Download Treatment of Severe Hypertension with Minoxidil

Clinical Science and Molecular Medicine (1976) 51, 587s-589s.
Treatment of severe hypertension with minoxidil and its
effects on systemic and pulmonary haemodynamics
D. H A L L , K . L . F R O E R A N D C. L O R A C H E R
German Heart Centre, Munich, West Germany
has been observed in several patients treated with
minoxidil for systemic arterial hypertension (Tarazi,
Magrini, Dustan, Bravo & Garvey, 1975; Dormois,
Young & Nies, 1975). Thus, in order to evaluate the
effects of minoxidil on the systemic as well as the
pulmonary circulation, treatment was initiated in
twelve of our patients under continuous haemodynamic monitoring.
summary
1. The chronic administration of minoxidil,
0.024-0.212 mmol (5-40 mg) daily, to fifty-two
severely hypertensive patients resulted in an average
reduction of mean arterial pressure from 170 to 111
mmHg.
2. Haemodynamic studies in twelve of these
patients indicated that the rise in pulmonary arterial
pressure in patients without heart failure appears
to be a direct result of a disproportionately large
increase in cardiac output with respect to a relatively small decrease in pulmonary vascular resistance. Anti-hypertensive treatment of patients with
congestive heart failure resulted in a decrease in
mean pulmonary arterial pressure.
Methods
Key words : haemodynamics, hypertension, minoxidil, pulmonary artery pressure.
Introduction
The effectiveness of the anti-hypertensive action of
minoxidil is well established (Gottlieb, Katz &
Chidsey, 1972; Pettinger & Mitchell, 1973). In our
present clinical evaluation we have achieved normal
or near-normal blood pressure in each of fifty-two
severely hypertensive patients whose blood pressure
could not be controlled with tolerable doses of
available anti-hypertensive agents.
By virtue of its action as an arterial vasodilator,
treatment with minoxidil usually results in a hyperdynamic circulation which necessitates concomitant
preceptor blockade. Although it has been reported
that minoxidil can reverse experimental hypoxic
pulmonary vasoconstriction (Weir, Chidsey &
Weil, 1975), a rise in pulmonary artery pressure
Correspondence: Dr D. Hall, German Heart Centre,
Lothstr. 11. 8 Munich 2, West Germany.
Fifty-two patients, more than half of whom have been
on minoxidil therapy for more than 1 year, were
studied. Patients were selected for treatment with
minoxidil on the basis of exhibiting hypertension
unresponsive to tolerable doses of available hypertensive agents. The patients, forty-one males and
eleven females, ranged in age from 24 to 71 years,
mean age 57 years. Mean arterial blood pressure
for the group before treatment was 256 f 15 @EM)/
137 f 12 (SEM) mmHg. The mean daily dose of
minoxidil was 0.126 mmol (range 0.0244212
mmol). All patients had a complete history and
physical examination. Laboratory evaluation, chest
X-ray, electrocardiogram and echocardiogram were
obtained from all patients at regular intervals of 3
months.
Initiation of treatment with 0.048 mmol every 8 h
was carried out under continuous haepodynamic
monitoring in twelve patients for an average of 60 h
by means of Swan-Ganz 7F Thermodilution Catheter
passed via a cubital vein into the pulmonary artery.
Group 1 consisted of patients who had no signs or
symptoms of congestive heart failure. Group 2
consisted of patients who were obviously in congestive heart failure (with cardiac enlargement,
third heart sound, and elevated pulmonary capillary
wedge pressure). Pressures were obtained with Sta-
5878
D. Hall, K. L. Froer and C . Loracher
588s
tham P23Db transducers and recorded on a Brush
481 recorder. Cardiac output was calculated at 6 h
intervals by the thermodilution technique. Right
atrial pressure, pulmonary artery pressure, pulmonary capillary wedge pressure and cuff measurements of brachial arterial blood pressure were
recorded at 6 h intervals. After stabilization of
systemic arterial and pulmonary arterial pressure
(usually 3 W 8 h after initiation of treatment),
0.042 mmol (10 mg) of isosorbide dinitrate was
administered sublingually during continuous recording of haemodynamic variables.
Results
The chronic administration of minoxidil, mean
dose 0.126 mmol (.-ange 0.024-0.212 mmol), combined with a mean dose of 1.7 mmol of propranolol
and appropriate diuretic treatment (hydrochlorothiazide or frusemide), resulted in a 37% reduction
of mean arterial blood pressure (population mean,
256/137 mmHg to 149/92 mmHg). In twelve patients
the initiation of treatment was carried out under
continuous haemodynamic monitoring for an
average of 60 h (range 38-120 h). Table 1 shows the
results of these studies. The oral administration of
0.048 mmol (10 mg) of minoxidil every 8 h lowered
mean arterial blood pressure during this initial
observation period in group 1 from a control value
of 167 mmHg to 119 mmHg ( - 29%), and in group 2
from 171 mmHg to 118 mmHg ( - 30%).In group 1
the heart rate rose from an initial value of 66/min
to 92/min (+32%), in group 2 from 83/min to
100/min ( + 17%). Cardiac output increased in
group 1 from 5.4 I/min to 8.3 I/min (+45%), in
group 2 from 4.8 I/min to 7.1 I/min (+32%).
