Effects of Minoxidil on Hemodynamics

in Patients with Congestive Heart Failure

JOSEPH A. FRANCIOSA, M.D., AND JAY N. COHN, M.D.

SUMMARY Vasodilators used in chronic congestive heart failure are not optimal in that nitrates are
predominant venodilators, prazosin is associated with tolerance development, and hydralazine produces
chronic toxicity. Therefore, we studied the acute hemodynamic effects of a single dose of minoxidil in 18
patients with chronic left ventricular failure caused by ischemic or primary cardiomyopathy. Peak effects were
observed 5 hours after single oral doses of minoxidil, averaging 15.3 ± 1.4 mg (SEM). Heart rate rose slightly,
from 85.4 ± 2.9 to 90.9 3.2 beats/min, after minoxidil (p < 0.02) and mean arterial pressure fell slightly,
from 88.0 ± 2.3 to 84.9 ± 2.5 mm Hg (p < 0.05). Cardiac index increased from 2.34 ± 0.14 to 2.95 ± 0.29
1/min/m2 after minoxidil (p < 0.02) and systemic vascular resistance fell from 19.6 ± 1.5 to 15.0 ± 1.3 units
(p < 0.01). Minoxidil did not affect right atrial, pulmonary arterial and pulmonary wedge pressures.
Hemodynamic effects of minoxidil persisted for at least 8 hours after a single dose. Minoxidil appears to be an
effective arterial dilating agent in patients with heart failure and resembles hydralazine in its actions. Because
of its potency, prolonged duration of action and relatively low toxicity, minoxidil may be a useful vasodilator
for heart failure. However, its long-term effect must be further evaluated.

NONE OF THE VASODILATORS available for use Methods

in heart failure is optimal.1 2 The effects of nitrates on
cardiac output are less consistent and smaller in
magnitude than those of other impedance reducing
agents.3 4 Prazosin may be associated with early
development of tolerance to its resting hemodynamic
effects, whereas hydralazine has little effect on ventric-
ular filling pressure in patients with heart failure.5-9
Although combining hydralazine with nitrates can
mimic the hemodynamic effects of a nitroprusside in-
fusion, a major limitation to the long-term use of
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Studies were performed in 18 male patients with
clinical and radiographic evidence of chronic left ven-
tricular failure due to ischemic or primary car-
diomyopathy. The former was diagnosed on the basis
of previous acute myocardial infarction documented
by serial electrocardiographic and serum enzyme
changes, or by coronary arteriographic demonstration
of significant coronary arterial occlusive disease.
Primary cardiomyopathy was diagnosed if no other

hydralazine is its propensity to produce a "lupus-like"
reaction.'0 11 To avoid this toxic effect, the dose of
hydralazine is usually limited, so patients may receive
suboptimal therapy.
Minoxidil, which has recently become available, is a
potent, orally effective vasodilator with predominant
arterial dilating activity, thus rendering it similar to
hydralazine.12 Unlike hydralazine, minoxidil has not
produced any major toxicity during long-term ad-
ministration to hypertensive patients.'3 It is an effec-
tive antihypertensive agent, and has been used in
isolated cases of left ventricular failure with good
results.'1216 Because currently available vasodilators
are less than optimal and because minoxidil has not
been systematically evaluated in patients with heart
failure, the present study was performed to define the
acute hemodynamic effects of a single dose of minox-
idil in patients with chronic left ventricular failure.
From the Cardiovascular Division, University of Minnesota
Medical School, and the Veterans Administration Medical Center,
Minneapolis, Minnesota.
Presented in part at the 52nd Annual Scientific Session of the
American Heart Association, Anaheim, California, November
1979.
Supported in part by the Medical Research Service of the
Veterans Administration, Washington, D.C.
Dr. Franciosa's present address and address for correspondence:
Joseph A. Franciosa, M.D., Veterans Administration Medical
Center, University and Woodland Avenues, Philadelphia, Penn-
sylvania 19104.
Received March 3, 1980; revision accepted July 25, 1980.
Circulation 63, No. 3, 1981.
652
cause of left ventricular failure was demonstrable. All
patients had objective evidence of left ventricular
dysfunction as measured by chest x-ray, M-mode
echocardiography or radionuclide angiography.
Patients with primary valvular heart disease, primary
pulmonary disease or acute myocardial infarction
within the last 3 months were excluded. Patients with
relative mitral insufficiency were included if left ven-
tricular ejection fraction was 45% or less.
All studies were performed in a special procedure
room adjacent to the coronary care unit. On the day of
study, all diuretics and vasodilators were withheld for
at least 24 hours before study; patients who were tak-
ing maintenance digitalis therapy were given their
daily dose of this medication.
After patients gave written informed consent, a
triple-lumen thermistor equipped Swan-Ganz catheter
(Edwards Laboratories) was inserted percutaneously
via an antecubital or femoral vein and advanced into
the pulmonary artery. In two patients, a #7 Cournand
catheter was inserted after unsuccessful attempts to
insert a Swan-Ganz catheter. In all patients, a
brachial artery was cannulated with a short Teflon
catheter advanced over an 18-gauge thin walled nee-
dle. All catheters and cannulae were connected to
P23D Statham pressure transducers positioned at the
level of the midaxillary line with the patient supine.
All pressures were recorded in this position on a Hew-
lett-Packard multichannel direct-writing recorder.
Pulmonary wedge pressure was taken as occluded
or diastolic pulmonary arterial pressure, and these
were not interchanged. Cardiac output was measured
 MINOXIDIL IN CHF/Franciosa and Cohn 653

