible role of salt in hypertension. Clin.
Pharmacol. Ther. 1:337, 1960.

(33) Wilson, I.M., and Freis, E.D.: Relationship between plasma and extracellular fluid volume depletion and
  antihypertensive effect of chlorothiazide. Circulation, 20: 1028, 1959.
(34) Veterans' Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on
  morbidity. III. Influence of age, diastolic blood pressure, and prior cardiovascular disease. Further analysis
  of side effects. Circulation, 45 :99 I, 1972.

(35) Smith, W.M., et al: Cooperative clinical trial of alpha methyldopa. III. Double-blind control trial of alpha
  methyldopa and chlorothiazide and chlorothiazide and reserpine. Ann. Intern. Med. 65:657, 1966.

(36) Freis, E.D.: Guanethidine.Progr. Cardiovasc. Dis. 8:183, 1965.

(37) Gilmore, E., Weil, J., and Chidsey, C.A.: Treatment of essential hypertension with a new vasodilator in
  combination with beta-adrenergic blockade. N. Engl. J. Med. 282:521, 1970.

(38) Freis, E.D.: Medical Treatment of Chronic Hypertension. Mod. Concepts Cardiovasc. Dis. 40: 17, 197 I .

Distribution: CO: (IOlAl) 3,(112B) 100
FD      FLD: HA, DO, OC - per VAF 3-7225