Combined Therapy with Vasodilator Drugs

and Beta-Adrenergic Blockade

in Hypertension
A Comparative Study of Minoxidil and Hydralazine
By THOMAS B. GOTTLIEB, M.D., FRED H. KATZ, M.D.,
AND CHARLES A. CHIDSEY III, M.D.

SUMMARY
The hypotensive efficacies of two vasodilators, hydralazine and minoxidil, were as-
sessed as these drugs were used individually in combination with beta-adrenergic
blockade and diuretics in 11 hypertensive patients in whom elevated blood pressure
had not been adequately controlled previously by other antihypertensive therapy.
Control supine blood pressure fell from 191/128 mm Hg on propranolol and hydro-
chlorothiazide to 169/108 mm Hg on hydralazine, with a significantly greater reduc-
tion to 142/92 mm Hg on minoxidil. Although sodium retention and tachycardia were
controlled by the use of concomitant diuretics and beta-blockade, an increment in each
of these drugs was occasionally required to prevent these complications. Renal func-
tion was changed little with the decrease in blood pressure. Plasma renin increased
from a standing control of 14.5 mgg/ml/hr to 35.9 and 31.1 m,gg/ml/hr, respectively,
on hydralazine and minoxidil. These data suggest the role of vasodilators used in
combination with beta-blockers and diuretics and indicate the greater therapeutic
efficacy of minoxidil.

Additional Indexing Words:

Antihypertensive therapy Propranolol Renin Aldosterone

T HE USE OF drugs which lower blood
pressure by direct dilation of the arterial
bed appears to be a logical approach to the
treatment of systemic hypertension. Such vaso-
dilator drugs will reverse the elevated periph-
eral vascular resistance characteristics of hy-
pertension without producing the side effects
so frequently encountered with drugs that in-
terfere with total adrenergic function.' In a
From the Department of Medicine, University of
Colorado Medical Center, Denver, Colorado.
Supported by grants from the National Heart and
Lung Institute (HE-05722 and HE-09932) and from
the Population Council, New York, New York.
Address for reprints: Dr. Charles A. Chidsey III,
Division of Clinical Pharmacology, University of Colo-
rado Medical Center, 4200 East Ninth Avenue, Den-
ver, Colorado 80220.
Received August 6, 1971; revision accepted for
publication October 21, 1971.
Circuation, Volume XLV, March 1972
previous study minoxidil, a new vasodilator,
was shown to lower blood pressure effectively
in hypertensive patients and to have a signifi-
cantly greater effect when combined with
beta-adrenergic blockade with propranolol.2
Beta-blockade itself has recently received con-
siderable attention in the treatment of hyper-
tension.3 4 However, the magnitude of the
antihypertensive response with beta-blockade
alone has been variable, with some investi-
gators reporting effective control of hyperten-
sion using propranolol,5 while others have
found minimal reductions using either pro-
pranolol6 or newer beta-blocking drugs, alpre-
nolol7 and practolol.8 In addition, propranolol
has been found not to lower vascular resis-
tance, and the observed hypotensive response
appears to be the consequence of a reduction
in cardiac output.6
571