by thermodilution (16 patients) or indicator dilution
using indocyanine green (two patients without Swan-
Ganz catheters). These two methods correlate very
closely, and the variation on successive determinations
by either method is less than 10% in our labora-
tory.'7' 18 Thermodilution outputs were done in tripli-
cate and dye-dilution curves in duplicate. Heart rate
and rhythm were recorded continuously electrocar-
diographically.
After allowing at least 30 minutes to elapse from
the time of completion of all invasive procedures, con-
trol measurements were made twice at 20-minute in-
tervals. These included heart rate, systemic arterial
pressure, right atrial pressure, pulmonary arterial
pressure, pulmonary wedge pressure and cardiac out-
put. To qualify for continuation in the study, patients
had to have systolic blood pressure 100 mm Hg or
higher and either pulmonary wedge pressure above 14
mm Hg or cardiac index below 2.5 I/min/.
In qualifying patients, oral minoxidil (Loniten, The
Upjohn Company) was then administered and
hemodynamics were measured at ½/2, 1, 1½/2, 2, 3, 4, 5,
6, 7 and 8 hours after drug. The effective dose of
minoxidil was established in the first several patients.
Pairs of patients were given the same dose of minox-
idil, which was progressively increased until both
patients in each pair had at least a 30% rise in cardiac
output without undesirable effects after minoxidil ad-
ministration. When this response was observed, eight
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more patients were given that dose. Ten patients were
studied after receiving the same effective dose of
minoxidil.
In addition to the hemodynamic responses, blood
specimens were drawn at control and at peak
hemodynamic effects after minoxidil for measurement
of plasma renin activity (method of Sealey et al.'9) and
plasma catecholamines (by radioenzymatic assay,
Cat-A-kit, Upjohn Company.)20 21 Systemic arterial
blood samples were also drawn for blood gas determi-
nation before and at peak minoxidil effect.
Systemic vascular resistance was calculated as the
ratio of mean systemic arterial pressure to cardiac
output and was expressed in units. Right atrial
pressures were not available in all patients and
therefore were not used in this calculation. Pulmonary
vascular resistance was calculated as mean pulmonary
arterial pressure minus pulmonary wedge pressure
divided by cardiac output, and was also expressed in
units. Statistical analysis was performed using the t
test to compare postdrug values to controls. These
latter were taken as an average of the two sets of con-
trol measurements.
Results
The baseline characteristics of the patient popula-
tion are summarized in table 1. Ischemic car-
diomyopathy was diagnosed in 10 patients and

TABLE 1. Characteristics of Patients with Left Ventricular Failure Given Minoxidil

Cardiothoracic Ejection
Age Clinical ratio fraction LVDD
Pt (years) Diagnosis class* (%) (%) (cm)t
1 68 IHD III 64 -
2 60 IHD IV 65 28 6.7
3 38 IHD III 55 15 5.7
4 60 PMD III 51 28 6.2
5 57 IHD III 59 24 5.6
6 56 IHD III 61 41 6.9
7 40 PMD III 55 37 7.0
8 52 PMD III 58 34 6.9
9 55 IHD III 57 16 6.1
10 65 PMD IV 62 22 7.4
11 57 IHD III 67 34 6.9
12 70 IHD III 63 39 6.8
13 54 PMD II 48 29 6.5
14 52 PMD III 52 47 5.3
15 53 IHD III 49 21 7.4
16 59 PMD III 58
17 61 IHD IV 55 45 5.5
18 61 PMD III 66 42 7.3
Mean 56.6 - 58.1 31.4 6.5
SEM -1.9 - 1.4 -2.5 0.2
*New York Heart Association criteria.
tM-mode echocardiography.
Abbreviations: IHD = ischemic cardiomyopathy; LVDD = left ventricular end-diastolic dimension;
PMD = pritnary cardiomyopathy.
 654 CI RCULATION VOL 63, No 3, MARCH 1981

