From the Department of Physiology, New York Medical College, Valhalla,
NY.
Correspondence to Thomas H. Hintze, PhD, Professor, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail Thomas-Hintze{at}NYMC.edu
Methods and Results—We hypothesized that a portion of the
beneficial actions of amlodipine may involve the release or action of
NO. Coronary microvessels were isolated from the heart of
normal dogs and incubated with increasing doses of the calcium channel
blockers nifedipine, diltiazem, and amlodipine or the ACE
inhibitors enalaprilat and ramiprilat. Neither
nifedipine nor diltiazem increased nitrite
production at any dose studied. In marked contrast, amlodipine
caused a dose-dependent increase in nitrite production from
74±5 to 130±8 pmol/mg (by 85±21%,10-5 mol/L,
P<.05) that was similar in magnitude to that of either
of the ACE inhibitors. Amlodipine also increased nitrite
production in large coronary arteries and in aorta.
N
Conclusions—Thus, unlike nifedipine and diltiazem,
amlodipine releases NO from blood vessels.
Our recent data suggested that a portion of the beneficial effects of
ACE inhibitors in the treatment of heart failure may be due
to the release of NO6 secondary to the generation
of kinins locally.6 7 8 These data support a large
number of other studies,9 10 and it is now widely
believed that NO contributes importantly to the mechanism of action of
ACE inhibitors used in the treatment of all disease states.
The release of NO by amlodipine or other calcium channel blockers would
not be expected because there are no known receptors for calcium
channel blockers in endothelial cells and because
calcium is a cofactor for NO synthase and required for activation of NO
synthase.11 12 However, because both ACE
inhibitors and organic nitrates release NO and are useful
in the treatment of heart failure, we reasoned that perhaps amlodipine
releases NO from blood vessels and that kinins mediate the release of
NO.6 7 8 Thus, the goal of our study was to
compare and contrast the ability of amlodipine and two other calcium
channel blockers to release NO with that of a group of compounds, the
ACE inhibitors, which are already known to release NO.
Isolation of Coronary Microvessels
Incubation of Coronary Microvessels
Isolation of Large Coronary Artery and Aorta
Comparison of Effects of Amlodipine, Ramiprilat, and Diltiazem on
NO Production
Comparison of Effects of Amlodipine, Nifedipine, and
Enalaprilat on NO Production
Drugs and Chemicals
Statistical Analysis and Calculation
Comparison of Effects of Amlodipine, Ramiprilat, and Diltiazem on
NO Production
As shown in Fig 3
Comparison of Effects of Amlodipine, Nifedipine, and
Enalaprilat on NO Production
Recent clinical studies have suggested that nifedipine is
without benefit in the treatment of heart failure and have questioned
its therapeutic use even when it may clearly be indicated and effective
in disease states in which nifedipine causes vasodilation,
such as hypertension or vasospasm. A preliminary study, PRAISE-1,
however, has shown that amlodipine has clear beneficial actions in
nonischemic dilated
cardiomyopathy.5 In heart
failure secondary to ischemia, amlodipine may also have no
effect on mortality when compared with a placebo-treated
group.5 The most widely used drugs in the
treatment of heart failure are organic nitrates and ACE
inhibitors.17 Both of these compounds
release NO either chemically, as in the nitrates, or due to inhibition
of kinin breakdown, by kininase II inhibition, as in the case of ACE
inhibitors. These actions result in vasodilation, increased
coronary blood flow, decreased peripheral vascular
resistance, and other actions, such as inhibition of platelet
aggregation.12 In addition, the organic nitrates
cause venous dilation to reduce preload and myocardial oxygen
consumption.18 19 20 Because amlodipine releases NO
and this may be mediated by a kinin mechanism, a portion of its
cardiovascular actions should be similar to that of ACE
inhibitors and organic nitrates. Indeed, amlodipine is a
long-acting vasodilator, increasing blood flow in the coronary,
renal, and mesenteric vascular beds.12 21 22 In
addition, amlodipine reduces myocardial oxygen
consumption.12 Amlodipine caused a potent
concentration-dependent relaxation of KCl-precontracted dog saphenous
veins and, to a lesser extent, jugular veins in
vitro.23 Interestingly, there is an acute fall in
peripheral resistance to amlodipine, whereas the maximum
effects on peripheral resistance may not occur for 4 hours
after its administration,12 suggesting two
mechanisms of action.