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572
It would seem preferable to control blood
pressure in hypertension by lowering vascular
resistance with direct-acting vasodilators and
to use beta-adrenergic blockade secondarily to
prevent reflex stimulation of the heart, thus
maintaining an unchanged cardiac output. In
fact, this approach has been demonstrated us-
ing minoxidil combined with propranolol.`
In the present report we have extended our
previous observations with minoxidil2 to com-
pare its therapeutic power or efficacy directly
with that of hydralazine, the standard vaso-
dilator available for treatment of hypertension.
In this study we have examined the relative
antihypertensive efficacy of minoxidil and hy-
dralazine in a group of hypertensive patients
who were difficult to manage with convention-
al antihypertensive therapy. These two vaso-
dilators were used sequentially in the same
patients together with beta-blockade and di-
uretic therapy to inhibit both the reflexly in-
duced tachycardia and the sodium retention
that are known to accompany the effect of
vasodilators in hypertension.9 Thus, we were
able to compare the efficacy of minoxidil with
that of hydralazine in the control of severe
hypertension.
Methods
Eleven patients were studied ranging from 29
to 55 years of age; seven were males and four
were females; two were Negroes. Essential hyper-
tension was present in 10 patients and unilateral
renal artery disease complicated by azotemia was
present in one (K L A). Severe hypertension was
present in spite of the administration of a variety
of major antihypertensive drugs together with
diuretics in all but one patient (table 1). The sole
patient (D A V) not on therapy was unable to
tolerate alpha-methyldopa or hydrochlorothiazide
because of previous drug reactions and would not
accept guanethidine. Side effects of those anti-
hypertensive drugs being used when the patients
were considered for the study occurred in seven
of the patients. The extent of therapy before in-
clusion into the study reflected the patients' tol-
erance to the drugs. In several instances major
drugs had been discontinued earlier because of
intolerable side effects or lack of response to these
drugs.
Retinopathy was present in all, varying from
grade II to grade IV. Cardiac evaluation revealed
either electrocardiographic evidence of left ven-
tricular hypertrophy or radiographic evidence of
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GOTTLIEB ET AL.
left ventricular dilation or both. Three patients had
mild to moderate symptoms of hypertensive en-
cephalopathy and one had had a previous sub-
arachnoid hemorrhage. In all but one patient
(H U R) renal function was depressed and serum
creatinine levels ranged from 1.4 to 7.5 mg/
100 ml.
A complete description of the experimental na-
ture of the study and of the drugs to be used was
presented to all the patients and written consent
was obtained. Antihypertensive therapy, with the
exception of hydrochlorothiazide, was then dis-
continued for 1 to 3 weeks in seven patients;
in four other patients (B R I, P U L, K A U, and
M A C) the patients' clinical status would not
justify stopping these drugs during this prestudy
period and the patients were admitted to the study
without such a preliminary drug-free period.
The patients were hospitalized in the Clinical
Research Center of the University of Colorado
Medical Center for study. Throughout the study
all were placed on a sodium intake that was con-
stant in each patient but varied among the pa-
tients from 50 to 160 mEq/day, the level of sodi-
um intake being determined by individual dietary
histories. Daily weights were obtained and blood
pressures and heart rates were measured four times
daily with the patients in the supine and erect
positions. Twenty-four hour urine collections were
obtained for analysis of creatinine and sodi-
um output together with 3-day stool collec-
tions for sodium output which provided the data
for sodium balance studies.
Serial laboratory determinations were monitored
during a control, hydralazine, and minoxidil pe-
riod, including chest film, electrocardiogram, lupus
erythematosis (LE) preparation, and serum cre-
atinine, lactate dehydrogenase (LDH), creatine
phosphokinase (CPK), serum glutamic oxaloacetic
transaminase (SGOT), and antinuclear factor. In
addition, renal function was measured by clear-
ance techniques using continuous infusion of para-
aminohippurate (PAHl) and inulin contained in
0.9% NaCl at a rate of 1 ml/min.10 The urines
were collected with spontaneous voiding during a
water diuresis. Plasma renin activity and aldoste-
rone concentration were determined during the
three study periods by radioimmunoassay;t1 12
bloods were drawn after 8 hours with the pa-
tients in the supine fasting state and after 2
hours in the erect position. The data were analyzed
by standard statistical methods using Student's t-
test for paired data and linear regression analysis.
In eight patients the study was begun with a
control period of 4 to 6 days during which
these patients received diuretics and propranolol,
with the latter administered every 6 hours. In
the remaining three patients, a drug-free control
period was not present before vasodilator drugs
C'rculation, Volume XLV. March 1972
 :>
VASODILATOR DRUGS IN HYPERTENSION 573

