Clinical Science (1979)57,115el17s
Acute and chronic effects of nifedipine on plasma renin
activity and plasma adrenaline and noradrenaline in
controls and hypertensive patients
L. C O R E A , N. M I E L E , M. B E N T I V O G L I O , E. B O S C H E T T I , E. A G A B I T I R O S E I * A N D G. M U I E S A N *
Istituto di Semeiotica Medica. University of Perugia, and*Clinica Medica V,University of Milan, Italy
Summary
Introduction
1. Nifedipine, a calcium antagonist drug, was
given sublingually (10 mg) to seven normal
subjects and 19 patients with essential hypertension. In addition, 12 of the hypertensive subjects
then received nifedipine (10 mg thrice daily) for 3
weeks.
2. Sublingual administration of nifedipine in
hypertensive patients induced a prompt and sustained reduction of blood pressure, without a
significant increase of heart rate; in normotensive
subjects blood pressure did not change, and heart
rate was significantly increased. After chronic
treatment, blood pressure remained reduced and
heart rate did not rise.
3. Plasma catecholamines and plasma renin
activity increased significantly in normotensive
subjects after acute administration.
4. After both acute and chronic administration,
only plasma noradrenaline was significantly
increased in hypertensive patients; in long-term
treatment, it was increased in both the lying and
standing positions.
5. Nifedipine is an active antihypertensive drug,
which may induce some degree of sympathetic activation.
Cardiac and vascular smooth muscle functions are
controlled, at least in part, by the intracellular ionic
environment, especially by the distribution of the
calcium ions in the cells. Calcium antagonists,
blocking contraction of myocardial and vascular
fibres and inducing their relaxation, lead to a
negative inotropic effect and vasodilatation (Kroneberg, 1975).
Several studies have shown that calcium antagonists (nifedipine, verapamil and others) are
potent antihypertensive agents (Bartorelli, Magrini,
Moruzzi, Olivari, Polese, Fiorentini 8c Guazzi,
1978; Bender, 1970). The use of vasoddating drugs
is often associated with a reflex activation of the
sympathetic nervous system, with consequent
increased heart rate, cardiac output and renin
release (Gilmore, Weil & Chidsey, 1970; Ueda,
Kaneko, Takeda, Ikeda & Yagi, 1970).
In this study we have investigated the effect of
nifedipine, a calcium antagonist, on blood pressure,
heart rate, plasma noradrenaline and adrenaline,
and plasma renin activity, in normotensive volunteer subjects and in hypertensive patients.
Material and methods
Key words: antihypertensive agent, calcium antagonists, catecholamines, plasma renin activity.
Abbreviation: PRA, plasma renin activity.
Correspondence: Dr L. Corea, Istituto di Semeiotica
Medica, University of Perugia, Perugia, Italy.
Seven normotensive healthy subjects (four males,
three females) with a mean age of 34 years (22-48
years) and 19 mild to moderate essential hypertensive patients (nine males, ten females) with a
mean age of 38 years (22-55 years) were studied.
All patients had a complete diagnostic examination to exclude secondary hypertension. All had
a normal renal function and no clinical signs of
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L . Corea et al.
116s
heart failure. All medication had been stopped at
least 2 weeks before the study. Investigations were
carried out in the morning, with the subjects lying
comfortably on a bed throughout the study. After
at least 30 min rest, each subject was given nifedipine (10 mg sublingually).
Arterial blood pressure and heart rate were
measured every 3-5 min in basal conditions and up
to 120 min after administration of the drug.
Venous blood for plasma renin activity (PRA),
noradrenaline and adrenaline determinations was
withdrawn by venepuncture 5 min before and 30,
60 and 120 mill after nifedipine administration.
In addition, 12 hypertensive patients were
subsequently given nifedipine ( 10 mg thrice daily):
in this group, arterial pressure, heart rate
and venous blood for plasma catecholamines and
PRA were taken, in the lying and standing position,
before and after 3 weeks' treatment. All measurements were performed 60 min after the last administration of nifedipine.
Arterial blood pressure was measured by the
auscultatory method and heart rate by an ECG
lead.
Plasma catecholamines were measured fluorimetrically by the sensitive and specific method of
Renzini, Brunori & Valori (1970). PRA determination was performed by radioimmunoassay
(Malvano, Zucchelli, Rosa & Salvetti, 1972).
Statistical analysis was performed by conventional methods with the paired t-test.
Results
After sublingual administration of nifedipine (10
mg), mean arterial pressure in normotensive subjects remained unchanged, and it was significantly
lowered in hypertensive patients at 30, 60 and 120
min. Heart rate was increased both in normal and
hypertensive subjects, but more so in normal
subjects in whom a statistically significant rise in
rate was found 30 min after nifedipine. PRA was
found to be significantly raised only in normals at
30 min although there was a non-significant
increase in hypertensive patients at 30 min.
Plasma noradrenaline was significantly increased
at 30 and 60 min, both in normal and hypertensive
subjects, remaining elevated at 120 min in the
normal subjects.
A slight increase in plasma adrenaline was
observed in both groups after nifedipine but this
increase was significant only in normals at 60 min.