Ours is not the first study to investigate whether a portion of the
actions of amlodipine is NO dependent. Bennett et
al24 compared the effects of chronic treatment of
SH rats with amlodipine, ACE inhibitors, and
hydralazine on endothelium-dependent vessel
relaxation in vitro. These authors found that chronic ACE
inhibitor therapy potentiated
endothelium-dependent relaxation to ACH and bradykinin
and that treatment with amlodipine did not. They concluded that a
product from the endothelium did not play an
important role in the action of amlodipine. On the other hand, Lyons et
al25 found that chronic treatment of patients
with enalaprilat or amlodipine reduced blood pressure and that L-NMMA
reduced forearm blood flow by 55% in the enalaprilat-treated group and
by 59% in the amlodipine-treated group compared with only 33% in the
placebo group. There was no statistical difference between the
enalaprilat and amlodipine groups. Clearly, that study implicated
altered vascular NO production in the mechanism of action of
amlodipine. Finally, amlodipine may stimulate cellular cGMP
production, an action shared by NO, although it was attributed
to altered phosphodiesterase activity.26
Our previous studies have indicated that a number of agents increase
nitrite formation in vitro due to effects on local
kinins.7 8 14 27 In those studies, nitrite
production was inhibited by L-NAME, by HOE-140 (Icatibant), and
by three different serine protease inhibitors. Furthermore,
the actions of bradykinin and ACE inhibitors were blocked
by a kinin antibody, indicating the formation of kinins
locally.28 The present study indicates that
amlodipine stimulates NO production through a similar mechanism
in that nitrite formation was entirely blocked by L-NAME, HOE-140, and,
in particular, DCIC. These results suggest that a portion of the
clinical benefit of ACE inhibitors, and perhaps amlodipine,
can be attributed to altered local production or activity of
kinins,29 although clinical trials will be needed
to confirm this hypothesis.
In summary, our data strongly suggest that amlodipine releases NO from
(1) isolated coronary microvessels, (2) large epicardial
coronary arteries, and (3) conduit vessels like the aorta. In
addition, these actions are not shared by nifedipine and
diltiazem. The mechanism responsible for the release of NO by
amlodipine is similar to that of ACE inhibitors—that is,
modulation of the actions or formation of kinins.
Received July 31, 1997;
revision received September 10, 1997;
accepted September 30, 1997.
© 1998 American Heart Association, Inc.
Basic Science Reports
Amlodipine Releases Nitric Oxide From Canine Coronary Microvessels
An Unexpected Mechanism of Action of a Calcium Channel–Blocking Agent
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Recent studies suggest
that amlodipine may reduce mortality in patients with heart failure,
especially those with dilated cardiomyopathy. In
general, drugs that release NO, such as organic nitrates and ACE
inhibitors, have been shown to be of substantial benefit in
the treatment of heart failure. 
-Nitro-L-arginine methyl
ester, HOE-140, and dichloroisocoumarin essentially abolished the
increase in nitrite production, indicating that (1) nitrite
production reflected NO formation, (2) nitrite
production was dependent on stimulation of the
kinin2 receptor, and (3) nitrite production is most
likely secondary to the formation of local kinins.
Key Words: nifedipine • bradykinin • calcium channels • endothelium-derived factors
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Recent studies
suggest that calcium channel blockers in general may not be beneficial
in the treatment of heart failure even if effective in the treatment of
other vascular diseases, including hypertension and
vasospasm.1 2 3 The mechanism of these effects may
be a negative inotropic action, particularly if there is some
abrogation of the reflex sympathetic actions caused by these drugs due
to the disappearance of sympathetic nerve endings in the heart as a
part of the heart failure process.4 In contrast
to these views, amlodipine has been reported in the PRAISE-1 trial to
have a substantial beneficial effect in a subgroup of patients with
dilated cardiomyopathy who underwent posthoc
analysis.5 For instance, there was a 31%
reduction in fatal events in a subgroup of patients with
nonischemic dilated cardiomyopathy who were
treated with amlodipine.5
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Nineteen male mongrel dogs (body weight, 23 to 30 kg) were used
in the study. Hearts were obtained immediately from
pentobarbital-anesthetized dogs and kept in ice-cold PBS
containing 0.1% bovine serum albumin, pH 7.4. All of the
studies in dogs were approved by the Institutional Animal Care and Use
Committee of New York Medical College and conform to current National
Institutes of Health and American Physiological
Society guidelines for the use and care of laboratory animals.
