AJH 2001; 14:963–968
Pilot Study to Evaluate a Water
Displacement Technique to Compare
Effects of Diuretics and ACE Inhibitors
to Alleviate Lower Extremity Edema
Due to Dihydropyridine Calcium Antagonists
Matthew R. Weir, Cynthia Rosenberger, and Jeffrey C. Fink
Combination therapy is required in many patients to
achieve goal blood pressure (BP). Calcium antagonists are
highly effective antihypertensive drugs in a broad range of
demographic groups. Yet, higher doses are associated with
an increased frequency of lower extremity edema. The
purpose of our open label, single-center clinical trial was
to evaluate the use of concomitant pharmacologic thera-
pies to attenuate the lower extremity edema associated
with dihydropyridine calcium antagonists therapy using a
water displacement technique. Forty-seven patients re-
ceived 5 mg/day of oral amlodipine for a period of 6
weeks after a 4-week wash-out off of all antihypertensive
medications to establish baseline BP. They were then
randomized to receive either an additional 5 mg of amlo-
dipine, 25 mg of hydrochlorothiazide (HCTZ), or 20 mg of
benazepril for an additional 6 weeks. Blood pressure de-
terminations and water displacement measurements were
obtained at the end of the 4-week placebo wash-out period,
after 6 weeks of 5 mg/day of oral amlodipine therapy, and
after an additional 6 weeks of 5 mg of amlodipine and
randomized drug therapy. Adjusted BP reductions (based
on pretreatment BP) were ⫺6.8/⫺3.8 mm Hg for the
10-mg amlodipine group, ⫺9.9/⫺8.2 mm Hg for the am-
lodipine (5 mg)/HCTZ (25 mg) group, and ⫺26.2/⫺16.4
mm Hg for the amlodipine (5 mg)/benazepril (20 mg)
C
urrent approaches to the treatment of hypertension
are less than optimal. Less than 50% of patients
receiving medication achieve a diastolic blood
pressure (BP) ⬍90 mm Hg.1 Even fewer achieve a systolic
BP of ⬍140 mm Hg. Despite these observations, newer
recommendations suggest that even more aggressive ef-
forts should be made to reduce both systolic and diastolic
Received September 5, 2000. Accepted March 29, 2001.
From the Department of Medicine, Division of Nephrology, Univer-
sity of Maryland School of Medicine, Baltimore, Maryland.
This research project was supported by a grant from Novartis Phar-
© 2001 by the American Journal of Hypertension, Ltd.
Published by Elsevier Science Inc.
group (P ⬍ .0167, group 3 v group 1 diastolic BP, which
was statistically significant by the improved Bonferroni
method). Seventeen of the 47 patients developed at least a
10% increase in lower extremity edema water displace-
ment in response to 5 mg/day of oral amlodipine therapy
(36.2%). Adding 5 mg of amlodipine to a baseline of 5 mg
of amlodipine resulted in no net change in lower extremity
edema (⫹58.0 mL, ⫹0.6% change, n ⫽ 5). Adding 25 mg
of HCTZ reduced lower extremity edema by a mean of
136.3 mL (⫺11.1% change, n ⫽ 4). Benazepril reduced
water displacement by 204.4 mL (⫺14.3% change, n ⫽ 8).
Our pilot study indicates that adding an angiotensin con-
verting enzyme inhibitor to a dihydropyridine calcium
channel blocker is the most effective way to not only
reduce systolic and diastolic BP but also attenuate lower
extremity edema. Due to the inherent daily variability of
lower extremity edema, power calculations indicate many
patients (n ⫽ 702, 356 in each group) would be needed to
compare the antiedema efficacy of the angiotensin con-
verting enzyme inhibitor and the thiazide diuretic. Am J
Hypertens 2001;14:963–968 © 2001 American Journal of
Hypertension, Ltd.
Key Words: Edema, calcium antagonists, ACE inhib-
itors, diuretics.