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574 GOTTLIEB ET AL.
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VASODILATOR DRUGS IN HYPERTENSION
were started and the control values represented
those obtained during an initial hospital treatment
period on the general medical service prior to
transfer to the Clinical Research Ward. These pa-
tients (B R I, K A U, and M A C) were all on
alpha-methyldopa and hydrochlorothiazide and,
in addition, one (K A U) was on guanethidine as
well. In these patients the therapy period was be-
gun by adding propranolol and hydralazine simul-
taneously, continuing hydrochlorothiazide, and
discontinuing alpha-methyldopa and guanethidine.
Minoxidil and hydralazine were generally given
every 6 hours, although those patients who were
treated with less than 20 mg of minoxidil daily
received the drug less frequently. In one patient
(S C H) minoxidil was given prior to hydralazine;
following its discontinuance blood pressure re-
mained at the reduced level for at least 9 days, at
which time the study was discontinued and the
patient discharged. Therefore, in the subsequent
10 patients hydralazine was administered first for
5 to 10 days followed by minoxidil for 7 to 14
days, completing the study. One patient (B R I)
was readmitted later while on chronic minoxidil
treatment specifically for study of the time of onset
and duration of the hypotensive activity of
minoxidil.
Results
The therapeutic response to minoxidil was
greater than that to hydralazine in these hyper-
tensive patients (table 2). Hydralazine con-
sistently lowered the blood pressure when the
patient was in the recumbent position from an
average control level of 191/128 to 169/108
(P <0.01). This hypotensive response was
achieved without any orthostatic symptoms
and no postural decline in diastolic blood pres-
sure was observed. A moderate decline in sys-
tolic blood pressure was observed in nine pa-
tients, but this was present in both the control
and hydralazine periods. Substitution of min-
oxidil resulted in a markedly improved anti-
hypertensive effect, with the average blood
pressure declining from 169/108 on hydral-
azine to 142/92 in the group of 10 patients in
whom it was possible to compare the minox-
idil response directly to that of hydralazine
(P < 0.02). Again, there was an orthostatic de-
cline in systolic blood pressure, but here it was
of smaller magnitude than in the other pe-
riods of observation.
Circulation, Volume XLV, March 1972
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575
The hospital course of one patient (BAL)
particularly emphasizes the therapeutic effi-
cacy of vasodilators when used in combination
with beta-adrenergic blockade (fig. 1). This
patient was difficult to control in clinic because
she could not tolerate alpha-methyldopa be-
cause of its central nervous system side effects,
and guanethidine produced severe postural
hypotension in the absence of significant re-
duction of supine blood pressure. She devel-
oped symptoms of hypertensive encephalop-
athy on hydrochlorothiazide therapy in the
clinic and was admitted to the Clinical Re-
search Center because of these symptoms.
Initial therapy with alpha-methyldopa was
unsatisfactory because of recurrence of som-
nolence and symptomatic postural hypoten-
sion. Consequently, alpha-methyldopa was
stopped and propranolol was begun, followed
sequentially by hydralazine and then minox-
idil. Although some control of blood pressure
was effected by hydralazine (600 mg/day),
it was only when minoxidil was substituted
that adequate blood pressure control was
achieved. With supine blood pressures in the
140/88 mm Hg range, systolic postural hypo-
tension was observed, but this was not sympto-
matic, nor was there any decline in diastolic
pressure on standing. The systolic hypotension
that was observed on standing may have been
due to a relatively inadequate blood volume,
the consequence of excessive diuretics, in the
presence of minoxidil-induced dilation of the
vascular bed.
The complications of any vasodilator used
in the hypertensive patient, such as tachycar-
dia, sodium retention, and weight gain, were
not observed in this group of patients. Al-
though tachycardia vas not encountered dur-
ing the hypotensive response with hydralazine
and minoxidil, increased adrenergic blockade
was required during minoxidil in four patients
to maintain heart rate at the control level
(table 3). It was of some interest to determine
how long propranolol would be required to
block the reflex adrenergic stimulation of car-
diac function associated with vasodilation and
a reduced blood pressure. In one patient (fig.
2), propranolol was discontinued for 2 days
/D GOTTLIEB ET AL.

200
cr
E
E

Un
150
llJJ
c0

0
0

m
100.

