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From the First Department of Internal Medicine (Y.H., S.S., H.M., G.K.)
and the Department of Clinical Laboratory Medicine (T.O., Y.N., M.K.),
Hiroshima University School of Medicine, Japan.
Correspondence to Yukihito Higashi, MD, PhD, First Department of Internal Medicine, Hiroshima University School of Medicine, 1–2-3 Kasumi, Minami-ku, Hiroshima 734, Japan. E-mail yhigashi{at}mcai.med.hiroshima-u.ac.jp
It is important to determine whether reduction in blood pressure
improves endothelial dysfunction in hypertensive
subjects. It is unclear whether endothelial dysfunction
is a cause or consequence of hypertension. Many investigators have
reported an improvement of endothelial dysfunction in
forearm circulation of patients with essential hypertension by
antihypertensive therapy with ACE
inhibitors.11 12 13 Several lines of
evidence in experimental hypertensive models support these
findings.14 15 16 17 In contrast, others have shown
that clinically effective antihypertensive therapy, including ACE
inhibitors, did not restore impaired
endothelium-dependent vascular relaxation in the
forearm.18 19 In addition, although the
relationship between the kidney and NO in the development and
maintenance of hypertension has been
demonstrated,20 21 there is little information
regarding the effects of antihypertensive drugs on renal
endothelial function in essential hypertensives.
We conducted a 12-week randomized, double-blind, parallel trial to
evaluate the effects on renal endothelial function of
the ACE inhibitor imidapril compared with the calcium
antagonist amlodipine in patients with mild to moderate
essential hypertension without atherosclerosis. For
this purpose, we measured RVR and the concentration of NOx in response
to L-arginine at the beginning and at the end of the
12-week treatment period in the 2 groups.
Treatment Protocol
24-Hour Ambulatory Blood Pressure Monitoring
L-Arginine Infusion Study
Mean daily dietary intake of NOx in the Japanese population is about 80
mg/d. In the preliminary study, we examined the effect of oral intake
of NOx on plasma concentration of NOx in 5 normotensive male subjects
(mean age, 30±4 years; age range, 26 to 36 years). After the subjects
ingested 30 mg NOx, plasma concentration of NOx was measured at 0, 1,
and 12 hours. Plasma concentration of NOx was increased from 37±10
to 43±11 µmol/L after 1 hour (P<0.05)
and returned to baseline levels after 12 hours in all subjects,
suggesting that a 12-hour fast may avoid the effect of dietary intake
of NOx on plasma concentration of NOx. Furthermore, the day-to-day
variation in plasma concentration of NOx in the fasting concentration
in the same individual is small (coefficient of variation, 5.1%).
In the preliminary study, to examine whether the effects of
L-arginine on renal hemodynamics are due to
its contribution to the release of NO, we administered
D-arginine, the enantiomer of L-arginine, as a
control for L-arginine. The effects of
L-arginine and D-arginine on renal
hemodynamics and urinary excretion of NOx in 7
normotensive male subjects (mean age, 26±5 years; age range, 23 to 35
years) were measured. These studies were carried out in a double-blind,
randomized fashion on a separate day. D-Arginine infusion
was performed in a protocol identical to that described for
L-arginine. D-Arginine caused a small but
significant increase in RPF and a decrease in RVR. The responses of RPF
and RVR to L-arginine were significantly greater than those
to D-arginine (RPF, 20.4±7.1% versus 7.0±4.2%,
P<0.05; and RVR, -28.1±7.6% versus -10.2±5.0%,
P<0.05, respectively). The infusion of
D-arginine did not significantly alter the GFR. The urinary
excretion of NOx markedly increased after L-arginine
infusion (from 121.2±47.8 to 286.4±101.1 µmol/mmol
creatinine, P<0.001) but not after
D-arginine infusion (from 119.5±47.1 to
129.7±67.2 µmol/mmol creatinine). Renal
vasorelaxation and urinary NOx responses were much greater after
L-arginine than after D-arginine.
