Download Prazosin: Preliminary Clinical and Pharmacological Observations

Clinical Science and Molecular Medicine (1915) 48, 177s-119s.
Prazosin :preliminary clinical and pharmacological observations
P. BOLLI, A. J. W O O D , E. L. P H E L A N , D. R. LEE
AND
F. 0. S I M P S O N
Wrllcome Medical Research Institute (Department of Mrdicine),
Unioersity of Otago Medical School, Dimedin, New Zraland
summary
in vitro (M. Aylott & H.-J. Hess,. unpublished
work).
.
1 . Pr&,sin had a considerable anti-hypertensive
effect in both lying and standing posture in a mixed
group of twenty-four patients in an open clinical
trial. The drug was well tolerated and side-effects
were few.
2. Tested on rat blood vessels, prazosin was ten
times more potent on a molar basis than phentolamine in blocking the vasoconstrictor effects of
noradrenaline.
the absence of vasoconstrictor
nervous activity, no vasodilatation was observed.
3. In genetically hypertensive rats, prazosin in
large doses caused a substantial fall in blood pressure,
total exchangeable sodium and extracellular fluid
volume. Tolerance to these effects started to develop
within 20 days. In normotensive rats, blood pressure
was
but total exchangeable sodium and
extracellular fluid volume were not affected.
w e have carried out an open clinical trial of
prazosin and also some pharmacological studies in
normotensive and genetically hypertensive (Smirk
& Hall, 1958; Phelan, 1968) rats.
clinical studies
Twenty-four patients (fourteen male, ten female,
mean age 57 years) with mainly essential hypertension
were given prazosin for periods of 2 months to 2
years. The drug was used either in addition to other
agent in
anti-hypertensive therapy Or as the
patients who had not had previous treatment'
Dosage ranged from to 36 mg/day bean
12'5mg).
Blood pressure was recorded in the lying and
standing positions with an electronic version of the
London School of Hygiene and Tropical Medicine
'blind' sphygmomanometer (Rose, Holland &
Crowley9 1964)*
The results obtained from the last half-day test
before prazosin was started were compared with
those obtained from the last three half-day tests
before a fixed assessment date, or before the withdrawal of prazosin or the addition of other antihypertensive drugs in three patients in whom
prazosin was not effective.
The mean fall in blood pressure was 20/10 mmHg
(lying) and 25/15 mmHg (standing). Other concomitant anti-hypertensive therapy did not greatljr
Key words : a-adrenoreceptor-blocking agents, antihypertensive therapy, exchangeable sodium, prazosin.
Introduction
Prazosin is a new anti-hypertensive drug (Cohen,
1970; Kincaid-Smith, Fang & Laver, 1973; BOHi Lk
Simpson, 1974). Its action has been ascribed to the
combined effects of direct relaxation of vascular
smooth muscle and blockade of a-adrenoreceptors,
possibly occurring at a site between the receptor and
the contractile process within the cell (Constantine,
McShane, Scriabine & Hess, 1973). Prazosin inhibits phosphodiesterases from rat heart and aorta
Correspondence: Dr P. Bolli, Wellcome Medical Research
Institute, P.O. Box 913, Dunedin, New Zealand.
influence the effect of prazosin. When prazosin was
added to a regimen including a beta-adrenergicblocking agent a postural fall in blood pressure
became more marked, particularly after the initial
dose, but postural hypotension was not a problem
in the long-term management. Though some patients
were more sensitive to the initial dose of prazosin
177s
P. Bolli et al.
178s
than to later similar doses there was n o evidence of
the development of tolerance once an effective dose
was found. Three patients did not respond satisfactorily to prazosin in doses u p to 30 mg daily.
After a n exercise test (80 steps in 2 min) the systolic blood pressure rose, the rise being greatest in
patients on prazosin alone. Pulse rate also rose with
exercise, except in the group takinga beta-adrenergicblocking drug.
Thirteen patients with well-controlled blood
pressure underwent a dose-reduction trial. The dose
of prazosin was reduced by one-third and the blood
pressure measured in a half-day test 1 week later.
The blood pressure rose significantly ( P < 0.01) by
15/8 mmHg (lying) and 17/11 mmHg(standing). The
degree of rise in blood pressure was not related to the
dose of prazosin, to the severity of the hypertension,
or to the type of concomitant therapy.
Side-effects were not a problem. One patient
(taking prazosin, methyldopa, cyclopenthiazide and
pindolol) dreamt of micturating and actually wet his
bed. One patient (taking reserpine, diazepam and
cyclopenthiazide) developed sinus tachycardia and
episodes of probable paroxysmal tachycardia; the
pulse rate fell on stopping prazosin. Routine
laboratory tests, including renal and hepatic function, gave normal results during prazosin therapy.