BP, particularly in patients with diabetes or evidence of
target organ damage.1
There are options in clinical practice to remedy this
situation. One could increase the dose of medication, sub-
stitute an agent from another drug class, add a second
agent from another class, or use a fixed-dose combination.
Angiotensin converting enzyme (ACE) inhibitors and
maceuticals, Inc.
Address correspondence and reprint requests to Matthew R. Weir,
MD, Department of Medicine, Division of Nephrology, University of
Maryland School of Medicine, 22 S. Greene Street, Baltimore, MD
21201; e-mail: mweir@medicine.umaryland.edu
0895-7061/01/$20.00
PII S0895-7061(01)02167-7
964 WATER DISPLACEMENT AND DIHYDROPYRIDINE
CALCIUM ANTAGONISTS
calcium antagonists are widely used antihypertensive
medications with somewhat different mechanisms of ac-
tion. Although both are vasodilators, mechanistically they
are entirely different.2,3 Each drug class has a somewhat
different efficacy profile. Calcium antagonists have been
demonstrated to be effective in the low renin, salt-sensitive
hypertensive individual and manifest more robust antihy-
pertensive properties in the face of a high salt diet relative
to other commonly used therapies.4,5 The ACE inhibitors
in lower doses are more effective in patients with higher
plasma renin activity such as younger patients and Cau-
casians. When used in higher doses, they do provide
incremental antihypertensive activity.6
Calcium antagonists, although highly effective antihy-
pertensive drugs, do present a clinical challenge in that a
sizable percentage of patients will develop the side effect
of lower extremity edema. This is more common, partic-
ularly in women and in obese hypertensives.7 Mechanis-
tically, this lower extremity edema is likely due to distal
arteriolar dilation with capillary leak as opposed to salt
and water retention, which is common with the direct-
acting vasodilators like hydralazine and minoxidil. Clini-
cians have struggled with therapeutic strategies to reduce
the pedal edema and facilitate better BP control in patients
receiving calcium antagonists by experimenting with other
antihypertensive drug classes like ACE inhibitors or di-
uretics. The purpose of our clinical trial was to evaluate a
water displacement technique to objectively evaluate the
effect of a thiazide diuretic or an ACE inhibitor to atten-
uate the lower extremity edema associated with the dihy-
dropyridine antagonist amlodipine.
Methods
Study Design
This was a single-center, open label, randomized clinical
study to evaluate the antihypertensive properties and im-
pact on water displacement of the lower extremity in
hypertensive patients by adding either 5 mg of amlodipine,
25 mg of hydrochlorothiazide (HCTZ), or 20 mg of benaz-
epril in hypertensives already receiving 5 mg/day of oral
amlodipine.
Newly diagnosed hypertensives or hypertensives re-
ceiving antihypertensive medication were observed for a
period of 4 weeks off all medication to determine baseline,
untreated BP and lower extremity water displacement
(phase 1). All patients were started on 5 mg/day of oral
amlodipine for a period of 6 weeks, after which time BP
and water displacement were determined (phase 2). All
patients were subsequently randomized to receive either
an additional 5 mg of oral amlodipine, 25 mg/day of oral
HCTZ, or 20 mg/day of oral benazepril (phase 3). After an
additional 6 weeks of therapy, patients had their BP de-
termined and lower extremity water displacement mea-
sured.
AJH–September 2001–VOL. 14, NO. 9, PART 1
Patients
Male and female outpatients between the ages of 21 and
80 years with uncomplicated diastolic essential hyperten-
sion where eligible. Women were at least 1 year post-
menopausal or surgically sterilized. Entry criteria required
that patients have either stage I or stage II diastolic hy-
pertension (mean sitting diastolic BP of ⱖ90 mm Hg and
⬍110 mm Hg off all antihypertensive medication). Pa-
tients were excluded from the study if they had any evi-
dence of clinically significant concurrent medical condi-
tions including cardiac, renal, hepatic, gastrointestinal, or
endocrinologic disease. Also excluded were patients with
known hypersensitivity or serious drug reactions to cal-
cium antagonists or ACE inhibitors. Patients were also
excluded if there were differences in lower extremity size
or any evidence of prior deep vein thrombosis, lymphatic
disease, or concurrent requirement for medications that
could effect BP or salt and water retention (eg, nonsteroi-
dal antiinflammatory drugs, estrogen containing drugs).