1. 1 .
- _ . . . . 2 . . .

10 20 3 i0 DAYS
500]_ 40j0 5]
ox-MD Hydralazine Minoxidil
Figure 1

Hospital courXse of patient B A L during treatment sequentially with alpha-methyldopa (a-MD),

hydralazine, and minoxidil. Hydr ochlorothiazide was adninlistered continually and propran-
olol wias combined with vasodilators. Supine blood pressure is indicated by the open circles
and erect by the closed circles.

after control of blood pressure was achieved observed a small increase of weight in only
with minoxidil. It is evident that in the absence one patient (PUL), and this occurred in the
of beta-blockade there was a striking increase absence of any change in diuretic therapy. In
in heart rate to 114 beats/minute and an un- this patient, after the recorded observations
questionable increase in blood pressure. We had been made, an increase of diuretics (to

Table 3
Drug Data in Patients duering Study
Drtugs (mg/day)
Vasodilators Hydrochlorothiazide Propranolol
Patient H MI C H M C H M
SCH 2.5 200 200 80 80
BAL 600 2.0 ;50 50 o0 80 120 120
KLA 600 4.0 .50 50 150 40 o0 80
YOU 400 5. 5( 30() 50 160 160 160
BRIi 600 7.5 100 100 100 0 80 120
PUL 800 30.0 100 100 100* 60 80 160
KAU 600 20.0 50 50 570 0 80 160
DAV 200 7.5 2,t 25t 25 t 8( 80 80
SEL 400 10.0 50 50 40t 160 160 160
HUR 600 30.0 100 30 50 80 160 160
MAC 800 20.0 40t 40$ 160t 0 80 160
Abbreviations: H hydralazirne; :1 = minoxidil; C control.
*Ftlrosemide was added after studv observations were made.
tEthacrynic acid.
tFurosemide.
Circulation, Volume XLV, Marcb 1972

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VASODILATOR DRUGS IN HYPERTENSION 577

[E] MINOXIDIL I and minoxidil, but the average increase in the

group as a whole was insignificant during each
200. treatment period. Although sodium retention
c,.
I was not observed on either vasodilator with
E the dietary sodium loads that were used, di-
E
X minished sodium excretion was observed tran-
W siently in six of seven patients during minoxidil
U) 150. with the acutely increased sodium load (150
Un
W
LL ,Eq/min) used during the renal clearance
er
studies.
0
0
Plasma renin was evaluated with the pa-
0 tients in both the supine and erect positions
m at the end of each study period in seven of 11
100
patients (fig. 3). During the control period
plasma renin was elevated in all but two of
these patients, with a mean value of 9.3 in the
E 100.
I- supine position and 14.5 mgg/ml/hr in the
erect position. These compared with control
values of 1.6 and 3.4 m,ug/ml/hr obtained in
W
80 normotensive subjects in the supine and erect
U)
positions, respectively.'1 Renin values tend-
CLj ^
ed to be higher during vasodilator periods
6'0 7 0,7 0, 2 '4' 6, 8' 10`12 DAYS with subjects in both the supine and erect
positions. However, the increases between the
IPROPRANOLOL8 80
treatment periods when blood pressure was
S 100
IHCTZ 100
reduced by the vasodilator were significant
Figure 2
Blood pressure and heart rate data are summarized
only when one compared the hydralazine, both
from one patient (P U L) during the control period supine and erect, or the supine minoxidil val-
(C), the hydralazine period (H), and the minoxidil pe- ues to control values (P < 0.05). It was notable
riod. The effect of withdrawing propranolol (arrows) that in spite of a greater reduction in blood
is shown by the increase in blood pressure and heart
rate. HCTZ = hydrochlorothiazide.
pressure during minoxidil, the plasma renin
values were somewhat lower than during hy-
dralazine, although these differences were not
40 mg/day of furosemide) effected a return
to her control weight. Similar increases in di-
significant. Indeed, when a comparison of the
uretics were required in only two other patients individual changes in blood pressure were
(SEL and MAC) during the study period, made with the renin values, no overall correla-
specifically in order to maintain weight at the tion could be observed between increases in
control level (table 3). The sodium balance renin and decreases in blood pressure with
data provided no evidence of sodium accumu- subjects in either the supine or the erect posi-
lation. tion. Plasma aldosterone was not consistently
Renal function was variable in the patients altered by either of these two vasodilators in
studied, ranging from normal values to levels spite of the increased renin levels (table 4).
of frank azotemia (table 4). The glomerular During the control period on diuretic and pro-
filtration rate was largely unchanged during pranolol therapy, supine and erect values aver-
the hypotensive response to either hydralazine aged 404 and 1,032 pg/ml, respectively, com-
or minoxidil. The effective renal plasma flow pared with control values of 139 and 334 pg/
was slightly increased during both hydralazine ml in normotensive subjects.12
Circulation, Volume XLV, March 1972