Examination of lenses and retinae at the Department
of Ophthalmology, Dunedin Public Hospital (Associate Professor J. C. Parr) on two occasions at 6-
monthly intervals in sixteen patients showed no
changes attributable to prazosin therapy.
Pharmacological studies
When prazosin (8 x
mol/l) was added to the
Locke's solution perfusing the isolated rat mesenteric
artery preparation (McGregor, 1965), the responses
to intra-arterial injections of noradrenaline (2 pg)
and to stimulation of periarterial nerves (75 V, 1 ms,
16 Hz for 10 s) were virtually abolished. Prazosin
and phentolamine produced qualitatively similar
shifts to the right of the noradrenaline doseresponse curve; on a molar basis prazosin was about
ten times the more potent antagonist. These results
are consistent with a-adrenoreceptor blockade, as
suggested by Constantine et a / . (1973). We were
unable to draw conclusions about the nature of the
n-receptor blockade by prazosin.
In normotensive and hypertensive rats both the
threshold dose required to produce a depressor
response and the depressor response to a dose of 10
,ug/kg were identical regardless of whether prazosin
was injected into a femoral vein or a lateral cerebral
ventricle. Prazosin therefore appears not to have its
principal anti-hypertensive effect in the central
nervous system.
Prazosin injected into the main circulation of a rat
whose vascularly isolated but nervously intact hind
limb was perfused with blood from a separate d o n o
u
Prazosin (IOpg/min)
L
60
-
Prazosin (IOpg/min)
Time ( m i d
FIG. I . Effect of prazosin (10 ,uug/min, intra-arterial infusion) on perfusion pressure of auto-nerfiisedhind limbs of
norniotensive rats, (a) with nerves intact and (b) w i t h nerves sectioned.
Preliminary observations on prazosin
rat (Field & Laverty, 1958) had no effect on the
perfusion pressure of the hind limb. In contrast,
clonidine when injected similarly produced a substantial nervously mediated fall in hind-limb perfusion pressure.
When prazosin (10 pglmin) was infused into the
arterial supply of the isolated hind limbs of normotensive and genetically hypertensive rats, perfused
with the rat’s own blood (Laverty, 1962), it caused a
significant fall in limb perfusion pressure as long as
the nerves were intact. After section of the nerves,
however, a direct vasodilator effect of prazosin could
not be demonstrated (Fig. 1). (Sodium nitroprusside
and sodium nitrite decrease perfusion pressure
substantially in these circumstances.) Constantine
et al. (1973), however, found an increase in femoral
arterial blood flow in dogs in response to prazosin,
even after hexamethonium treatment.
Prazosin (approximately 25 mg day- kg-I)
added to the diet of normotensive and genetically
hypertensive rats lowered blood pressure (intraarterial, ether anaesthesia) from 112 to 76 mmHg in
normotensive rats and from 174 to 122 mmHg in
genetically hypertensive rats, after 7 days. By day 17
some tolerance had developed. Heart rate rose by
day 3 of prazosin treatment and heart rate remained
elevated, about 33% above normal, for the duration
of the 17-day treatment period.
Total exchangeable sodium was measured repeatedly by the method of Dusting, Harris & Rand
(1973) at intervals during a 24-day treatment (25
mg day- kg- I ) period. Genetically hypertensive
rats showed a striking fall of about 30-35% in total
exchangeable sodium, maximum at about day 8.
Total exchangeable sodium had returned to normal
by day 20. Extracellular fluid volume (measured by
the method of Belcher & Harriss, 1957) was similarly
affected. The sodium loss was confirmed in another
series of experiments by measurements of total
carcass sodium (Wood & Lee, 1974). In normotensive rats total exchangeable sodium and extracellular fluid volume were not affected although
prazosin lowered blood pressure in these animals
also.
Conclusions
Prazosin appears to be a promising anti-hypertensive
agent. It has powerful a-adrenoreceptor-blocking
properties and is a phosphodiesterase inhibitor. A
direct effect on vascular smooth muscle, i.e. not due
179s
to a-receptor blockade, was not found in the bloodperfused rat hind limb. The large fall in total
exchangeable sodium produced by prazosin in high
dosage in genetically hypertensive rats is unexplained.
Acknowledgments
The work of the Dunedin Hypertension Clinic is
supported by the Otago Hospital Board and the
Medical Research Council of New Zealand. Some of
the expenses were met from a grant from Pfizer
Laboratories Ltd. D.R.L. is a Commonwealth
Scholar. The exchangeable sodium studies were made
possible by equipment purchased with grants from
the National Heart Foundation of New Zealand and
the Medical Research Distribution Committee.
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