(Hypertension. 1998;31:32.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
Efficient Inhibition of the Development of Cardiac Remodeling by a Long-Acting Calcium Antagonist Amlodipine
From the Department of Medicine III (T.Y., I.K., Y.Z., S.K., I.S., T.M., Y.H., Y.Y.), University of Tokyo School of Medicine; the Health Service Center (T.Y.), the University of Tokyo; the Second Department of Medicine (R.N.), Gumma University, Japan.
Correspondence to Issei Komuro, MD, Department of Medicine III, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. E-mail komuro-tky{at}umin.ac.jp
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Abstract |
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Abstract—The purpose of the present study was to examine the effects of a long-acting calcium antagonist, amlodipine, on the development of cardiac remodeling. Dihydropyridine calcium antagonists have been used widely for many years in the treatment of hypertension and angina pectoris. It has been reported, however, that a prototype of dihydropyridines, nifedipine, does not reduce mortality of patients with ischemic heart disease, possibly because of reflex stimulation of the sympathetic nervous system. A calcium antagonist, amlodipine, has been reported to have potential benefits by virtue of a gradual onset of action and a long duration of effects. Amlodipine (8 mg/kg per day, once a day) or nifedipine (24 mg/kg per day, three times a day) was administered to spontaneously hypertensive 12-week-old rats for 12 weeks. Left ventricular wall thickness was measured by echocardiography, and relative amounts of myosin heavy chain isoforms were assessed by pyrophosphate gels. Expressions of "fetal type" genes and type 1 collagen gene were examined by Northern blot analysis. Amlodipine and nifedipine both markedly reduced systolic blood pressure. However, the decrease in systolic blood pressure caused by nifedipine continued for no more than 8 hours, whereas the blood pressure-lowering effect of amlodipine continued for more than 16 hours post dose. Amlodipine markedly reduced left ventricular wall thickness, whereas nifedipine only weakly attenuated an increase in the wall thickness. Amlodipine, but not nifedipine, prevented an increase in the relative amount of V3 myosin heavy chain isoform and suppressed an increase in mRNA levels of ß-myosin heavy chain, skeletal
-actin, and type 1
collagen. Unlike nifedipine, amlodipine effectively
preveted cardiac remodeling secondary to high blood
pressure at biochemical levels and morphological levels. These results
suggest that a long-acting calcium antagonist is more
effective than a short-acting one in preventing organ injury in
hypertensive subjects.
Key Words: calcium antagonists • amlodipine • nifedipine • cardiac remodeling • myosin heavy chain • gene expression
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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It is quite important to prevent end-organ damage secondary to hypertension. The heart is one of the target organs of high BP, and cardiac remodeling evoked by high BP is an important and independent risk factor of cardiac morbidity and mortality.1 Nowadays, many kinds of antihypertensive drugs have been developed. Among them, dihydropyridine calcium antagonists continue to maintain a major position, and newer dihydropyridines have been developed with the aim of improving their therapeutic efficacy as well as decreasing the frequency of adverse effects. Although clinical studies have shown that calcium antagonists have shown inhibitory effects on cardiac hypertrophy induced by hypertension,2 the therapeutic effects of calcium antagonists on cardiac morbidity and mortality caused by hypertension remain unproved. It has been reported recently that a prototype of the dihydropyridines, nifedipine, does not reduce mortality of patients with ischemic heart disease.3
Amlodipine [3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulphonate], a third-generation dihydropyridine-based calcium antagonist, has potential clinical benefits by virtue of a gradual onset of action and a long duration of effects.4 Amlodipine has been shown to have a favorable effect on the survival of patients with heart failure due to nonischemic dilated cardiomyopathy in the prospective randomized amlodipine survival evaluation (PRAISE) trial.5 Therefore, amlodipine may be able to reduce cardiac injury secondary to hypertension. Recently, Nayler6 has reported that orally administered amlodipine slows the progression of hypertension-induced cardiac hypertrophy in SHR. However, it remains unknown whether amlodipine ameliorates cardiac remodeling as well as cardiac hypertrophy.