Informed consent as approved by the Institutional Review
Board of the University of Maryland School of Medicine
was obtained from each patient.
Study Procedures
Study procedures included a baseline medical history and
physical examination, laboratory examination including
complete blood count and chemistry, and electrocardio-
gram. Visits were conducted every 2 weeks and included
brief physical examination, measurement of systolic and
diastolic BP using a mercury sphygmomanometer on the
same arm in sitting and standing positions. Three consec-
utive sitting BP measurements were taken at no less than
30-sec intervals. The recorded BP was the average of three
measurements. One-minute pulse rate was recorded after
BP measurements. All BP and pulse measurements
throughout the study were made at trough, approximately
the same time of day, always between 8 and 10 AM,
approximately 24 h after the last dose. A physical exam-
ination and laboratory evaluation was performed at the
midpoint and at study conclusion.
All medications were given once daily in an open label
fashion. Patients received instructions on how to take the
medications. Pill counts were conducted at each study
visit. Less than 90% compliance with medication resulted
in study termination.
No effort was made to adjust the diet of the patients
participating in the study.
Water displacement measurements were made by using
a large tub (52 cm long, 37 cm wide, and 33 cm deep). The
tub was filled to 23 cm. Patients were instructed to im-
merse their right leg into the tub after standing for 4 min.
Water was removed down to the 23-cm level while the
foot was in the tub and measured with a graduated cylinder
to assess water displacement. All measurements were per-
formed at room temperature (20° to 22°C) during trough
AJH–September 2001–VOL. 14, NO. 9, PART 1
Table 1. Diastolic and systolic blood pressure changes (mm Hg) during the study
Group 1:
Amlodipine 10 mg
(n ⴝ 15)
Baseline after 4 week
washout (phase 1) 142.7 ⫾ 9.6/93.8 ⫾ 6.9
BP reduction (mm Hg)
with amlodipine 5 mg
(phase 2) ⫺2.4/⫺0.1
Incremental BP reduction
(mm Hg) with
amlodipine 5 mg ⫹
randomized therapy
(phase 3) ⫺4.4/⫺3.7
Total BP reduction ⫺6.8/⫺3.8
* P ⬍ .016, group 3 v group 1, statistically significant by the improved Bonferroni method.
blood pressure measurements approximately 22 to 24 h
dosing.
Statistical Analysis
Descriptive statistics were used to summarize water dis-
placement and BP at the end of each phase. Changes and
percent changes in these outcomes within phases were also
described by descriptive statistics. A phase 2 versus phase
3 within treatment group analysis (not shown) was per-
formed by applying the Wilcoxon signed rank statistic to
the change during phase 3 minus the change during phase
2.
The primary efficacy variable was percent change in
water displacement during phase 3 assessed by using the
water immersion method. Secondary efficacy variables
were percent change in diastolic and systolic BP during
phase 3. In this analysis, ANOVA was performed. Pair-
wise treatment group comparisons were performed using
Tukey’s simultaneous 95% confidence intervals. Addition-
ally water displacement, diastolic and systolic BP at the
end of phase 3 in the treatment groups were compared
using analysis of covariance (ANCOVA) with the read-
ings at the end of phase 1 and phase 2 as covariates.
Holm’s multiple comparison procedure was used to com-
pare the pairwise differences in this ANCOVA model.
Results
Patient Demographics
Seventy-four patients were enrolled in phase 1 (4-week
wash-out phase). Nineteen of these 74 patients discontin-
ued to study during phase 1 and 55 patients were enrolled
in phase 2 (5 mg/day of amlodipine for 6 weeks). Eight
patients discontinued the study during phase 2 (one with-
drew consent and seven withdrew for other reasons). The
remaining 47 patients were enrolled in phase 3.