In group 1 the mean pulmonary arterial pressure
rose from 14 mmHg to 20 mmHg (+29%), in
group 2 the mean pulmonary artery pressure decreased from 48 mmHg to 38 mmHg (-22%).
The pulmonary arterial resistance and the pulmonary
arteriolar resistance remained unchanged in group
1 , but showed a decrease in group 2 of 47% and
31 % respectively. The administration of 0.042
mmol (10 mg) of isosorbide dinitrate resulted in a
22% decrease in cardiac output in group 1 and
an 8% decrease in cardiac output in group 2, as well
as a 27% reduction in pulmonary arterial pressure
in group 1, and a 14% reduction in pulmonary arterial pressure in group 2. The pulmonary capillary
pressure was not significantly affected in group I ,
but showed a further 14% decrease in group 2.
Discussion
The efficacy of minoxidil as an anti-hypertensive
agent is well established. In our evaluation sustained
reduction of arterial blood pressure was achieved
TABLE
1. Haemodynomic changes resulting from treatntent with minoxidil only (0.048 mmol every 8 h )
Mean v a l u e s + s ~are
~ shown for all patients in each group.
Group 2 ( n = 5 )
Group 1 ( n = 7)
Change
Control
Mean arterial pressure
(mmHg)
167+8
Heart rate (beats/min)
66+7
Cardiac output (l/min)
5.4+0.4
Mean pulmonary artery
pressure (mmHg)
14+4
Pulmonary capillary
pressure (mmHg)
Ilk4
Total peripheral resistance
(dynes s cm-')
2460+168
Pulmonary vascular resistance
(dynes s an-')
212+31
Pulmonary arteriolar resistance
(dynes s cm-')
76k7
(%) Isosorbide")
Control
Minoxidil
119+7
92+8
8.3k0.8
-29
i-28
+45
116+8
96+7
6.5k0.7
171+17
llS+lO
20+4
+29
13+5
Minoxidil
Change
(%) Isosorbide")
-30
+I7
+32
112k11
103*5
6.6k0.6
83+11
100+6
4*8+0*3
7.1k0.6
15+4
48511
38+7
-22
33f7
+8
12+ 5
34+6
26+5
-24
21k6
1088+152
-54
1293+193
2856k220
l272+ 189
-55
1357k208
182k45
-13
184+36
810+96
431k42
-47
406+51
74+8
-2
72+8
200+32
136+24
-31
135+35
Values obtained 10 min after sublingual administration of 0.042 mmol (10 mg) of isosorbide dinitrate.
Minoxidil in hypertension
in all patients treated. Concomitant administration
of propranolol and diuretics was necessary to
counteract vasodilator-induced hyperdynamic circulatory states and retention of sodium and water.
Treatment was not terminated in any case because of
lack of blood pressure control. Hypertrichosis of
varying degrees was observed in two-thirds of the
patients. T-wave changes consisting primarily of
T-inversion evolved during the first 6 weeks of
treatment in the electrocardiogram in 70% of the
patients. These changes tended to revert to pretreatment appearances during chronic therapy.
The results of the haemodynamic studies of the
unopposed effects of minoxodil show that the
elevation of pulmonary arterial pressure in hypertensive patients without heart failure correlates well
with, and appears to be the result of, increased
cardiac output caused by arterial vasodilatation.
This conclusion is supported by the observation
that the rise of mean pulmonary artery pressure is
not associated with a rise in either pulmonary vascular resistance or pulmonary arteriolar resistance.
In fact, pulmonary vascular resistance is uniformly
seen to decrease during minoxidil therapy. This
decrease, however, i s not of the same magnitude as
that of the decrease in total peripheral resistance
and, apparently, not enough to offset the elevation
589s
of mean pulmonary pressure as cardiac output
increases. This is further supported by the fact that
the acute reduction of cardiac output caused by the
venodilatation and peripheral blood pooling of
nitrates is accompanied by a prompt return of
elevated mean pulmonary artery pressure to control
values. Finally, all of these changes occur in the
presence of a virtually unchanged pulmonary
arteriolar resistance. In contrast, the reduction in
mean pulmonary artery pressure documented in
hypertensive patients with congestive heart failure
is most probably the result of improved ventricular
performance subsequent to after-load reduction.
References
DORMOIS,
J.C., YOUNG,J.L. & NIES,A S . (1975) Minoxidil
in severe hypertension : value when conventional drugs
have failed. Anierican Heart Journal, 90, 360-368.
GOTTLIEB,
T.B., KATZ,F.H. & CHIDSEY,
C.A. (1972) Combined therapy with vasodilator drugs and beta-adrenergic
blockade in hypertension. Circulation, 45, 571-582.
PETTINGER,
W.A. & MITCHELL,
H.C. (1973) Minoxidil--an alternative to nephrectomy for refractory hypertension.
New England Journal of Medicine, 239, 167-171.
TARAZI,
R.C., MAGRINI.F., DUSTAN,H.P.,BRAVO,E.L. &
GARVEY,
J . (1975) Pulmonary hypertension with diazoxide
and minoxidil. American Journal of Cardiology, 35, 172.
WEIR,E.K..CHIDSEY,
C. & WEIL,J.V. (1975) Minoxidil acts
as a pulmonary vasodilator. Circulation, 51 (Suppl. 2).
133.