In the group of hypertensive patients on long-term
treatment with nifedipine a significant decrease of
mean arterial pressure in comparison with pretreatment values was seen. Heart rate and PRA
increased slightly, although not significantly, both
in lying and standing positions. Plasma noradrenaline increased significantly after 3 weeks'
treatment whereas adrenaline remained substantially unchanged.
In six hypertensive patients the acute reduction
of blood pressure induced by nifedipine was
TABLE1. Mean arterial pressure, heart rate, plasma renin activity and plasma catecholamines in normal subjects
and hypertensive patients. after acute and chronic administration of nifedipine
All results are mean values ( ~ s E M ) . MAP, Mean arterial pressure; HR, heart rate; PRA, plasma renin activity.
Significance of differences from basal values: **P< 0.01; *P < 0.05.
Subjects
Normal (n = 7) Nifedipine
(I0 mg sublingually)
Hypertensive ( n = 19)
Nifedipine (I0 mg
sublingually)
Hypertensive (n = 12)
Nifedipine (I0 mg oral
thrice daily)
Time
(min)
MAP
(mmHg)
HR
(beatshin)
PRA
(ng h-' ml-I)
0
85 f 1.9
67 f 2.6
1.7 f 0.5
I47 & 12
I5 & 1 . 1
30
60
120
82 f 1 . 5
85 f 2.6
83 f 1.5
79 f 3.8.
70 f 2.6
67 f 1.9
5.0 f 1.0'.
2.7 f 0.5
2 . 0 f 0.5
282 f 28..
285 f 30..
183 f 15.
20 f 2.6
21 f 2.6.
16 f 1 . 5
0
128 f 2 . 7
78 f 2 . 0
1.8 f 0 . 4
I72 f 22
32 f 3.6
1 I4
f 2.9..
117 f 2.7..
119 f 2.7.
85 f 2.9
81 f 1.8
80 f 2.5
3.0 f 0 . 6
2.6 f 0 . 4
2.1 f. 0 . 4
254 f 24'.
232 f 16.
185 f 23
43 f 4 . 5
44 f 5 . 2
36 f.4 . 5
128 2 3.1
126 f 3.0
75 f 2.9
79 f 3.0
1.5 f0.5
2 . 4 f 0.7
208 f 18
338 f. 21
30 f 5 . 2
48 f 6.9
113 f 3.l**
f 3.2..
81 f 2.9
85 f 2.9
2.8 f 0.5
3.3 f.0.5
328 f 19**
442 f 22.
41 f 6.9
65 f 9.5
30
60
I20
Basal
Lying
Standing
After 3 weeks
Lying
Standing
1I 1
Noradrenaline
(ne/l)
Adrenaline
(w/O
Nifedipine in hypertension
associated with side effects (facial flushing and/or
headache).
Discussion
This study confirms previous results (Aoki, Kondo,
Mochizuki, Yoshida, Kato, Kato C Takikawa,
1978; Bartorelli ef al., 1978) indicating that
sublingual administration of nifedipine is very
effective in acutely lowering arterial blood pressure
in hypertensive patients. The antihypertensive
effect of nifedipine can be maintained when the
drug is subsequently given orally in long-term
treatment.
Normal subjects do not show any consistent
change of mean arterial pressure after acute
administration of nifedipine.
Nifedipine induces a fall in systemic vascular
resistance through a direct dilating action on the
arteriolar bed. Therefore, as with other vasodilators, a reflex increase of sympathetic activity may
be expected. We observed increased plasma noradrenaline concentrations, which were associated
with a raised heart rate and PRA, after both acute
and chronic administration of nifedipine. Changes
of plasma noradrenaline, heart rate and PRA were
slightly greater in normal than in hypertensive
subjects. The smaller sympathetic and renin responses observed in hypertensive patients may
explain, at least in part, the more pronounced blood
pressure-lowering effect of nifedipine in these
patients. On the other hand, recent studies in spontaneously hypertensive rats suggest that abnormalities of Ca2+flux through cell membranes may
play a role in the development and maintainance of
hypertension (Jones, 1974; Wei, Janis C Daniel,
1976). These findings may suggest a further partial
explanation for the different antihypertensive effect
of nifedipine in normal subjects and hypertensive
patients. The absence of a significant increase of
PRA in hypertensive patients after acute and
chronic administration of nifedipine might be interpreted hypothetically in dfierent ways. A change
of intrarenal blood flow might have opposed renin
secretion caused by sympathetic stimulation.
Moreover, especially on a long-term treatment,
some degree of fluid retention might occur, as with
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other vasodilators, with consequent further blunting of renin release.
In conclusion, nifedipine is an effective and
relatively safe antihypertensive agent both in acute
and chronic treatment. In normals, nifedipine (10
mg sublingually) induces an acute significant
increase of plasma noradrenaline and PRA, without any change of arterial pressure. In the group
of hypertensive patients, this increase is slightly
smaller despite the evident reduction of blood
pressure both after acute and chronic administration of nifedipine. This observation, however,
may suggest a potentially useful combination with
padrenoreceptor-blocking agents.
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