primary cardiomyopathy in the other eight. Murmurs
of relative mitral insufficiency were present in eight
patients (nos. 2, 6, 7, 8, 12, 15, 17 and 18); atrial
fibrillation was present in four patients (nos. 5, 8, 14
and 17), and the others all had normal sinus rhythm.
All patients had been taking digitalis and diuretics and
four (nos. 1, 12, 15 and 17) had also been receiving
vasodilators (hydralazine and/or nitrates) for their
heart failure. The patient group as a whole had in-
creased cardiac dimensions by both chest x-ray and
echocardiogram, while ejection fraction was below
50% in every patient in whom it was measured. Thus,
all patients had objective evidence of left ventricular
dysfunction; heart failure had been present from 3
months to 5 years (average duration 21.5 ± 3.8
months (SEM).
Although all doses of minoxidil increased cardiac
output at some point after minoxidil administration,
the 5- and 7.5-mg doses did not produce an increase of
more than 30% in any patient. A dose of 20 mg was
the first to raise cardiac output by more than 30% in
both patients of a pair, and this dose was used in the
eight subsequent patients studied.
The time course of hemodynamic changes after
minoxidil administration is shown in figure 1. Cardiac
index was significantly increased by 1 hour, with the
increase peaking at 5 hours and persisting through 8
hours. Mean systemic arterial pressure was maximally
reduced also between 4 and 6 hours, but returned to
control by 8 hours.
Based on this time course of cardiac output
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analyzed at 5 hours (table 2). Heart rate rose slightly
but significantly, and mean systemic arterial pressure
fell slightly but significantly. The product of heart rate
and systolic pressure was unchanged (4.8 ± 3.6%).
Cardiac index at peak effect was significantly in-
creased; stroke volume was also higher, while systemic
vascular resistance decreased significantly. Pulmonary
wedge pressure did not change after minoxidil. The
three patients in whom cardiac index did not increase
at 5 hours, all had increases in cardiac index at other
times after minoxidil. When patient 14, whose cardiac
index more than doubled at 5 hours after minoxidil,
was excluded from analysis, the rise in cardiac index
was still significant in the other 17 patients
(0.42 ± 0.14 1/min/M2, p < 0.01). Right atrial and
mean pulmonary arterial pressures were not
significantly changed by minoxidil (9.2 ± 1.3 vs
9.9 ± 1.3 mm Hg and 34.8 ± 3.3 vs 36.1 ±2.0 mm
Hg, respectively). Pulmonary vascular resistance was
insignificantly reduced, from 2.9 ± 0.4 to 2.7 ± 0.3
units. Systemic arterial oxygen tension averaged
74.2 ± 4.5 mm Hg before and 72.5 ± 3.5 mm Hg
after minoxidil.
Only 10 of the 18 patients received 20 mg of minox-
idil, while the others received lower doses, so results in
the 10 who received the 20-mg dose were analyzed
separately. Their hemodynamic responses were like
those of the group as a whole; that is, a significant rise
in cardiac index and fall in systemic vascular

changes, peak hemodynamic effects of minoxidil were

PRA NEPI EPI DOP
(ng/ml/hr) (pg/mi) (pg/ml) (pg/ml)
8 * = P< 0.05 28- 700- 140- 70-
**= p <0.01
6 ***= p(0.00I
4 24 600- 120- 60-
Change in 2
mean
arterial C 1ir.. 1*
l l T T J
l0-
pressure 1 20
20*.
500- 100 50
(mmHg) -2
1i- x
-4
-6
-8L
*
16- 400- 80- 40- 1i
1.2 12- 300- 60- 30-
1.0
0.8 8- 200- 40- 20-
Change in 0.61
Cardiac 0.41 4- 100- 20- 10-
Index
(L/min/m2)0. 2
0- 0- 0- 0-
CM
FIGURE 2. Effect of minoxidil on plasma renin activity
(PRA) and catecholamine levels in patients with left ven-
0 2 3 4 5 6 7 E tricular failure. The dashed lines indicate the upper limits of
Time After Minoxidil ( hours ) normal in our laboratory. The asterisk indicates p < 0.05.
FIGURE 1. Time course of hemodynamic changes after Values are mean ± SEm. NEPI = norepinephrine; EPI =
minoxidil administration in patients with left ventricular epinephrine; DOP = dopamine; C = control, M = minoxi-
failure. Values are mean ± SEM. dil.
 MINOXIDIL IN CHF/Franciosa and Cohn 655