Drugs
Analytic Methods
Serum PAH concentration was analyzed by spectrophotometry. GFR
was measured by the clearance of inulin.25 Serum
inulin concentration was analyzed by the anthrone
method.26 Renal blood flow was calculated from
PAH clearance and hematocrit level. RVR was calculated as the mean
blood pressure divided by renal blood flow, and FF was calculated as
GFR divided by RPF. RPF, GFR, and RVR were normalized to body surface
area divided by 1.48 m2 (1.48
m2 being the average body surface area of the
Japanese population).
Statistical Analysis
Effects of Imidapril and Amlodipine on Baseline Clinical
Characteristics
Effects of L-Arginine on Systemic and Renal
Hemodynamics at Beginning and End of 12-Week
Treatment Period
Figures 2
Effects of L-Arginine on cGMP and NOx at Beginning and
End of 12-Week Treatment Period
We evaluated the effects of chronic treatment of the calcium
antagonist amlodipine on the responses of renal
hemodynamics and urinary NOx excretion to the different
dosages of L-arginine (250, 500, and 1000 mg/kg,
respectively) in 5 of 13 patients. The duration of amlodipine treatment
was 37 to 49 weeks. The response of RPF to each dose of
L-arginine was similar before and after amlodipine
treatment (3.9±3.3% to 3.6±3.0%, 9.2±5.3% to 10.1±5.6%, and
13.4±6.2% to 14.1±6.5%, respectively). The increment in urinary
excretion of NOx in response to each dose of L-arginine was
also similar before and after amlodipine treatment (42±22% to
44±30%, 122±53% to 133±56%, and 164±62% to 171±65%,
respectively).
Because several lines of evidence have suggested that
endothelial function is impaired as blood pressure
increases, and that the degree of endothelial
dysfunction is related to the severity of blood pressure elevation, the
hypothesis has been proposed that endothelial
dysfunction is a consequence of hypertension. If this hypothesis is
correct, endothelial dysfunction should be improved
with the normalization of blood pressure by antihypertensive drug
treatment. Thus, in the present study, we evaluated the effects of
the reduction in blood pressure by the ACE inhibitor
imidapril or the calcium antagonist amlodipine on renal
endothelial function. After a 12-week study, the
responses of RPF and RVR to L-arginine were augmented in
the imidapril group, whereas L-arginine–induced changes
within those parameters remained unchanged in the
amlodipine group, indicating that only imidapril produced a significant
improvement of renal vasorelaxation in response to
L-arginine, although the decrease in blood pressure and
increase in RPF were similar in both groups. Our findings are
consistent with previous studies in that there was no
relationship between the improvement of endothelial
dysfunction and the decrease in blood pressure in the brachial artery
and small arteries of essential
hypertensives.11 13 27 These findings suggest
that endothelial dysfunction may not be a consequence
of hypertension.
Many investigators have reported an improvement of
endothelial dysfunction with ACE inhibitors
in patients with essential hypertension.11 13 27
Results of ACE inhibitor treatment in several experimental
models of hypertension support these
findings.14 15 16 17 28 On the other hand, Creager and
Roddy19 reported that antihypertensive therapy
for up to 7 to 8 weeks with the ACE inhibitors captopril or
enalapril did not improve endothelium-dependent
vasodilation in the brachial artery of patients with essential
hypertension, regardless of whether a sulfahydryl group is present.
Although the precise reason for this discrepancy is unknown, it may be
due to the differences in patients or treatment periods.
Some possible mechanisms by which the ACE inhibitor
imidapril augments endothelium-dependent renovascular
relaxation have been postulated. First, ACE inhibitors
decrease the production of Ang II through the inhibition of
circulating ACE activity and renal tissue ACE. Ang II causes
vasoconstriction of the renal artery and a decrease in renal blood
flow.29 30 Sumners and
Myers31 showed that reduced generation of Ang II
may alter the activity of the NO/cGMP pathway. It is postulated that
Ang II increases superoxide anions through the stimulation of NADH and
NADPH oxidase activity in the smooth muscle cells, leading to an
inactivation of NO.32 Sigmon et
al33 reported that local interaction of Ang II
and NO may be an important factor in selective regulation of renal
blood flow. Several lines of evidence show that NO synthesis inhibition
with NG-nitro-L-arginine methyl
ester elevates blood pressure and RVR, and decreases RPF in control
rats, but has little effect on renal hemodynamics in
rats treated with an ACE inhibitor, suggesting that
renovascular constriction evoked by NO synthesis inhibition is mainly
due to Ang II.15 34 In the present study,
after 12 weeks, imidapril inhibited basal circulating ACE activity by
69% and basal circulating Ang II level by 78%. On the basis of animal
experiments, we speculate that the local level of Ang II is also
diminished. Thus, during L-arginine infusion, in the
imidapril group the influence of Ang II may be somewhat removed.