We have recently reported the cardioprotective effects of an antihypertensive agent.7 In SHR, an Ang II type 1 receptor antagonist, TCV-116, not only reduced the left ventricular wall thickness determined by echocardiography but also prevented cardiac remodeling, which was evaluated by inhibition of MHC isoform switching from V1 to V3 and of cardiac interstitial fibrosis.7 The purpose of the present study was to examine the efficient effects of amlodipine over nifedipine on hypertensive cardiac remodeling.
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Methods |
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This study was carried out in compliance with the guidelines for animal usage of the University of Tokyo.
Chemicals and Reagents
Amlodipine and nifedipine were gifts from Pfizer
Pharmaceuticals, Inc (Tokyo, Japan) and Bayer Yakuhin Ltd (Tokyo,
Japan), respectively. [-32P]dCTP and
[
-32P]dATP were purchased from DuPont-New England
Nuclear, and other reagents were purchased from Sigma.
Animals and Experimental Protocols
Male SHR and normotensive WKY were obtained from Charles River
Japan (Tokyo, Japan). SHR were randomly divided into three groups, and
amlodipine (8 mg/kg per day, once a day), nifedipine (24
mg/kg per day, three times a day), or vehicle (distilled water, three
times a day) was administered daily through a stomach tube for 12 weeks
from the age of 12 weeks, when cardiac hypertrophy had
already developed.7 These doses were chosen from the
previous report8 and our preliminary experiment (data not
shown). Vehicle (distilled water, three times a day) was also
administered to WKY daily through a stomach tube for 12 weeks from the
age of 12 weeks. Each group consisted of 18 rats. At the age of 12, 16,
and 24 weeks, 6 rats of each group were killed, and the determination
of MHC isoform profiles and the Northern blot analysis were
performed (Fig 1). The rats killed at 24
weeks old were also used for the measurement of systolic BP and
the determination of left ventricular wall thickness by
echocardiography.
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Measurement of Systolic BP and
Echocardiographic Evaluation of
Left Ventricular Wall Thickness
Systolic BP was measured every week by the tail-cuff
plethysmography method in conscious rats,7 and the left
ventricular wall thickness was serially measured by M-mode
echocardiography every 4 weeks (Fig 1). At days 0,
7, and 13 after the start of the oral administration, the changes in
systolic BP were measured. Echocardiographic
studies were performed with a Hewlett-Packard HP Sonos 100 mechanical
sector scanner using a single element transducer with a frequency of 10
MHz as previously described.7 Conscious rats were held in
the supine position, and M-mode tracings of the left
ventricular wall were obtained using a two-dimensional
reference sector. The thickness of the IVS was measured from M-mode
tracings by using the leading edge method every 4 weeks (Fig 1).
Determination of MHC Isoform
For MHC isoform analysis, left ventricles of 8-, 12-,
16-, or 24-week-old rats were used (Fig 1). Left
ventricular MHC isoform profiles were determined by
pyrophosphate gel electrophoresis as previously described by Hoh et
al.9 Briefly, a small piece of heart was
homogenized in 10% glycerol and 20 mmol/L
Na4P2O4, pH 8.8. After
centrifugation, electrophoresis of the supernatant was
performed in nondenaturing pyrophosphate gel, and relative amounts of
V1, V2, and V3 MHC isoforms were analyzed by a laser
densitometer after Coomassie blue staining.
Northern Blot Analysis
Left ventricles of 12-, 16-, or 24-week-old rats were used (Fig 1). Total cellular RNA was extracted from the heart using 201B (Cinna
Biotecx Laboratories, Inc). Twenty micrograms of total RNA was
size-fractionated by 1.2% agarose gels and transferred to nylon
membranes according to the manufacturer’s instructions. The 3'
untranslated region of rat skeletal -actin (184 bp) was used as a
probe as described previously.10 Type 1 collagen cDNA
(
1.2 kbp) was isolated by polymerase chain reaction using the
primers specific to the triple helical region and the carboxyl-terminal
region of rat 1 chain of type 1 collagen.11 A 20-mer
oligonucleotide specific to the 3' untranslated region
of rat ßMHC was synthesized as described before.12 cDNA
was labeled by a random priming method using
[-32P]dCTP and oligo DNA was labeled at the 5' end by
T4 polynucleotide kinase using [-32P]dATP.