TABLE 2. Systemic Hemodynamic Effects of Minoxidil in Patients with Left Ventricular Failure
Mean
systemic Pulmonary Systemic
arterial wedge Stroke vascular
Minoxidil Heart rate pressure pressure Cardiac index volume resistance
dose (beats/min) (mm Hg) (mm Hg) (1/min/M2) (ml/beat) (units)
Pt (mg) C M C M C M C M C M C M
1 5.0 86 84 83 79 24 25 2.25 2.18 46 45 19 19
2 5.0 94 92 94 93 33 32 1.38 1.51 27 30 33 30
3 7.5 75 72 76 74 28 27 2.45 2.70 58 67 15 13
4 7.5 65 63 85 83 15 14 2.09 2.16 61 65 20 19
5 10.0 102 108 106 100 34 38 2.41 2.61 39 40 24 19
6 10.0 75 78 84 73 27 15 1.72 2.70 40 61 23 13
7 15.0 79 87 83 75 31 29 1.83 2.83 45 63 20 11
8 15.0 96 105 87 87 19 26 3.36 2.66 73 53 12 14
9 20.0 67 93 86 86 21 16 2.65 4.01 68 74 18 11
10 20.0 107 120 94 80 20 19 2.82 3.41 51 55 15 10
11 20.0 106 96 91 81 32 32 1.50 2.75 24 48 36 17
12 20.0 86 100 90 93 29 34 2.13 3.35 45 61 20 12
13 20.0 81 88 80 88 16 17 2.00 2.06 50 47 19 19
14 20.0 91 90 84 85 15 19 3.54 7.36 83 173 11 5
15 20.0 84 100 71 68 23 28 2.49 2.38 55 44 14 13
16 20.0 84 90 108 113 16 17 2.93 3.21 77 79 16 14
17 20.0 87 95 99 85 26 24 2.15 2.81 47 56 19 12
18 20.0 73 76 83 85 10 7 2.41 2.45 58 57 19 19
Mean 15.3 85.4 90.9 88.0 84.9 23.3 23.3 2.34 2.95 52.6 62.1 19.6 15.0
`- SEM 1.4 -2.9 -3.2 -2.3 -2.5 -1.7 i1.9 i 0.14 i0. 29 - 3.8 -7.1 1. 5 --1.3
Downloaded from http://ahajournals.org by on February 28, 2021

p < 0.02 < 0.05 NS < 0.02 < 0.1 < 0.01
Abbreviations: C - control; M = 5 hours after minoxidil.