Second, ACE inhibitors have been shown to inhibit the
breakdown of bradykinin through the inhibition of kininase II. The
prevention of bradykinin degradation by ACE inhibitors is
speculated to induce an augmentation of the production of
endothelium-derived relaxing factors such as NO via
endothelial bradykinin B2
receptors, potentiating the vasodilator.35 36 37 In
addition, the increase in bradykinin per se directly causes the
vasodilation.38 In the present study,
imidapril solely enhanced L-arginine–induced
renovascular relaxation and increased the production of NO.
h-ANP induces natriuresis, diuresis, and vasodilation. Both
h-ANP and NO cause vascular relaxation by generating cGMP through the
activation of the particulate and soluble guanylate
cyclases, respectively.39 In the present
study, L-arginine–induced increase in h-ANP was
similar in both the imidapril and amlodipine groups. Thus, differences
in the L-arginine–induced increase in cGMP between the 2
groups may have been due to differences in the production of
NO. Unlike NO, h-ANP may not have played a paracrine role in the
increase in L-arginine–induced renovascular relaxation in
the imidapril group. Hishikawa et al40
demonstrated that h-ANP was increased by both L-arginine
and a saline vehicle in humans, suggesting that volume load may elevate
h-ANP.
In our study, the dihydropyridine calcium
antagonist amlodipine did not restore
L-arginine–induced renovascular relaxation, although it is
clinically effective antihypertensive therapy, suggesting that the
antihypertensive effect of amlodipine may be accompanied with
vasodilation in renal artery independence of the
L-arginine/NO pathway. Our findings are consistent
with many clinical and experimental studies in that calcium
antagonists did not improve impaired
endothelial function. In renal and forearm arteries,
calcium antagonists may not be beneficial in improving
endothelial dysfunction with lowered blood pressure in
patients with essential hypertension.
In the present study, the subjects did not ingest a constant amount
of NOx. Because it is well known that the measurement of NOx is
affected by dietary intake of these substances in food and drinking
water, one would raise the possibility that the patients ingested more
NOx during the imidapril period. However, as shown in the preliminary
study, the increase in plasma NOx by food intake is abolished after 12
hours. A 12-hour fast may avoid the effect of dietary intake of NOx.
Furthermore, because the day-to-day variation in plasma NOx in the
fasting concentration is small, this possibility is unlikely.
In the preliminary study, exogenous D-arginine, not being a
substrate for the NO pathway, had a small effect on renal
hemodynamics and did not produce an increase in NO
generation. It has been reported that other amino acids, which are not
substrates for NO, also produce renal
vasodilation.41 Although the precise mechanism is
unclear, only one third of the effects of L-arginine on RPF
can be explained by the effects of these amino acids. Although we
consider that L-arginine–induced renovascular relaxation
is mainly due to activation of an L-arginine/NO/cGMP
pathway, these findings may suggest that exogenous
L-arginine infusion may cause renal vasorelaxation mostly
through the release of NO rather than the nonspecific effect of amino
acids.
The use of specific NO synthase inhibitors, such as
NG-monomethyl-L-arginine
and NG-nitro-L-arginine methyl
ester, and agonists to stimulate NO release, such as acetylcholine or
bradykinin, would allow us to draw more specific conclusions concerning
the role of the basal and stimulated release of NO in the renal
circulation. However, because the intravenous infusion of
NO synthase inhibitors can increase the blood pressure and
vascular resistance, these agents may lead to adverse effects in
hypertensive patients. We therefore did not investigate these agents
from certain aspects due to ethical considerations.
Plasma concentration of NOx was not altered significantly by
L-arginine infusion, whereas urinary NOx excretion markedly
increased after L-arginine infusion. These results are
consistent with previous
observations.42 43 Wennmalm et
al44 reported that NO produced in the
endothelial cells was rapidly oxidized to NOx in blood,
and NOx was subsequently rapidly excreted via urine. The measurement of
plasma NOx is not adequate to determine NO production in vivo.