Northern blot analysis was performed as described
previously.13 14 In brief, the blots were hybridized with
a 32P-labeled cDNA probe at 42°C for 10 hours in 50%
formamide, 5x SSPE, 1% SDS, 5x Denhardt’s solution, and 100 mg/L
salmon sperm DNA and washed to a stringency of 0.1% SDS at 42°C. In
the case of oligo DNA, the blots were hybridized in the same solution
at room temperature and washed in 6x SSC and 2x SSC at room
temperature. The filter was dried and exposed to x-ray film at
-80°C. The density of each band was quantified using a laser
densitometer.
Statistical Analysis
All values are expressed as mean±SEM of six experiments in each
instance. Comparisons among three or more groups were made by one-way
ANOVA followed by Dunnetts’ modified t test. Values of
P<.05 were considered statistically significant.
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Results |
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Blood Pressure
Treatment of SHR with amlodipine (8 mg/kg per day, once a day) or nifedipine (24 mg/kg per day, three times a day) was started from 12 weeks after birth. Systolic BP at 2 hours after oral administration of these agents was measured by the tail-cuff method. At the start of the experiments, 12-week-old SHR had much higher systolic BPs (approximately 210 mm Hg, n=6) compared with the age-matched WKY (approximately 140 mm Hg, n=6). Systolic BP was gradually decreased in both amlodipine- and nifedipine-treated SHR. During the treatment (12 weeks), amlodipine and nifedipine both efficiently lowered BP in SHR compared with vehicle-treated control animals (n=6) (Fig 2A). Changes in systolic BP were also recorded every 4 hours on days 0, 7, and 13 after treatment. Nifedipine exerted a maximal lowering effect on systolic BP at 0.5 hours postdose, and the effect disappeared at 8 hours postdose (Fig 2B). In contrast, treatment with amlodipine induced a gradual decrease in systolic BP, and the BP-lowering effect of amlodipine was still recognized at 20 hours after the administration at days 7 and 13 (Fig 2B). No significant differences were observed in heart rates and body weights among vehicle-, amlodipine-, and nifedipine-treated SHR (data not shown).
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—, SHR treated with
vehicle; —•—, SHR with nifedipine; —
—, SHR with
amlodipine; —
—, WKY with vehicle. *P<.05,
**P<.01 vs age-matched vehicle-treated SHR.
Left Ventricular Wall Thickness on
Echocardiography
Two-dimensional long-axis images were clear enough to obtain
adequate M-mode tracings, and the thickness of the IVS was measured
from M-mode images during six successive beats as previously
reported7 (Fig 3A). The
thickness of the IVS was increased progressively along with the
elevation of systolic BP in vehicle-treated SHR
(1.71±0.04 mm for 12-week-old SHR, 1.75±0.07 mm for
16-week-old SHR, 2.12±0.10 mm for 20-week-old SHR, and
2.20±0.12 mm for 24-week-old SHR). Amlodipine strongly attenuated
the increase in the thickness of the IVS (1.49±0.12 mm for
amlodipine-treated 20-week-old SHR versus 2.12±0.10 mm for
vehicle-treated 20-week-old SHR, P<.05; 1.50±0.04 mm
for amlodipine-treated 24-week-old SHR versus 2.20±0.12 mm for
vehicle-treated 24-week-old SHR, P<.01). On the other hand,
when SHR were treated with nifedipine, the IVS thickness
was not reduced to the same level as with amlodipine treatment
(1.71±0.04 mm for 12-week-old SHR, 1.84±0.11 mm for
20-week-old SHR, 1.91±0.07 mm for 24-week-old SHR) (Fig 3B).