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578 GOTTLIEB ET AL.
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 VASODILATOR DRUGS IN HYPERTENSION
100
- 80'
-f 60-
z
z dilation.2 Minoxidil has been shown to lower
m 40
tn
4 20
0C
S E E E
CONTROL
S
HYDRALAZINE
S
MINOXIDIL
Figure 3
Plasma renin activity (mgig/ml/hr) as measured with
patients in both supine (S) and erect (E) positions in
all three study periods. The mean and individual values
are given.
Symptomatic improvement was noted in
those three patients who had significant symp-
tomatology in the control period (BAL,
BRI, and PUL). These patients all had evi-
dence of mild to moderate encephalopathy,
and these findings cleared completely when
blood pressures were established within the
therapeutic range. Although some improve-
ment of symptoms was observed with the
hypotensive effect of hydralazine, it was only
with the administration of minoxidil that com-
plete resolution of the patients' symptoms was
achieved. Untoward symptoms were minimal
in both the hydralazine and minoxidil periods,
and these were confined to transient angina in
three patients (KLA, KAU, and MAC)
during the initiation of minoxidil therapy. This
symptom was controlled by adjustment of the
minoxidil dosage so that more gradual reduc-
tion in blood pressure was accomplished or
by increasing the propranolol dosage. The an-
gina occurred without changes in serial electro-
cardiograms or in serum enzymes.
Clinical studies of potential chemical toxicity
of hydralazine, as used in these high doses,
and of minoxidil were carried out. No altera-
tion in serum enzymes, antinuclear factor, or
LE preparations was observed. Also, the ECG
and chest films were unchanged during the
two treatment periods.
Discussion
There is a rational physiologic basis in an
approach to the therapy of hypertension based
Circulation, Volume XLV, March 1972
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579
on peripheral vascular dilators used in com-
bination with beta-adrenergic blocking drugs,
with the latter being used to attenuate the
reflex adrenergic activity stimulated by vaso-
arterial blood pressure in experimental animals
by a direct action on vascular smooth muscle
and to exhibit no interference with autonomic
function (W. A. Freyburger: Unpublished ob-
servations). Furthermore, recent animal stud-
ies have shown the drug to be specifically re-
tained in arterial tissue, which supports the
contention that this may be its locus of action.13
The results of our present observations of the
use of minoxidil in hypertensive patients who
are relatively refractory to conventional anti-
hypertensive therapy establish this approach as
an effective means of lowering blood pressure
and confirm earlier preliminary observations
from this laboratory that minoxidil can reduce
blood pressure when used in combination with
propranolol.2 In the present study we have
shown, by direct comparison in the same group
of patients, that minoxidil is in fact more ef-
fective as an antihypertensive drug than is
hydralazine. Not only were much smaller
amounts of drug required to achieve blood
pressure control in these patients, indicating
greater pharmacologic potency, but in addi-
tion minoxidil exhibited clearly greater efficacy
or power. Thus, in four patients the hypoten-
sive response to hydralazine was inadequate
in spite of extremely large doses, whereas sub-
stitution of minoxidil resulted in a substantially
greater hypotensive effect. In only one patient
(BRI) was the blood pressure response in
minoxidil less than adequate, and in this pa-
tient the maximum hypotensive effect was not
pursued because of a history of cerebral vas-
cular disease in this patient. Furthermore, in
eight patients on chronic therapy of up to 10
months we have recently encountered no evi-
dence of tachyphylaxis to minoxidil. It must
be emphasized that the doses of hydralazine
were clearly excessive and were of a magnitude
that could not be justified on any but a short-
term basis because of the possibility of devel-
opment of a lupus erythematosis-like syn-
drome.14 This problem, although considered
580
as a potential complication of minoxidil in our
earlier report,' has not been found to be of
substance in these present observations, and