There were a total of 25 men and 22 women who
completed the study of whom 23 were Caucasian and 24
WATER DISPLACEMENT AND DIHYDROPYRIDINE 965
CALCIUM ANTAGONISTS
Group 2: Amlodipine Group 3: Amlodipine
5 mg ⴙ HCTZ 25 mg 5 mg ⴙ Benazepril
(n ⴝ 17) 20 mg (n ⴝ 15)
142.6 ⫾ 14.5/96.3 ⫾ 8.8 164.3 ⫾ 28.1/99.7 ⫾ 9.7
6.4/⫺5.1 ⫺15.9/⫺8.5
⫺3.5/⫺3.1 ⫺10.3/⫺7.9
⫺9.9/⫺8.2 ⫺26.2/⫺16.4*
of African American descent. The mean age was 49.9
years and mean body mass index was 33 kg/m2.
Mean systolic and diastolic BP at the end of phase I
(4-week wash-out period) was 149.5 ⫾ 21.1 and 96.6 ⫾
8.7 mm Hg. As depicted in Table 1, the baseline BP after
the 4-week wash-out was lower in group 1 and group 2
compared to group 3.
Blood Pressure Efficacy
The secondary goal of this study was to compare the
efficacy of the randomized therapies added to 5 mg/day of
amlodipine to lower BP. As illustrated in Table 1, the
optimal therapy was adding 20 mg of benazepril to 5 mg
of amlodipine, which provided clinically meaningful im-
provements (⫺10.3/⫺7.9 mm Hg) in both systolic and
diastolic BP compared to increasing the dose of amlodip-
ine from 5 to 10 mg (⫺4.4/⫺3.7 mm Hg) or adding 25 mg
of HCTZ to 5 mg of amlodipine (⫺3.5/⫺3.1 mm Hg).
However, the BP reduction in group 3 would be expected
to be greater due to the higher pretreatment BP (164.3/99.7
mm Hg). Yet, even after statistical adjustment for the
higher pretreatment blood pressure in group 3, the dia-
stolic BP reduction was statistically significantly superior
in group 3 than in group 1 (adjusted estimate 7.3 mm Hg
lower). Diagnostic plots did not reveal departures from
ANCOVA model assumptions. The adjusted estimate of
diastolic BP at the end of phase 3 was 5.7 mm Hg lower
in group 3 than in group 2 (not significant by the improved
Bonferroni method). Percent change in diastolic BP reduc-
tion during phase 3 was also analyzed by ANOVA with
Tukey’s simultaneous confidence intervals. Although not
statistically significant, the adjustment indicates a trend
with close to a 5% greater reduction in group 3 than in the
other two groups.
Water Displacement Measurements
Tables 2 and 3 summarize the effects of phase 2 therapy (5
mg/day of oral amlodipine) and the phase 3 randomized
966 WATER DISPLACEMENT AND DIHYDROPYRIDINE AJH–September 2001–VOL. 14, NO. 9, PART 1
CALCIUM ANTAGONISTS

Table 2. Water displacement results in all randomized patients (n ⫽ 47)

Group 2: Group 3:
Group 1: Amlodipine 5 mg Amlodipine 5 mg
Amlodipine ⴙ HCTZ 25 mg ⴙ Benazepril
10 mg (n ⴝ 15) (n ⴝ 17) 20 mg (n ⴝ 15)
Baseline (phase 1) 1385.7 ⫾ 212.5 mL 1293.8 ⫾ 355.8 mL 1244.0 ⫾ 384.4 mL
Amlodipine 5 mg (phase 2) 1394.3 ⫾ 359.3 mL 1110.3 ⫾ 260.4 mL 1419.0 ⫾ 300.7 mL
Amlodipine 5 mg and
randomized therapy
(phase 3) 1485 ⫾ 595.2 mL 1135.6 ⫾ 351.0 mL 1322.7 ⫾ 315.6 mL
Net change ⫹91.4 mL ⫹25.3 mL ⫺96.3 mL
% Change (phase 2 to 3) 6.6% 2.3% ⫺6.8%

Data expressed as mean ⫾ SEM.