However, although we measured the urinary NOx levels as one of the
indices of renal NO production, we could not directly measure
NO produced from endothelial cells under the
physiological conditions and stimuli. Such direct
measurement would allow us to draw more specific conclusions concerning
the role of NO per se.
In conclusion, the present findings suggest that the effects of ACE
inhibitor on L-arginine–induced renovascular
relaxation may be due in part to changes in endothelial
function. ACE inhibition is beneficial not only in lowering blood
pressure but also in improving renal endothelial
dysfunction in patients with essential hypertension.
Received November 10, 1997;
first decision November 28, 1997;
accepted March 6, 1998.
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© 1998 American Heart Association, Inc.
Scientific Contributions
Angiotensin-Converting Enzyme Inhibition, But Not Calcium Antagonism, Improves a Response of the Renal Vasculature to L-Arginine in Patients With Essential Hypertension
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Abstract—Endothelial
function has been shown to be impaired in patients with essential
hypertension. The purpose of the present study was to determine
whether antihypertensive drug therapy improves impaired
endothelium-dependent renal vasorelaxation in essential
hypertensive patients without atherosclerosis. We
evaluated the effects of intravenous infusion of
L-arginine (500 mg/kg given over 30 minutes) on systemic
and renal hemodynamics in 27 patients with mild to
moderate essential hypertension who were randomly assigned to treatment
with either the angiotensin-converting enzyme
inhibitor imidapril or the calcium antagonist
amlodipine for 12 weeks in a double-blind fashion. After the 12 weeks,
the decrease in blood pressure was similar in the imidapril (n=14) and
amlodipine (n=13) groups. The increase in renal plasma flow was also
similar in both groups. L-Arginine–induced renovascular
relaxation was increased by imidapril (renal plasma flow, 9.6±5.1% to
14.4±7.4%; renal vascular resistance, -10.4±8.1% to -16.7±9.2%,
P<0.05, respectively) but not by amlodipine. Urinary
excretion of nitrite/nitrate in response to L-arginine was
significantly increased by imidapril (90±29% to 134±63%,
P<0.05) but remained unchanged by amlodipine. These
findings suggest that angiotensin-converting enzyme
inhibition improves the impaired endothelium-dependent
renovascular relaxation in patients with essential hypertension due to
the increase in nitric oxide production and that the reduction
in blood pressure with a calcium antagonist does not play a
major role in the potentiation of L-arginine/nitric
oxide–mediated effects.
Key Words: angiotensin-converting enzyme inhibitor • calcium antagonist • nitric oxide • endothelium • kidney • hypertension, essential
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Nitric oxide plays an
important role in the regulation of systemic and renal
hemodynamics.1 2 3 In hypertensive
patients, endothelium-dependent vascular relaxation in
coronary4 and forearm
arteries5 6 7 was impaired, and
endothelial dysfunction being involved in the
development of atherosclerosis increases the risk of
cardiovascular and cerebrovascular diseases. We also
demonstrated that endothelium-dependent renovascular
relaxation was impaired in essential hypertensive patients compared
with normotensive subjects.8 9 10
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Subjects
We recruited 29 Japanese patients with mild to moderate
essential hypertension, 27 (16 men and 11 women; mean age, 56±15
years) of whom completed the study. Hypertension was defined as
systolic blood pressure of >160 mm Hg and/or
diastolic blood pressure of >95 mm Hg, with the
subject in a sitting position, on at least 3 different occasions.
Measurements were obtained in the outpatient clinic of Hiroshima
University School of Medicine. Patients with secondary forms of
hypertension were excluded on the basis of complete history; physical
examination; radiological and ultrasound examinations; urinalysis; PRA;
plasma aldosterone and norepinephrine
concentrations; serum creatinine, potassium, calcium, and
free thyroxine concentrations; and the 24-hour urinary excretion of
17-hydroxycorticosteroids, 17-ketogenic steroids, and
vanillymandelic acid. No patients had a history of
cardiovascular or cerebrovascular disease, diabetes
mellitus, hypercholesterolemia, liver disease,
or renal disease. The study protocol was approved by the ethics
committee of the First Department of Internal Medicine of Hiroshima
University. Informed consent for participation was obtained from
all subjects.