Isolation of coronary microvessels from the left
ventricle of the dog heart was performed using the method originally
developed by Gerritsen and Printz.13
Coronary microvessels were obtained free of both large arteries
and veins and also of myocytes by a series of steps involving
sequential dissection, homogenization, sieving, and
glass bead purification. We have previously used these
methods.6 7 8 14 15 16
Microvessels were placed in a small package of 80-µm nylon
mesh, transferred into a tissue bath containing PBS, and
oxygenated with 95% O2/5%
CO2 for 30 minutes. About 20 mg (wet weight) of
tissue was placed in 5-mL plastic tubes that contained 500 µL of PBS
as control or 450 µL of PBS and 50 µL of drugs dissolved in PBS
used to stimulate (eg, amlodipine and ramiprilat) or inhibit (eg,
L-NAME) NO formation. All drugs were incubated with tissue for 20
minutes. At the end of the incubation time, the tubes were removed from
the tissue bath, and sulfanilamide (450 µL of 1%) and
N-(1-naphthyl)-ethylenediamine (50 µL of 0.2%) were
added to each tube for diazotization of sulfanilic acid by NO. After 5
to 10 minutes' incubation at room temperature, the supernatant was
removed from each tube. Formation of NO was measured as nitrite that is
the major metabolite of NO in aqueous solution. Nitrite was measured
using a spectrophotometer (Uvikon 930 Spectrophotometer; Kontron
Instruments) as the increase in absorbance at 540 nm and compared with
known concentrations of nitrite. L-NAME was used to block NO synthase.
HOE-140 (Icatibant) was used to block the kinin2
receptor, and DCIC used to block the action of kinin-forming enzymes.
We described these methods recently.14 15 16
Either the left circumflex or left anterior descending
coronary artery was removed and cut into rings 
20 mg in
weight. In addition, pieces of the descending thoracic aorta (20 mg)
were removed and studied. Rings were incubated in a fashion similar to
microvessels. We used this technique
previously.15 16
The effects of increasing doses of amlodipine
(10-10 to 10-5
mol/L) on nitrite production were compared with
those of ramiprilat (10-10 to
10-8 mol/L). The highest dose of
amlodipine or ramiprilat was examined after preincubation of the
microvessels with L-NAME, HOE-140, or DCIC. A standard dose-response
curve for bradykinin (10-8 to
10-5 mol/L) was also examined. A
comparison of the effects of amlodipine on large coronary
arteries, ascending aorta, and coronary microvessels was
performed. To make a comparison with another water-soluble calcium
channel blocker, the effects of increasing doses of diltiazem
(10-10 to 10-5
mol/L) on NO production were determined in
microvessels from five dogs.
We compared the ability of amlodipine to release NO with that of
nifedipine. However, unlike amlodipine and diltiazem,
nifedipine is not soluble in aqueous solution. Therefore,
we compared the actions of nifedipine, amlodipine, and
enalaprilat with all of the drugs dissolved in 0.01% DMSO (n=7). In
coronary microvessels, the effects were assessed of increasing
doses of amlodipine, nifedipine, and enalaprilat on NO
production. The effects of the highest dose of each of these
was also assessed after preincubation of the microvessels with L-NAME,
HOE-140, or DCIC.
The PBS used in these studies consisted of 139 mmol/L NaCl,
2.7 mmol/L KCl, 8.1 mmol/L NaHPO4,
1.5 mmol/L KH2PO4,
0.68 mmol/L CaCl2, 0.49 mmol/L
MgCl2, and 0.1% bovine serum albumen.
L-NAME is an inhibitor of NO synthase; HOE-140 (Icatibant)
is a bradykinin2 receptor antagonist;
and DCIC is a serine protease inhibitor that blocks the
activity of kinin-forming enzymes (serine proteases). Drugs
(bradykinin, enalaprilat, diltiazem) and chemicals (L-NAME, DCIC, and
nitrite) were purchased from Sigma Chemical. Amlodipine and
nifedipine were generously supplied by Pfizer
Pharmaceutical (Groton, CT). Ramiprilat and HOE-140 were
generously supplied by Hoechst-Roussel Inc (Somerville, NJ). In only
one study, amlodipine, nifedipine, and enalaprilat were
dissolved in 0.01% DMSO and PBS. In all of the other studies, the
drugs were dissolved in PBS.