antinuclear factor and LE preparations have
been consistently negative.
Although the rationale for the use of beta-
adrenergic blocking drugs in conjunction vith
vasodilators has been suggested in earlier re-
ports,2-4 the importance of these drugs requires
further definition. Vasodilators have long been
recognized as being capable of producing
symptoms of myocardial ischemia,9 and these
drugs have not customarily been employed
without some form of generalized inhibition of
adrenergic function.15 The specificity of beta-
blockade in inhibiting primarily the cardiac
component of adrenergic innervation makes it
possible to utilize powerful vasodilators in
hypertension without the side effects attendant
on generalized inhibition of adrenergic func-
tion. Interference with the reflex stimulation of
cardiac activity may also be important in
diminishing the subjective manifestations, such
as palpitations and headache, which have been
noted with two vasodilators, hydralazine9 and
guancydine.'6
A further property of beta-blockade that
should be emphasized is its capacity to effect
a greater hypotensive response than that
achieved with a vasodilator drug used alone.2
This effect is accomplished by preventing or
attenuating the augmentation of cardiac out-
put, thereby lowering blood pressure without
any further alteration of vascular resistance.
Propranolol used in this manner appears to be
better justified than when used alone in the
hypertensive patient, since vascular resistance
remains elevated under these latter eircum-
stances.6 Combined therapy with propranolol
and minoxidil requires judicious adjustment of
the levels of beta-blockade while achieving a
maximal hypotensive effect with minoxidil.
Thus, it was necessary in the present study
occasionally to increase the amount of propran-
olol or to adjust the amount of minoxidil to
avoid excessive cardiac activity with the oc-
casional transient appearance of angina.
The diuretics are drugs of equal importance
for use in combination with minoxidil or, in
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GOTTLIEB ET AL.
fact, with any vasodilator. Sodium retention
has been observed clinically with a variety of
vasodilators, and it has been suggested that
the renal tubular basis of this response is
mediated by enhanced sodium reabsorption in
the proximal convoluted tubule.17 We have
shown that small amounts of hydrochlorothi-
azide are adequate to prevent sodium reten-
tion under most circumstances. In three
patients with varying degrees of renal insuffi-
ciency it was necessary to increase the diuretic
therapy to include furosemide during maximal
blood pressure reduction with minoxidil. So-
dium excretion during the renal clearance
studies under the stimulus of a sodium load of
150 gEq/min was in fact reduced in all pa-
tients. However, with the exception of the
three patients mentioned above, sodium bal-
ance was maintained on the individual dietary
sodium intakes, suggesting preservation of the
capacity to handle sodium under normal cir-
cumstances but a defective potential for dis-
posing of large acute sodium loads. The use of
diuretics in this study may have been re-
sponsible for the fact that approximately equiv-
alent hypotensive responses were achieved
with smaller amounts of minoxidil than were
employed in our earlier study.2 Furthermore,
we observed some moderate postural systolic
hypotension in the present study, whereas this
was not appreciated earlier with minoxidil.
This may have been the result of diuretic ther-
apy which induced a hypovolemia, relative to
the dilated vascular bed. It should be empha-
sized that such hypovolemia may be especially
undesirable in the presence of inadequate
renal function and in these circumstances
might be unnecessary with the use of minox-
idil, which has such marked pharmacologic
power. Perhaps these patients would have had
a similar therapeutic response with smaller
amounts of diuretics and larger amounts of
minoxidil.
There were no other side effects except those
of increased cardiac activity and sodium re-
tention during the short-term evaluation of
minoxidil. Headache and palpitations specifi-
cally were not encountered. The laboratory
Circulation, Volume XLV, March 1972
VASODILATOR DRUGS IN HYPERTENSION S81