There were significant differences in IVS thickness between amlodipine-
and nifedipine-treated SHR at 20 (P<.05) and 24
(P<.01) weeks of age.
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P<.05,
MHC Isoforms
To elucidate whether amlodipine prevents not only morphological
changes but also biochemical changes from hypertension, we first
examined MHC isoforms. At the age of 8, 12, 16, and 24 weeks, SHR were
killed, and the hearts were excised. The relative amounts of V3 MHC
isoform increased progressively from the age of 8 weeks to 24 weeks in
vehicle-treated SHR (Fig 4A and 4B).
Treatment with amlodipine markedly inhibited an increase in the ratio
of V3 MHC isoform. The relative amount of V3 MHC in amlodipine-treated
24-week-old SHR was almost the same as that of 8-week-old SHR (Fig 4B).
The attenuation of the increase in V3 MHC was much less in
nifedipine-treated SHR than in amlodipine-treated SHR (Fig 4A and 4B).
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ßMHC and Skeletal -Actin mRNA
To elucidate whether the isoformic change of MHC is regulated at
pretranslational levels, we analyzed mRNA levels of ßMHC by
Northern blot analysis. In vehicle-treated SHR, the levels of
ßMHC mRNA were increased progressively along with the age (Fig 5A and 5B). Nifedipine did
not significantly reduce the increase in ßMHC levels. On the other
hand, amlodipine significantly inhibited the increase in the levels of
ßMHC transcripts, by approximately 70%.
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It is well known that "fetal type" genes such as ßMHC and
skeletal -actin genes are induced during cardiac
hypertrophy (for a review see reference 15). To elucidate
whether amlodipine generally attenuates the expression of "fetal
type" genes, we next analyzed the expression of skeletal
-actin gene. The levels of skeletal -actin mRNA increased
progressively along with age in SHR hearts (Fig 6). In SHR treated with amlodipine, the
mRNA levels of skeletal -actin were much lower than those of
vehicle-treated SHR, by approximately 80%. In contrast,
nifedipine had no significant effects on the mRNA levels of
skeletal -actin.
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Type 1 Collagen mRNA
Cardiac collagen fibers are composed predominantly of type 1 and
type 3 collagen, about 80% and 15%, respectively.16 In
hypertrophic hearts, extracellular matrix proteins such as collagen and
fibronectin are increased, and perivascular and
interstitial fibrosis occurs as one of the features of
cardiac remodeling. The increase in extracellular matrix proteins is
detrimental because fibrosis is one of the main causes of
diastolic dysfunction. To examine the effects of calcium
antagonists on fibrosis, we finally examined the expression
levels of the type 1 collagen gene by Northern blot analysis.
In vehicle-treated SHR, mRNA levels of type 1 collagen were increased
progressively along with age (Fig 7A and 7B). Treatment with amlodipine inhibited
the age-dependent increase in type 1 collagen mRNA levels in SHR.
However, treatment with nifedipine did not significantly
inhibit the increase (Fig 7A and 7B).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Previous studies using animal models have demonstrated that angiotensin-converting enzyme inhibitors17 18 and the Ang II type 1 receptor antagonist TCV-1167 prevented hypertrophy- associated ventricular remodeling, suggesting that these agents are cardioprotective. In the present study the long-acting third-generation dihydropyridine calcium antagonist amlodipine markedly reduced left ventricular wall thickness as evaluated by echocardiography, whereas nifedipine had a minimal effect. Amlodipine prevented not only cardiac hypertrophy but also cardiac remodeling by inhibiting increases in MHC V3 isoform and in gene expressions of ßMHC, skeletal
-actin, and type 1 collagen. These results suggest
that amlodipine as well as angiotensin-converting enzyme
inhibitors and Ang II receptor antagonists work
to protect the heart from high BP. The BP-lowering effect of amlodipine in SHR reached a maximum at 4 hours and continued up to 24 hours postdose, in contrast to nifedipine, which produced a maximal effect at 0.5 hours with a prompt loss of efficiency at 8 hours postdose (Fig 2B). Therefore, a possible reason for the better effect of amlodipine than nifedipine in preventing cardiac remodeling is that amlodipine has a longer duration of BP-lowering effect.
