The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 2 457-460
Copyright © 1997 by The Endocrine Society
Effects of Nifedipine Treatment on the Renin-Angiotensin-Aldosterone Axis1
Tarek M. Fiad,
Sean K. Cunningham,
Frances J. Hayes and
T. Joseph McKenna
Department of Investigative Endocrinology, University College
Dublin, Dublin, Ireland
Address all correspondence and requests for reprints to: Prof. T. J. McKenna, Department of Investigative Endocrinology, St. Vincent’s Hospital, Elm Park, Dublin 4, Ireland.
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Abstract
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Nifedipine is a commonly used agent in treating hypertension and angina
because of its vasodilator properties. An inhibitory role of nifedipine
on aldosterone (Aldo) biosynthesis has been documented in in
vitro studies. This study was designed to examine the impact of
a sustained release nifedipine formulation on Aldo biosynthesis and its
clinical consequences. Early and late effects of nifedipine on Aldo,
PRA, and Aldo/PRA ratio levels were studied in a single blind,
placebo-controlled, 10-day pilot study. Ten normotensive subjects and
10 patients with hypertension were studied. Blood samples for the
measurement of Aldo and PRA were obtained at 2-h intervals for 10
h on a control day and on days 1 and 8 of nifedipine treatment for the
determination of baseline, early, and late values. Placebo was
administered at 0800 h on the first and second days of the study,
whereas nifedipine (60 mg/day) was given for the following 8 days. The
Aldo/PRA ratio was used as a sensitive indirect index of the
responsiveness of Aldo secretion to adrenal stimulation with
angiotensin. Compared to those on the control day, a significant rise
in the integrated PRA levels occurred on the first day of nifedipine
treatment, with a further rise observed on the eighth day of the
treatment in the normotensive subjects (1.1 ± 0.6, 1.7 ±
1.2, and 2.5 ± 1.8 ng/mL·h on the control day and the first and
eighth days of treatment, respectively; P < 0.05)
and by the eighth day in the hypertensive subjects (2.2 ± 2.8 and
4.0 ± 4.1 ng/mL·h; P < 0.05). A
significant rise in integrated Aldo levels occurred in the normotensive
subjects on the eighth day of nifedipine treatment (control day,
319 ± 187; eighth day of nifedipine, 363 ± 167 pmol/L;
P < 0.05) and in the hypertensive subjects
(426 ± 219 and 535 ± 284 pmol/L; P <
0.05). This was associated with a significant lowering of the Aldo/PRA
ratio on the first day of the treatment, with further lowering on the
eighth day in the normotensive (435 ± 454, 269 ± 209, and
182 ± 107; P < 0.05) and by the eighth day
in the hypertensive subjects (716 ± 833 and 305 ± 315;
P < 0.05). When individual time points were
examined in the normotensive subjects, Aldo/PRA levels were
significantly lower on day 8 of nifedipine treatment at 1000, 1200, and
1400 h than corresponding values on the control day. The fall in
the Aldo/PRA ratio during nifedipine treatment indicates that the
previously reported in vitro inhibition of Aldo
biosynthesis in adrenal cells is reproduced in vivo. In
the absence of nifedipine, it is likely that Aldo levels would be
higher for any given level of PRA. It is probable that the Aldo
inhibition and the vasodilatatory effect of nifedipine combine to bring
about the lowering of blood pressure. Drugs that inhibit
renin-angiotensin axis activity are likely to be particularly effective
when additional lowering of blood pressure is required.
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Introduction
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NIFEDIPINE IS a calcium channel blocker of
the dihydropyridine class that inhibits the influx of calcium ions into
the cell, leading to the relaxation of vascular smooth muscle and thus
lowering of the blood pressure (1). Because of its vasodilator
properties (2, 3), nifedipine is a commonly used agent in treating
hypertension and angina. A slow release, once a day, dosage formulation
of nifedipine using a gastrointestinal therapeutic system (GITS) based
on osmotic push-pull technology (4) has been developed. Compared with
nifedipine capsules and tablets, nifedipine GITS has been shown to
provide a constant plasma nifedipine concentration over a 24-h period
with minimal fluctuation (5). Nifedipine has an acute and sustained
natriuretic effect (6), and its withdrawal causes a positive sodium
balance (7). The slow release formulation of nifedipine (30–90 mg) was
associated with elevation of PRA and aldosterone (Aldo) levels within 4
days of treatment while also leading to acute and chronic negative
sodium balance in hypertensive subjects (6). These observations suggest
that the entire renin-angiotensin-Aldo axis is activated by the
nifedipine-induced negative sodium balance. However, the major
physiological stimulators of Aldo production by the adrenal zona
glomerulosa cells, angiotensin II and potassium, are to a varying
degree dependent on extracellular calcium influx to achieve maximum
stimulation (8, 9). An inhibitory role of nifedipine on Aldo
biosynthesis was documented in in vitro studies (10).