tests that were monitored revealed no altera- hypertension, may be used clinically. We have
tion of- renal or hepatic function. However, made preliminary observations regarding dura-
moderate hypertrichosis has been observed in tion and onset of action of the drug when used
five of eight patients on chronic treatment for orally. The hypotensive effect was found to
more than 2 months. The mechanism of this persist for several days after the drug was dis-
side effect has not been identified. This com- continued (fig. 4). After reinstitution of ther-
plication has also been seen with diazoxide.18 apy with a single oral dose of the drug, the
Observations on plasma renin were generally onset of hypotensive action was rapid, occur-
consistent with that response which could be ring within a few hours. Although the rate at
anticipated with the use of vasodilators.19 Plas- which controlled blood pressure values will
ma renin tended to be higher during blood return to a hypertensive level when therapy is
pressure reduction with both vasodilators, al- stopped may be extremely variable, more se-
though, despite the greater therapeutic re- verely hypertensive patients generally tend to
sponse to minoxidil, plasma renin was no great- revert more rapidly to their pretreatment
er during that period than during hydralazine. levels.23 However, no data directly comparing
Individual patient responses were not exactly the duration of action of minoxidil with that of
compatible with existing concepts of renin se- other vasodilators are available at this time.
cretion.20 Thus, changes in plasma renin could If the suggestion of the prolonged action which
not be correlated with individual hypotensive we have derived from our clinical observations
responses or with decreases of sodium output. can be substantiated, minoxidil would provide
One important pharmacologic factor in the an important advantage in therapy of hyper-
renin response of this group of patients may be tension, since patients might be treated with
that of propranolol. This drug has been sug- a single daily dose.
gested to interfere with renin release,21 and
this factor may have played a role in the pres-
ent observations.
The lack of increase of aldosterone levels as 200'
the renin values increased was an unexpected
finding in view of the well-established relation-
ship between plasma renin activity and both I
aldosterone secretion and excretion rates.22 E
These findings are consistent with our previous E
measurements of aldosterone excretion, which W 150
demonstrated that aldosterone excretion was Cl)
unchanged in patients treated with minoxidil (n
C)
W
when they received propranolol concurrently.2 a-
However, the explanation of the failure of
aldosterone secretion to increase (as indicated 0 100
by the -plasma aldosterone concentration) in 0
the face of significant increases in plasma renin m
iM 20mg/d
4.M 20mg
is not readily apparent. It is interesting to spec-
ulate that propranolol may not only interfere |PROPRANOLOL 160 mg/d
with renin release21 but may alter the effect of FUROSEMIDE 80 mg/d
the renin stimulus on the secretion of aldoste- 0 2 4 6 8 6 4 A 2 16 2
rone either by inhibition of angiotensin I con- DAYS HOURS
version or by a direct effect on the adrenal Figure 4
cortical response to angiotensin II. Blood pressure data on a patient (B R I) following
As a final point, we have considered how discontinuance of minoxidil (M) and after readminis-
minoxidil, which clearly is effective in severe tration of a single oral dose (arrow).
Circulation, Volume XLV, March 1972

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582
Acknowledgment
The authors wish to acknowledge the excellent tech-
nical assistance of Misses Dorothy Walker and Karen
Yoor, and the secretarial help of Mrs. Dale Scarbor-
ough.
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Circulation, Volume XLV, March 1972
Combined Therapy with Vasodilator Drugs and Beta-Adrenergic Blockade in
Hypertension: A Comparative Study of Minoxidil and Hydralazine
THOMAS B. GOTTLIEB, FRED H. KATZ and CHARLES A. CHIDSEY III

Circulation. 1972;45:571-582
doi: 10.1161/01.CIR.45.3.571
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX
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