To construct a standard curve for nitrite, a stock solution of
NaNO2 (10-5 mol/L), was
prepared and diluted each day. Sulfanilamide (450 µL of 1%) and
N-(1-naphthyl) ethylene diamine (50 µL of 0.2%) were
added to each tube and mixed well. The tubes were allowed to stand at
room temperature for 5 to 10 minutes for full color (pink) development
and absorbance of nitrite measured at 540 nm. Absorbance was computed
and converted to a straight line using a regression analysis
(y=ax+b, r>.99). Nitrite
production was calculated using the linear regression formula
and resulting values computed. Data were expressed as mean±SEM in
pmol · mg of wet weight-1 · 20-min
incubation-1. Differences in nitrite
production from control were determined with ANOVA. A value of
P<.05 was considered statistically significant. Statistical
analysis and graphs were produced on a 486 computer (Everex)
using commercially available software (Lotus1,2,3; GB STAT; Slide
Write). The differences between individual data points were determined
using Tukey's test (GB STAT).
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
The average weight of the heart in these dogs was 211±7 g, the LV
free wall weight was 83±3 g, and the amount of microvessels collected
was 2.0±0.1 g per heart. The average weight of rings of
coronary arteries was 21±2 mg, and the weight of pieces of the
aorta was 20±4 mg. The average body weight of the dogs was 27±0.5 kg.
The data in the figures are the actual changes in nitrite
production in pmol · mg of wet
weight-1 · 20-min
incubation-1, whereas the data in the text are
the actual values.
The effects of increasing doses of amlodipine and ramiprilat in
coronary microvessels (n=7) are shown in Fig 1
. Both agents caused a substantial
increase in nitrite production; however, ramiprilat was
significantly more potent. The highest dose of amlodipine increased
nitrite production from 74±5 to 130±8 pmol/mg. and this was
reduced to 60±7 pmol/mg in the presence of L-NAME, to 76±10 pmol/mg
in the presence of HOE-140, and to 90±8 pmol/mg in the presence of
DCIC (all P<.05 from amlodipine, Fig 2). In contrast, diltiazem did not
increase NO production at any dose studied (Fig 1). Bradykinin
caused a dose-dependent increase (n=7) in nitrite production
with 10-5 mol/L, increasing from
78±8 to 153±9 pmol/mg. The increase in nitrite was entirely blocked
by L-NAME (to 85±11 pmol/mg) and HOE-140 (to 82±9 pmol/mg, both
P<.05; baseline, 89±8 pmol/mg).
View larger version (17K):
[in a new window]
Figure 1. Increase in nitrite production due to
amlodipine, ramiprilat, and diltiazem in isolated coronary
microvessels. Although amlodipine and ramaprilat caused a
dose-dependent increase in nitrite production, diltiazem had no
significant effect at any dose.
View larger version (22K):
[in a new window]
Figure 2. Role of NO, bradykinin2 receptor, and
local kinin formation in the production of nitrite. The
production of nitrite in coronary microvessels was
entirely blocked by L-NAME, indicating that nitrite production
reflects NO synthesis. The enhanced nitrite production was also
blocked by HOE-140 and DCIC, indicating that NO production was
a consequence of stimulation of the bradykinin 2 receptor and the
formation of kinins, respectively. , amlodipine caused a
significant, comparable, and dose-dependent increase (n=7) in nitrite
production in large coronary arteries, aorta, and
coronary microvessels. NO production was blocked by
L-NAME (from 145±17 to 110±14), by HOE-140 (from 145±17 to 92±10),
or by DCIC (from 145±17 to 98±8; baseline, 80±4 pmol/mg) in large
coronary artery (all P<.05) and by L-NAME (from
140±18 to 90±11 pmol/mg), by HOE-140 (from 140±18 to 102±14
pmol/mg), and by DCIC (from 140±18 to 97±14; baseline, 88±9 pmol/mg)
in aorta (all P<.05). At no dose did diltiazem
significantly increase nitrite production in large
coronary artery or aorta.
View larger version (18K):
[in a new window]
Figure 3. Amlodipine caused similar increases in nitrite
production in large coronary arteries, aorta, and
coronary microvessels.
When dissolved in DMSO (n=7), enalaprilat and amlodipine both
increased NO production in a dose-dependent manner (Fig 4). Amlodipine increased nitrite
production from 76±5 to 153±12 pmol/mg, and enalaprilat
increased nitrite production from 80±7 to 146±11 pmol/mg.