No patient had a history of antihypertensive treatment before
the study. Patients were randomly assigned to treatment either with ACE
inhibitor (imidapril) or calcium antagonist
(amlodipine) in a double-blind fashion. A 4-week run-in period with a
placebo was followed by a 12-week treatment period. During the initial
4 weeks of the active treatment period, patients were treated with
single daily doses of imidapril (5 mg) or amlodipine (5 mg) in the
morning. When diastolic blood pressure was found to be
>90 mm Hg or a decrease of <15 mm Hg was seen at the end
of the first 4 weeks, dosages were increased to 10 mg for imidapril and
10 mg for amlodipine during the following 4-week period. If blood
pressure was not controlled with this regimen, the daily dosages were
increased to 15 mg for imidapril and 15 mg for amlodipine during the
last 4 weeks, at which time patients received the same daily dose of
each drug.
To confirm the basal blood pressure profile and the effects of
antihypertensives, 24-hour ambulatory blood pressure monitoring was
also performed at the beginning and end of the treatment period using a
TM2420 (AND Co) device, a noninvasive ambulatory blood pressure monitor
that is attached to the upper left arm. Blood pressure was measured
using the Korotkoff microphone method during stepwise deflations
(3.0±1.0 mm Hg per step) of the cuff. The within-run precision
of blood pressure and heart rate measurements were ±4.0 mm Hg
and ±5.0%, respectively. Blood pressure and heart rate measurements
were obtained at 30-minute intervals from daytime (6 AM to
9 PM) and nighttime hours (9 PM to 6
AM).
The vasodilatory response to L-arginine was
evaluated at the beginning and end of the 12-week treatment period.
Before and after the 12-week antihypertensive treatment, the
L-arginine infusion study began at 8:30 AM.
Subjects fasted the previous night for at least 12 hours. They were
kept in the supine position in a quiet, dark, air-conditioned room
(constant temperature of 22°C to 25°C) throughout the study. A
19-gauge polyethylene catheter (Terumo Co) was inserted into the right
antecubital vein for the infusion of PAH, inulin, and
L-arginine. A second catheter was inserted into the left
antecubital vein to obtain blood samples. After a 30-minute rest
period, an initial dose of PAH (8.0 mg/kg) and inulin (16 mg/kg) was
infused as a bolus. PAH and inulin were subsequently infused at
constant rates of 12 and 20 mg/min, respectively, by a syringe pump
(Terfusion; Terumo Co) throughout the study.22
Sixty minutes after beginning the infusions, we initiated the infusion
of L-arginine (500 mg/kg) given over 30 minutes using an
infusion pump (PEI-1000; Pal Medical Co). The end of the
L-arginine infusion was followed by a 30-minute recovery
period. Blood pressure and heart rate were determined every minute by a
TM2420 monitor attached to the upper part of the left arm. Mean blood
pressure was calculated as the diastolic pressure plus one
third of the pulse pressure. Blood samples were obtained to determine
serum PAH, inulin, and plasma cGMP, NOx, norepinephrine,
and h-ANP at 0 minutes and at 15, 30, and 60 minutes after the start of
L-arginine administration. Baseline fasting serum
concentrations of total cholesterol,
creatinine, insulin, glucose, electrolytes, and ACE
activity and PRA, Ang II concentration, and PAC were obtained at 0
minutes. The urinary excretions of cGMP, NOx, creatinine,
and electrolytes were obtained during 1 hour before and after the start
of L-arginine infusion.
The ACE inhibitor used was imidapril hydrochloride
(Tanabe Pharmaceutical Co). The calcium antagonist was
amlodipine (Pfizer Pharmaceutical Co). The L-arginine used
for intravenous administration was L-arginine
hydrochloride (Morishita-Rusel Pharmaceutical Co).
D-Arginine was D-arginine hydrochloride (Sigma
Chemical Co). The administered inulin was Inutest
(Laevosan-Gesellschaft Co), whereas the PAH was from Daiichi
Pharmaceutical Co.