resistance and no change in pulmonary wedge
pressure. When these 10 patients were compared to
the eight receiving smaller doses of minoxidil, the
magnitude of responses was not significantly different
between the two groups, although the rise in cardiac
index achieved significance only in the group receiv-
ing 20 mg of minoxidil.
Since an increase in cardiac index was the major
response to minoxidil, the data were analyzed to
assess factors that might have influenced this
response. There were no significant correlations
between changes in cardiac index and baseline
pulmonary wedge pressure, cardiac index, systemic
vascular resistance, left ventricular end-diastolic
dimension, cartiothoracic ratio or left ventricular ejec-
tion fraction. Also, mitral regurgitation did not affect
the change in cardiac index, which rose by 0.56 + 0.20
I/min/M2 in patients with this lesion, and by
0.65 ± 0.36 1/min/M2 in those without it. The rise in
cardiac index was also not different between patients
with ischemic (0.59 + 0.18 1/min/M2) or primary car-
diomyopathy (0.65 + 0.48 1/min/m2).
The effects of minoxidil on plasma renin activity
and catecholamine levels are shown in figure 2. All of
these variables were elevated at baseline, and only
plasma renin activity increased significantly after
minoxidil, while catecholamines were unchanged.
There were no significant correlations between
baseline plasma renin activity or catecholamines and
baseline hemodynamics. These measurements also
failed to correlate with any hemodynamic responses to
minoxidil.
Discussion
Minoxidil is a direct-acting vascular smooth-muscle
relaxant with a predominant arterial site of action; it
has been extensively evaluated as an antihypertensive
agent and is extremely potent, more so than
hydralazine, which acts similarly.12-15 Minoxidil has
been used to treat isolated cases of heart failure, and it
has significantly increased cardiac output.'6 The pres-
ent study extends these earlier isolated observations to
a series of patients with chronic normotensive left ven-
tricular failure in which the principal effect of minox-
idil was to raise cardiac output and stroke volume,
while lowering systemic vascular resistance. Heart
rate increased only slightly and blood pressure was
minimally reduced. Pulmonary wedge, pulmonary
arterial and right atrial pressures were unchanged.
 656 CIRCULATION
These hemodynamic changes are consistent with an
arterial dilating effect unaccompanied by venodila-
tion. The hemodynamic effects were demonstrable to
varying degrees, with single doses of minoxidil rang-
ing from 5-15 mg, but a single dose of 20 mg was
needed to obtain more uniform hemodynamic effects.
The presence of continued significant hemodynamic
effects at 8 hours after a single dose is consistent with
the previously reported prolonged duration of an-
tihypertensive effect of minoxidil.22 23
The clinical pharmacology of minoxidil has been
well documented in hypertensive patients in whom
both systolic and diastolic blood pressures are
reduced, even in patients refractory to other agents,
including hydralazine. 12-15, 22, 23 Cardiac output also
rises after minoxidil administration in hypertensive
patients without heart failure, but this increase may
result from significant tachycardia as well as increased
stroke volume.'2' 24, 25 Pulmonary arterial and wedge
pressures are likewise unaffected by minoxidil in these
patients, and earlier reports of pulmonary hyperten-
sion have not been substantiated, as more recent
studies have demonstrated reduced pulmonary vas-
cular resistance due to increased flow after minox-
idil.26 27 Pharmacodynamic studies demonstrate
almost complete absorption of minoxidil after oral
administration, with detectable blood levels evident by
0.5-1 hour and a plasma half-life of 4 hours.22' 23 How-
ever, antihypertensive activity peaks at 4-8 hours and
lasts more than 24 hours, consistent with the time
course of hemodynamic changes observed in the pres-
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ent patients with heart failure. This discrepancy
between blood levels and prolonged hemodynamic
effects might be explained by tissue binding in arterial
walls.23' 28 Thus, minoxidil is suited to once- or twice-
daily administration.
Long-term use of minoxidil in hypertensive patients
has not been associated with serious tox-
icity. 13-15, 24, 26, 29 The most common disturbing effect
has been hypertrichosis. Another side effect of long-
term minoxidil administration in hypertensive patients
is sodium and fluid retention, which would be un-
desirable in patients with heart failure. Most patients
with advanced heart failure take diuretics; they may
be mandatory when minoxidil is required. The in-
crease in heart rate after minoxidil in the present study
was small, and appears to be considerably less than
that in patients without heart failure.25
Minoxidil increases plasma renin activity and
catecholamine levels in hypertensive patients.12' 13 Pro-
longed stimulation of the renin-angiotensin system or
catecholamines in patients with heart failure could off-
set the initial acute hemodynamic benefits. However,
hemodynamic improvement could also lead to a
withdrawal of sympathetic tone in patients with heart
failure, which might explain the lack of a significant
rise in plasma catecholamine levels after minoxidil.
The present study shows that minoxidil is an orally
effective arterial dilator in patients with chronic left
ventricular failure. It produces hemodynamic im-
provement primarily by raising cardiac output and is
thus similar to hydralazine in this setting. Hydralazine
VOL 63, No 3, MARCH 1981
is associated with chronic toxicity, and minoxidil may
be more potent and less toxic, so minoxidil may be
preferable to hydralazine and deserves further evalua-
tion in patients with chronic left ventricular failure.
Switching from hydralazine to minoxidil should not be
done routinely, however, until the long-term safety of
minoxidil is established in heart failure. In the mean-
time, minoxidil should be considered only as an alter-
native to hydralazine when this latter agent has
produced toxicity or when its effects are suboptimal
and further increase in dose is considered unsafe.30
Acknowledgement
The authors are indebted to Mary Wilen and Susan Ziesche,
R.N., for their skilled technical assistance and to Ethel McGee for
her help in preparing the manuscript. We also thank Dr. William B.
Martin of the Upjohn Company, Kalamazoo, Michigan, for
generously providing supplies of minoxidil.
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