There was no statistical difference in the peak response to these
agents. In marked contrast, at no dose did nifedipine cause
a statistically significant increase in NO production in
coronary microvessels (Fig 4) or in large coronary
arteries (117±12 to 107±10 pmol/mg) and aorta (90±8 to 102±10
pmol/mg, n=7). The increase in nitrite production to amlodipine
and enalaprilat was reduced to 76±7 and 72±12 pmol/mg by L-NAME, to
77±7 and 81±10 pmol/mg by HOE-140, and to 87±11 and 77±15 pmol/mg
by DCIC, respectively.
View larger version (17K):
[in a new window]
Figure 4. Amlodipine and enalaprilat caused similar and
dose-dependent increases in nitrite production in
coronary microvessels. In marked contrast,
nifedipine had no effect on nitrite production at
any dose studied. The vehicle for all these drugs was DMSO because
nifedipine is not soluble in aqueous solution.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The most significant finding of the present study was that
unlike the other calcium channel–blocking agents,
nifedipine and diltiazem, amlodipine causes the release of
NO from large and small coronary arteries and aorta. The
magnitude of the stimulation of NO at the highest dose studied is not
different from that of ACE inhibitors. It is interesting
that the same mechanism that is responsible for ACE
inhibitor-induced NO production (ie, a
kinin-dependent mechanism) appears also to be responsible for the
ability of amlodipine to release NO. It is therefore very likely that
part of the difference between amlodipine and nifedipine or
diltiazem stems from the unexpected property of amlodipine to release
NO.
Selected Abbreviations and Acronyms
DCIC
=
dichloroisocoumarin
DMSO
=
dimethylsulfoxide
L-NAME
=
N
-nitro-L-arginine methyl
ester
Acknowledgments
This study was supported by grants PO-1-HL-43023, HL-50142, and
HL-53053 from the National Heart, Lung, and Blood Institute and by
Fellowship 96–103 (Dr Zhang) from the American Heart Association, New
York Affiliate. We would like to thank Xiaobin Xu, MD, for assistance
with this study.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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D. Sun, A. Huang, G. Zhao, R. Bernstein, P. Forfia, X. Xu, A. Koller, G. Kaley, and T. H. Hintze Reduced NO-dependent arteriolar dilation during the development of cardiomyopathy Am J Physiol Heart Circ Physiol, February 1, 2000; 278(2): H461 - H468. [Abstract] [Full Text] [PDF]
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M. Kitakaze, H. Asanuma, S. Takashima, T. Minamino, Y. Ueda, Y. Sakata, M. Asakura, S. Sanada, T. Kuzuya, and M. Hori Nifedipine-Induced Coronary Vasodilation in Ischemic Hearts Is Attributable to Bradykinin- and NO-Dependent Mechanisms in Dogs Circulation, January 25, 2000; 101(3): 311 - 317. [Abstract] [Full Text] [PDF]
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T. J. Anderson, E. Elstein, H. Haber, and F. Charbonneau Comparative study of ACE-inhibition, angiotensin II antagonism, and calcium channel blockade on flow-mediated vasodilation in patients with coronary disease (BANFF study) J. Am. Coll. Cardiol., January 1, 2000; 35(1): 60 - 66. [Abstract] [Full Text] [PDF]
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J. Yang, K. Fukuo, S. Morimoto, T. Niinobu, T. Suhara, and T. Ogihara Pranidipine Enhances the Action of Nitric Oxide Released From Endothelial Cells Hypertension, January 1, 2000; 35(1): 82 - 85. [Abstract] [Full Text] [PDF]
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K. E. Loke, C. M. L. Curran, E. J. Messina, S. K. Laycock, E. G. Shesely, O. A. Carretero, and T. H. Hintze Role of Nitric Oxide in the Control of Cardiac Oxygen Consumption in B2-Kinin Receptor Knockout Mice Hypertension, October 1, 1999; 34(4): 563 - 567. [Abstract] [Full Text] [PDF]
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K. E. Loke, S. K. Laycock, S. Mital, M. S. Wolin, R. Bernstein, M. Oz, L. Addonizio, G. Kaley, and T. H. Hintze Nitric Oxide Modulates Mitochondrial Respiration in Failing Human Heart Circulation, September 21, 1999; 100(12): 1291 - 1297. [Abstract] [Full Text] [PDF]
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