Whether this effect is reproducible in vivo is uncertain.
Therefore, the aim of this study was to examine the impact of the
sustained release of nifedipine on Aldo biosynthesis and its clinical
consequences.
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Subjects and Methods
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Patients
Ten normotensive (7 men and 3 women) and 10 hypertensive (6 men
and 4 women) subjects were studied. The mean age was 52 yr (range,
42–62) in the normotensive subjects and 56 yr (range, 47–62) in the
hypertensive subjects. Eight of the hypertensive subjects had received
blood pressure-lowering agents, 6 patients were receiving monotherapy,
1 patient was taking 2 agents, and another patient was receiving triple
therapy. The antihypertensive agents used before entering the study
included angiotensin-converting enzyme inhibitors, calcium channel
blockers, ß-blockers, and diuretics. Angiotensin-converting enzyme
inhibitors, calcium channel blockers, and ß-blockers were withdrawn
for at least 2 weeks before the patients entered the study, whereas
patients taking diuretics discontinued treatment at least 4 weeks
before participating in the study.
Protocol
Participants were entered into a single blind study of 10 days
duration. They were given, in a single blind fashion, one placebo
tablet to be taken in the morning for 2 days. Thereafter, nifedipine
GITS (60 mg) was administered every morning for 8 days. Pulse rate and
blood pressure determinations and blood samples for the measurement of
Aldo and PRA were obtained at 2-h intervals for 10 h while the
patient was sitting upright on day 1 of placebo treatment and on days 1
and 8 of nifedipine treatment for the determination of baseline, early,
and late effects. The first blood sample was obtained just before the
placebo/active agent was administered on all study days. Subjects were
ambulatory between blood sampling. Free diet and normal activities were
maintained throughout the study. Side-effects of nifedipine were
recorded at each visit. The study protocol was approved by the ethics
and research committee of St. Vincent’s Hospital, and written informed
consent was obtained from each participant before enrollment in the
study.
Assays
Aldo was assayed using a highly specific RIA (11). PRA was
estimated using reagents from Serono-Biodata (Milan, Italy) to measure
by RIA the angiotensin I generated from endogenous substrate. The
reference range for PRA, which was derived from the mean ±
SD of the log-transformed values obtained from 106 control
subjects (men and women ranging in age from 15–74 yr) in the upright
position was 0.5–6.8 ng/mL·h. The between-assay reproducibility for
PRA, estimated by calculating the average coefficient of variation of 3
controls, each measured on at least 30 occasions, was 13%. The
Aldo/PRA ratio was used as a sensitive indirect index of the
renin-angiotensin-Aldo axis activity (12). The reference range for Aldo
and Aldo/PRA ratio was derived from measurement of random upright
plasma Aldo and PRA values in 96 healthy volunteers (11). Serum
potassium was measured using Beckman ion-selective electrodes. Serum
cortisol was measured by specific RIA without extraction of
chromatographic purification using a 
-coat
[125I]cortisol kit (Travenol-Genentech Diagnostics,
Cambridge, MA; catalogue no. CA-529).
Statistical analysis
When comparing values obtained in the same subjects at different
times on the same day and when comparing values before and during
nifedipine treatment, ANOVA following logarithmic transformation of
data was used (StatView II software program for the Apple Macintosh
computer, Abacus Concepts, Berkeley, CA). When significance was
detected, the post-hoc Fisher’s protected least
significance difference test was used to identify the points where
significant differences existed. Values are expressed as the mean and
SD unless otherwise stated. Differences in PRA, Aldo, and
Aldo/PRA ratio between the normotensive and the hypertensive subjects
were analyzed by nonparametric Mann-Whitney unpaired t test.