Samples of venous blood were placed in tubes containing EDTA-Na
(1 mg/mL) and in polystyrene tubes. The EDTA-containing tubes were
promptly chilled in an ice bath. Plasma was immediately separated by
centrifugation at 3100g at 4°C for 10
minutes, and serum at 1000g (at room temperature) for 10
minutes. Samples were stored at -80°C until assayed. Routine
chemical methods were used to determine serum concentrations of total
cholesterol, creatinine, glucose and
electrolytes, and urinary electrolytes. PRA (Gamma Coat PRA, Baxter
Travenol Co), plasma Ang II (antiangiotensin II antibody,
SRL Co), and PAC (SPAC-S, Aldosterone kits, Daiichi Radio
Laboratory Co) were assayed by radioimmunoassay; the intra- and
interassay coefficients of variation were 6.2% and 7.6% for PRA,
8.9% and 9.4% for Ang II, and 7.1% and 8.8% for PAC, respectively.
Determination of ACE activity was based on the
colorimetry of the quinoneimine dye as previously
described23 ; the intra- and interassay
coefficients of variation were 2.1% and 3.3%, respectively. The
plasma concentration of norepinephrine was measured by
high-performance liquid chromatography (HPLC);
the intra- and interassay coefficients of variation were 2.4% and
2.1%, respectively. The plasma concentration of h-ANP was assayed by
radioimmunoassay (Amersham Co); the intra- and interassay coefficients
of variation were 3.8% and 5.3%, respectively. Plasma and urine
concentrations of cGMP were measured by radioimmunoassay using a cGMP
kit (Yamasa Shoyu Co); the intra- and interassay coefficients of
variation were 4.8% and 5.2%, respectively. Plasma and urine
concentrations of NOx were assayed by colorimetric
methods using NOx assay kits (Cayman Chemical Co). Briefly, nitrate in
the sample is converted to nitrite utilizing nitrate reductase. The
second step is addition of Griess reagents24 (1%
sulfonamide, 0.1% N-1-naphthylethylenediamide, and 5%
HCl), which convert nitrite into a deep purple azo compound. The
absorbance of this azo dye at 540 nm was measured by a microplate
reader (M-Tmax; Wako Co). Urine samples were diluted with HPLC-grade
water (1:100) because urine contained relatively high levels of
nitrate. Urinary excretions of cGMP and NOx were corrected by
creatinine excretion. The intra- and interassay
coefficients of variation were 0.8% and 1.2%, respectively. The least
detectable levels of PRA, Ang II concentration, PAC, ACE activity,
norepinephrine, h-ANP, cGMP, and NOx are 0.1 ng/mL per
hour, 2 pg/mL, 15 pmol/mL, 0.1 IU/L, 2 pg/mL, 0.5 pmol/L, 0.15 pmol/mL,
and 1 µmol/L, respectively.
Results are presented as mean±SD. Values of
P<0.05 were considered significant. The Mann-Whitney
U test was used to evaluate differences between the
imidapril and amlodipine groups concerning the parameters
at baseline before treatment. Comparisons between treatment groups with
respect to changes in parameters were performed with
adjusted means by ANCOVA using baseline data as the covariates.
Comparisons of time-course curves of parameters during
L-arginine infusion were analyzed by 2-way ANOVA
for repeated measures. The data were processed using either StatView IV
(Brainpower) or Super ANOVA (Abacus Concepts) software packages.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Clinical Characteristics and Drug Dosages
With a double-blind, randomized, and parallel method, 29 patients
were divided into either the imidapril group (n=15) or the amlodipine
group (n=14). One of 15 patients in the imidapril group withdrew
because of adverse effects resulting in a cough and rash, and 1 of 14
patients in the amlodipine group withdrew because of a change of
address. Of the 27 patients completing the study, 14 were randomized to
receive imidapril (9 men and 5 women; mean age, 57±11 years) and 13 to
receive amlodipine (7 men and 6 women; mean age, 55±11 years). To
achieve blood pressure control, 14 patients received an imidapril dose
of 8.8±3.7 mg/d and 13 patients received an amlodipine dose of
6.3±2.1 mg/d. There were no significant differences in age and gender
in the 2 groups. The baseline values for parameters in the
imidapril and amlodipine groups at the beginning of the treatment
period were similar in both groups, as shown in Table 1
.