therapy on the water displacement results for the whole
group (Table 2) and only for those patients who had a 10%
increase in water displacement in response to 5 mg/day of
amlodipine therapy (Table 3). In Table 2, one can see the
data for all randomized patients (n ⫽ 47). There was no
significant change from baseline in group 1 with 5 mg of
amlodipine, but with the increase in dose from 5 to 10 mg,
there was an incremental change of 6.6% (P ⫽ NS). In
group 2, there was a slight decrease in water displacement
during phase 2 and no significant increase with the ran-
domized therapy of 25 mg/day of HCTZ. In group 3, 5
mg/day of amlodipine did result in a 14.1% increase in
water displacement during phase 2. Subsequent therapy
with 20 mg of benazepril reduced that by almost 100 mL,
a decrease of about 6.8%. For the whole group, 5 mg of
amlodipine did not result in a statistical change in water
displacement (1307.0 to 1299.5 mL). However, of the 47
patients, 17 (36.2%) had an increase in water displacement
of at least 10% over baseline.
Table 3 illustrates the water displacement results in
those patients (n ⫽ 17) who demonstrated at least a 10%
increase over baseline. Note that during phase 3, group 1
(10 mg of amlodipine) had a continued increase in volume
displacement, whereas in groups 2 and 3 a reduction in
water displacement occurred. Note, that no increase in
edema occurred when 5 mg was increased to 10 mg.
Increased edema was not seen likely because these pa-
tients were preselected for already having at least a 10%
increase on 5 mg alone. Adding HCTZ resulted in a 136.3
mL reduction (⫺11.1%), and adding 20 mg/day of benaz-
epril resulted in a 204.4 mL water displacement reduction,
a decrease of 14.3%.
Safety
The drug therapies during the course of the study were
extremely well tolerated. There were no drop outs due to
intolerability or evidence of serious adverse reactions.
There were no reported laboratory adverse events.
Discussion
In this pilot study, the impact of adjunctive therapies,
either HCTZ or ACE inhibitor was evaluated with regard
to their ability to attenuate lower extremity edema (with a
water displacement technique) and facilitate reduction in
systolic and diastolic BP in patients already receiving the
dihydropyridine calcium antagonist amlodipine. We dem-
onstrated that the optimal strategy to reduce both systolic
and diastolic BP and attenuate edema is to combine an
ACE inhibitor with a calcium antagonist.
Essential hypertension remains a complicated and com-
plex illness to treat. The disease is largely symptomless,
and medications, particularly those titrated to higher doses
frequently cause adverse events. In an effort to facilitate

Table 3. Water displacement results in patients with at least a 10% increase in volume during phase 2

Group 2: Group 3:
Group 1: Amlodipine 5 mg Amlodipine 5 mg
Amlopidine ⴙ HCTZ 25 mg ⴙ Benazepril
10 mg (n ⴝ 5) (n ⴝ 4) 20 mg (n ⴝ 8)
Baseline (phase 1) 1298.0 ⫾ 83.7 mL 907.5 ⫾ 208.9 mL 1085.1 ⫾ 106.4 mL
Amlodipine 5 mg (phase 2) 1640.0 ⫾ 215.7 mL 1281.3 ⫾ 120.6 mL 1522.5 ⫾ 94.2 mL
Amlodipine 5 mg and
randomized therapy
(phase 3) 1698.0 ⫾ 318.8 mL 1145.0 ⫾ 222.3 mL 1318.1 ⫾ 138.9 mL
Net change (phase 2 to 3) ⫹58.0 mL ⫺136.3 mL ⫺204.4 mL
% Change (phase 2 to 3) ⫹0.6 ⫺11.1 ⫺14.3
AJH–September 2001–VOL. 14, NO. 9, PART 1
better BP control, an effort has been made to develop
low-dose fixed combinations, not only to facilitate effi-
cacy, but improve compliance and ease of administration.