Differences between 0800 and 1800 h values for cortisol and
potassium levels were analyzed by nonparametric Wilcoxon signed rank
paired t test.
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Results
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Basal hormonal profile of normotensive and hypertensive subjects
and observations on control day (Tables 1
and 2)
On the control day, integrated Aldo levels were higher in the
hypertensive than in the normotensive subjects (426 ± 31 and
319 ± 27 pmol/L; P < 0.05). No significant
differences in PRA or the Aldo/PRA ratio were observed between the two
groups. No significant changes in Aldo, PRA, Aldo/PRA, or potassium
levels were seen in either study groups during the day. Cortisol levels
fell significantly between 0800 and 1800 h on each study day in
both study groups (Table 2).
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Table 1. Levels for aldosterone, PRA, and Aldo/PRA on the
control day and on the first and eighth days of nifedipine treatment
(mean ± SD) in 10 normotensive and 10 hypertensive
subjects
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Table 2. Mean (±SD) levels for systolic and
diastolic blood pressure, pulse rate, potassium and cortisol on control
day and on the first and eighth days of nifedipine treatment in 10
normotensive and 10 hypertensive subjects
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Basal, early, and late nifedipine effects (Tables 1
and 2 and Fig. 1)
A significant rise in integrated Aldo levels occurred in the
normotensive subjects on the eighth day of nifedipine treatment
(control day, 319 ± 187; eighth day of nifedipine, 363 ± 24
pmol/L; P < 0.05) and in the hypertensive subjects
(426 ± 219 and 535 ± 284 pmol/L; P <
0.05). A significant rise in the integrated PRA levels occurred on the
first day of nifedipine treatment, with a further rise observed on the
eighth day of treatment in the normotensive subjects (1.1 ± 0.6,
1.7 ± 1.2, and 2.5 ± 1.8 ng/mL·h on the control day and
the first and eighth days of treatment, respectively;
P < 0.05) and the hypertensive subjects on the eighth
day of treatment (2.2 ± 2.8 and 4.0 ± 4.1 on the control
day and the eighth day of treatment, respectively; P <
0.05). This was associated with a significant lowering of the Aldo/PRA
ratio on the first day of the treatment, with further lowering on the
eighth day in the normotensive subjects (435 ± 454, 269 ±
209, and 182 ± 107, P < 0.05) and on day 8 of
nifedipine treatment in the hypertensive subjects (716 ± 833 and
305 ± 315 on the control day and eighth day of treatment,
respectively; P < 0.05).
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Figure 1. Integrated Aldo, PRA, and Aldo/PRA levels on
control day and on the first and eighth days of nifedipine treatment
(mean ± SE) in 10 normotensive and 10 hypertensive
subjects.  , Normotensive;  , hypertensive; C, control day; 1, day
1 of nifedipine treatment; 8, day 8 of nifedipine treatment. *,
Significantly different from the control day, P <
0.05; #, significantly different from day 1 of nifedipine treatment,
P < 0.05;  , significantly different from
equivalent value in control subjects, P < 0.05.
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When individual time points were examined, no change in Aldo or PRA
levels was observed throughout nifedipine treatment days 1 and 8 in the
two study groups. In the normotensive subjects, Aldo/PRA levels were
significantly lower on day 8 of nifedipine treatment at 1000, 1200, and
1400 h than corresponding values on the control day. Nifedipine
treatment led to a significant fall in systolic and diastolic blood
pressures and a rise in the pulse rate only in the hypertensive
subjects. Potassium levels did not change significantly during the 3
study days (Table 2).