View this table:
[in a new window]
Table 1. Clinical Characteristics of Patients Before and
After Treatment
The effects of imidapril and amlodipine on the baseline values of
parameters are shown in Table 1
. After 12 weeks, the
decrease in casual blood pressure was similar in the imidapril and
amlodipine groups. The 24-hour ambulatory blood pressure was
significantly decreased: with imidapril, systolic fell from
152.0±13.7 to 132.2±12.7 mm Hg, diastolic from
91.6±10.7 to 81.4±10.2 mm Hg, and mean from 111.4±12.8 to
96.2±12.1 mm Hg (all P<0.01); with amlodipine,
systolic fell from 153.3±13.8 to 130.2±11.9 mm Hg,
diastolic from 92.8±10.9 to 80.1±10.1 mm Hg, and
mean from 113.1±13.8 to 95.7±11.5 mm Hg (all
P<0.01). There was no significant difference in decline in
24-hour mean ambulatory blood pressure between the 2 groups. Mean
daytime and nighttime ambulatory blood pressures were also similar
before and after treatment with imidapril and amlodipine (data not
shown). ACE activity and Ang II were significantly decreased (69±15%
and 78±19%, respectively; P<0.01) by imidapril but
remained unchanged by amlodipine. In the imidapril group, PRA tended to
increase and PAC tended to be depressed but not significantly. Both
treatments increased RPF significantly and decreased RVR significantly.
The increase in RPF was similar in both the imidapril and amlodipine
groups. Thus, drug-induced decline in RVR was also similar in both
groups. Other parameters such as lipid and glucose
metabolism remained unchanged by both antihypertensive
treatments.
Figure 1 shows the effects of
L-arginine infusion on mean blood pressure and heart rate.
After L-arginine administration began, mean blood pressure
promptly decreased and plateaued after 20 minutes. A prompt return to
the baseline level occurred after the end of L-arginine
infusion. Changes in systolic and diastolic blood
pressures were exactly paralleled by the change in mean blood
pressure (imidapril group: before treatment, systolic
-10.2±2.1% and diastolic -9.8±1.8%; after treatment,
systolic -9.9±2.1% and diastolic -9.1±1.9%;
amlodipine group: before treatment, systolic -10.3±2.2% and
diastolic -10.1±1.8%; after treatment, systolic
-9.7±2.0% and diastolic -9.4±1.8%). The time course
of percent changes in blood pressures was similar in the 2 groups and
was not changed by either treatment. Conversely, heart rate gradually
increased during L-arginine infusion and gradually returned
to the baseline during the recovery period. The percent changes in
heart rate were similar in the 2 groups before and after treatment.
View larger version (29K):
[in a new window]
Figure 1. Effects of L-arginine infusion on mean
blood pressure and heart rate before and after treatment in the
imidapril and amlodipine groups. The responses of mean blood pressure
and heart rate to L-arginine were similar in the 2 groups.
Results are presented as mean±SD. Probability value refers to
the comparison of time-course curves using ANOVA for repeated
measurements. and 3 show the effects of
L-arginine infusion on renal hemodynamics
such as RPF, RVR, GFR, and FF in the imidapril and amlodipine groups at
the beginning and at the end of the antihypertensive treatment period.
L-Arginine infusion caused RPF to increase significantly
and RVR and FF to decrease significantly and did not produce a
significant change in GFR in either group before or after treatment.
RPF, RVR, and FF returned to baseline level at 30 minutes after the end
of L-arginine infusion. Before treatment, the degree of
L-arginine–induced renovascular relaxation was similar in
the imidapril and amlodipine groups. After 12 weeks, the responses of
RPF and RVR to L-arginine were augmented (9.6±5.1%
to 14.4±7.4% and -10.4±8.1% to -16.7±9.3%, respectively;
P<0.001) by imidapril, whereas
L-arginine– induced changes in the
parameters were not altered by amlodipine.