The recent Joint National Committee on Prevention, De-
tection, Evaluation and Treatment of High Blood Pressure
consensus report has endorsed this approach.1
In this clinical trial, we have successfully demonstrated
that there are two therapies that demonstrate benefit in
attenuating the lower extremity edema associated with
dihydropyridine calcium antagonists. Although the num-
ber of patients are small in our pilot study, 2 of 4 patients
receiving amlodipine had their lower extremity edema
improved when adding a thiazide diuretic (25 mg of
HCTZ). Similarly, 6 of 8 patients receiving 20 mg/day of
benazepril had their lower extremity edema improved.
Moreover, the addition of these medications besides atten-
uating lower extremity edema, also facilitated better BP
reduction. Thus, this type of therapeutic strategy provides
a more rational approach to facilitate BP control when
adequate BP control is not achieved on a dihydropyridine
calcium antagonist. Besides better BP control and im-
proved tolerability, ACE inhibitors may provide additional
opportunities with regard to reducing proteinuria,8 atten-
uating sympathetic nervous system activity, which may be
important in patients with heart disease,9 as well as has
been shown to provide secondary risk reduction in patients
with heart disease10 and kidney disease.11,12 The combi-
nation of the better BP reduction and attenuation of lower
extremity edema would argue that the ACE inhibitor may
be the ideal strategy to combine with the calcium antag-
onist.
The mechanism of thiazide diuretic- or ACE inhibitor-
induced reduction in water displacement is not easily
described. Thiazide diuretics primary reduce BP through
only subtle changes in blood volume and act primarily
through vasorelaxation (over the long term). Short-term
studies demonstrate mild volume reduction associated
with the use of thiazides.13 However, that is not likely to
explain the observations seen in our studies where water
displacement measurements were carried out 6 weeks
apart.
The ACE inhibitors are a class of drugs that provide
both preload and afterload reduction.3 The ability to dilate
venous capacitance vessels may explain why ACE inhib-
itors reduce the lower extremity edema associated with the
calcium antagonists. Because calcium antagonists provide
potent vasodilation, even in distal arteriolar beds, this may
lead to a capillary leak syndrome. Thus, venous capaci-
tance dilation and reduction in venular pressure may mod-
ify this effect and explains the mechanism of ACE inhib-
itors in reducing the increased lower extremity water
displacement associated with dihydropyridine calcium an-
tagonists.
Unfortunately our pilot study did not provide the sta-
tistical power to differentiate between the ability of thia-
zide diuretic or the ACE inhibitor to reduce lower extrem-
ity edema using our water displacement technique.
WATER DISPLACEMENT AND DIHYDROPYRIDINE 967
CALCIUM ANTAGONISTS
However, some useful information can be gleaned from
this new, previously not reported technique that can assist
in the design of larger clinical trials. There is an inherent
variability in the lower extremity edema measurements,
perhaps related to age, gender, weight, time of day of
measurement, and even dietary salt consumption. Al-
though not studied in our clinical trial, this is not uncom-
monly observed in clinical practice where patients report
changes in lower extremity edema. Using power calcula-
tions based on the data in Table 3 to detect a significant
difference (with 90% power) between the HCTZ group
and the ACE inhibitor, one would need to study 702
patients (356 in each group). On the other hand, many
fewer patients would need to be studied (16, 8 in each
group) to achieve statistical significance with 90% power
between the calcium antagonist group alone and the ACE
inhibitor/calcium antagonist combination.
In summary, we have demonstrated in a pilot study that
thiazide diuretics or ACE inhibitors may provide an op-
portunity to reduce lower extremity edema in patients
receiving the dihydropyridine calcium antagonist amlodip-
ine. This benefit is seen in at least 50% of the patients and
remains evident at 6 weeks after concomitant therapy.
Moreover, both therapies provide incremental reduction in
BP in conjunction with the calcium antagonist. This was
most notable with the ACE inhibitor. Consequently, the
latter approach appears to be the ideal strategy to combine
with a calcium antagonist for BP control and avoidance of
lower extremity edema.
Acknowledgment
We thank Vondalee Cowling for her excellent secretarial
support.
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