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Discussion
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This study demonstrated that in vivo nifedipine
reproduces the previously reported in vitro inhibition of
Aldo biosynthesis (10). Normotensive and hypertensive subjects
responded in a similar manner by demonstrating a rise in PRA and a
lowering of the Aldo/PRA ratio. The increase in PRA probably occurred
as a consequence of a fall in blood pressure and increased sympathetic
discharge and was seen on day 1 of nifedipine treatment (13). The
delayed rise in Aldo that was only observed on day 8 of the treatment
is probably due to the nifedipine effect and to a lag in the Aldo
response to the acute rise in PRA seen on day 1 of nifedipine
treatment. The role of nifedipine in Aldo synthesis has been the
subject of conflicting reports. In patients with essential
hypertension, it was previously reported that nifedipine (10–20 mg)
lowers Aldo levels acutely, and this is sustained for at least 4 weeks
of treatment (14, 15), whereas others reported no change in Aldo after
3 months of treatment (16). In contrast, elevations of PRA and/or Aldo
levels within the first 4 weeks of nifedipine treatment using
nifedipine (30 mg) and nifedipine GITS (30–90 mg) were reported (6, 17). The inconsistencies in these reports are probably related to
differences in the dosage used, the duration of treatment, and the
preparation used. Although elevations of PRA and Aldo levels were
reported, their relationship has not been established. The rise in Aldo
observed in this study was less pronounced than that in PRA, so the
Aldo/PRA ratio fell. Nifedipine lowers blood pressure predominantly by
arteriolar dilatation and natriuresis (6), but lowering of the Aldo/PRA
ratio also appears to facilitate these antihypertensive effects. In
contrast, the natriuresis induced by antihypertensive agents devoid of
Aldo synthesis inhibition, such as diuretics, is associated with
secondary hyperaldosteronism and normal Aldo/PRA ratio values (12). In
the absence of nifedipine it is likely that plasma Aldo would have been
higher proportionate with the increasing PRA levels. As Aldo levels
rose after treatment with nifedipine in this study, it is clear that
the natriuretic effects of nifedipine (6, 15, 16) are not mediated
through inhibition of Aldo, and this is consistent with the idea that
calcium antagonists have a direct tubular natriuretic effect (18).
Thus, the net hypotensive response to nifedipine results from a
combination of effects on arteriolar smooth muscle and modification of
the development of secondary hyperaldosteronism that is seen in
subjects treated with a diuretic (12) in addition to its previously
reported direct tubular natriuretic effect. Although absolute Aldo
levels in the present study rose on the eighth day of nifedipine
treatment, Nadler et al. (19) reported lowering of plasma
Aldo, improvement in blood pressure, and correction of hypokalemia in
patients with primary hyperaldosteronism due to either idiopathic
hyperaldosteronism or adenoma, which was observed immediately and
maintained for at least 4 weeks of nifedipine treatment. It is likely
that the chronic inhibition of PRA in primary hyperaldosteronism
allowed for full expression of the effect of nifedipine on Aldo
biosynthesis independent of the usual compensatory rise in PRA, at
least until renin suppression recovered.
Integrated Aldo levels were higher in the hypertensive group than in
the normotensive group before and during nifedipine treatment. However,
after treatment with nifedipine a very similar response was seen in the
normotensive and hypertensive groups. A significant increase in PRA
occurred on day 1 and became more significant after 1 week of
treatment. There was a gradual significant increase in mean plasma Aldo
levels and a significant decrease in the Aldo/PRA ratio. This is most
consistent with a nifedipine-induced declining sensitivity of Aldo
secretion to stimulation by angiotensin, as previously described
in vitro (10). This effect of nifedipine probably inhibited
the development of frank secondary hyperaldosteronemia and thereby
inhibited more effective salt retention at the level of the renal
tubule, which, had it occurred, would have partially offset the
therapeutically useful blood pressure-lowering effects of nifedipine.
As a consequence of increasing PRA values it is likely that plasma
levels of angiotensin II, a potent vasoconstrictor, increase in
response to treatment with nifedipine (20). These observations prompt
the speculation that where the hypotensive effects of nifedipine are
considered clinically inadequate, the opportunity exists to potentiate
the hypotensive effect of nifedipine by the addition of agents that
either inhibit the generation of angiotensin II, such as
angiotensin-converting enzyme inhibitors, or agents that inhibit
angiotensin II action (21, 22).
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Footnotes
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1 This work was supported by a grant from Bayer Pharmaceuticals,
United Kingdom. 
Received January 2, 1996.
Revised October 17, 1996.
Accepted October 18, 1996.
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Top
Abstract
Introduction