View larger version (24K):
[in a new window]
Figure 2. Effects of L-arginine infusion on
renal hemodynamics such as RPF, RVR, GFR, and FF in the
imidapril group. Patients who received imidapril at 12 weeks showed
increased responses of RPF and RVR to L-arginine compared
with at the beginning of treatment. Results are presented as
mean±SD. Probability value refers to the comparison of time-course
curves using ANOVA for repeated measurements.
View larger version (24K):
[in a new window]
Figure 3. Effects of L-arginine infusion on
renal hemodynamics such as RPF, RVR, GFR, and FF in the
amlodipine group. Renal responses to L-arginine in patients
who received amlodipine were similar both before and after treatment.
Results are presented as mean±SD. Probability value refers to
the comparison of time-course curves using ANOVA for repeated
measurements.
L-Arginine infusion significantly increased the
urinary excretions of NOx and cGMP and plasma concentrations of cGMP
and h-ANP but did not change plasma concentrations of NOx and
norepinephrine (Figure 4 and
Tables 2 and 3). The increment in urinary excretion of
NOx in response to L-arginine infusion was
significantly increased from 90±29% to 134±63% (P<0.05)
by imidapril treatment but was unchanged by amlodipine treatment (from
88±32% to 102±58%) (Figure 4, top). The increment in urinary
excretion of cGMP in response to L-arginine was also
significantly increased from 119±37% to 187±97%
(P<0.05) by imidapril treatment but was unchanged by
amlodipine treatment (from 112±43% to 138±87%) (Figure 4, bottom).
Before and after the 12 weeks, plasma concentrations of h-ANP in
response to L-arginine were similar in both treatments
(Tables 2 and 3).
View larger version (14K):
[in a new window]
Figure 4. Effects of L-arginine infusion on
urine NOx (top) and cGMP (bottom) excretion in the imidapril and
amlodipine groups. Patients who received imidapril at 12 weeks showed
increased responses of NOx and cGMP to L-arginine compared
with at the beginning of treatment. NOx and cGMP responses to
L-arginine in patients who received amlodipine were similar
both before and after treatment. Results are presented as
mean±SD. *P<0.05 vs before treatment.
View this table:
[in a new window]
Table 2. Effects of L-Arginine on Plasma cGMP,
NOx, Norepinephrine, and h-ANP in Imidapril
Group
View this table:
[in a new window]
Table 3. Effects of L-Arginine on Plasma cGMP,
NOx, Norepinephrine, and h-ANP in Amlodipine
Group
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
In the present study, we demonstrated that ACE inhibition with
imidapril improved impaired endothelium-dependent
renovascular relaxation in patients with essential hypertension without
atherosclerosis. Urinary excretion of NOx, as an index
of renal NO release, in response to L-arginine was
significantly augmented by the imidapril treatment, suggesting that
improvement of renal endothelial dysfunction by ACE
inhibitors may be due to the increase in NO
production. Reduction in blood pressure per se did not play a
major role in this potentiation of
L-arginine/NO/cGMP–mediated effects because there was no
alteration in the renal endothelial function in the
amlodipine-treated group despite a hypotensive action and renal
vasodilation similar to those of the imidapril group.
Selected Abbreviations and Acronyms
ACE
=
angiotensin-converting enzyme
Ang
=
angiotensin
FF
=
filtration fraction
GFR
=
glomerular filtration rate
h-ANP
=
human atrial natriuretic peptide
NO
=
nitric oxide
NOx
=
nitrite/nitrate
PAC
=
plasma aldosterone concentration
PAH
=
para-aminohippurate
PRA
=
plasma renin activity
RPF
=
renal plasma flow
RVR
=
renal vascular resistance
Acknowledgments
This study was supported in part by a grant-in-aid for
scientific research from the Ministry of Education, Science, and
Culture of Japan (08457639). The authors thank Dr Hiroaki Ikeda for the
preparation of the D-arginine hydrochloride and Yuko Omura
for her secretarial assistance.
Footnotes
Presented in part at the Council for High Blood Pressure Research 51st Annual Fall Conference and Scientific Sessions, Washington, DC, September 16-19, 1997, and published in abstract form (Hypertension. 1997;30:486).
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
1.
Ress DD, Palmer RMJ, Moncada S. Role of
endothelium-derived nitric oxide in the regulation of
blood pressure. Proc Natl Acad Sci U S A. 1989;86:3375–3378.
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