Recently, we have reported that an Ang II type 1 receptor antagonist induces regression of cardiac hypertrophy and prevents left ventricular remodeling in SHR.7 Accumulating evidence has suggested that Ang II plays an important role in the development of left ventricular remodeling.7 19 We and others have reported that the calcium ion partly mediates Ang II-induced hypertrophic events.19 20 Actually, nifedipine partly inhibited Ang II-induced activation of mitogen-activated protein kinases, which is critical for the induction of cardiac hypertrophy.19 Therefore, the better prevention of cardiac remodeling by amlodipine over nifedipine may be due to the more efficient inhibition of calcium channels by amlodipine than nifedipine. We are now examining this hypothesis by in vitro study.
Although short-acting calcium antagonists such as nifedipine have shown favorable acute hemodynamic effects by effectively reducing afterload, long-term studies with such agents have demonstrated the potential unfavorable effects, including negative inotropic effects and neurohormonal activation.3 The fall in BP caused by nifedipine is associated with reflex activation of the sympathetic nervous system, with a consequent increase in renin release.21 On the other hand, Aber- nethy et al22 have observed that treatment with amlodipine for 14 weeks induces no increase in plasma levels of norepinephrine, epinephrine, renin, or aldosterone. In addition, Lund-Johansen et al23 have reported on hormonal responses at rest and during exercise in patients with essential hypertension treated with amlodipine or nifedipine. In amlodipine-treated patients, plasma norepinephrine levels were not significantly increased after exercise; whereas in nifedipine-treated ones, exercise strongly elevated plasma norepinephrine levels. Moreover, it has been shown that the pressure response to norepinephrine is blunted after amlodipine treatment24 but not after nifedipine treatment25 in patients with essential hypertension. These results suggest that treatment with amlodipine avoids reflex stimulation of the sympathetic nervous system. Catecholamines have been reported to also be potent inducers of cardiac hypertrophy (for a review, see reference 26), and aldosterone has been shown to play an important role in inducing fibrosis in the heart (for a review, see reference 27). The lack of stimulation of neurohormonal factors by amlodipine may partly explain why amlodipine, but not nifedipine, effectively prevents cardiac remodeling. With respect to the mechanisms, Terland et al28 have reported that in the bovine adrenal medulla, nifedipine-induced inhibition of the proton pump activity induces an increased adrenergic activity by inhibiting the catecholamine uptake into storage vesicles and that only amlodipine increases the proton pump activity in a concentration-related manner compared with several calcium antagonists such as diltiazem, felodipine, and nicardipine.
Cardiac fibrosis, which is increased in accordance with the duration of hypertension in SHR,7 is a major determinant of diastolic stiffness in hypertensive heart disease.29 In the present study, amlodipine strongly reduced type 1 collagen gene expression and interstitial fibrosis (Fig 7, data not shown). Recently, Ang II (as well as aldosterone) has been demonstrated to induce cardiac fibrosis.7 27 Although the precise mechanisms of how these molecules are involved in interstitial fibrosis remain unresolved, amlodipine may prevent an increase in fibrotic tissues by inhibiting the effects or production of these humoral factors.
Amlodipine, but not nifedipine, inhibited the shift of MHC isoforms from V1 to V3 in SHR in the present study. Although in the ventricle of larger animals including humans, little or no isoform transition occurs in response to hemodynamic overload because of the predominance of V3 in the normal ventricle,30 in chronically pressure-overloaded human atria, the shift from V1 to V3 has been shown to be accompanied by atrial enlargement.31 Thus, we think at present that amlodipine, which exerts prevention of switching from V1 to V3 on the SHR heart, may also have a potential cardioprotector role in human hearts.
In conclusion, in SHR, which is a good model of human essential hypertension, cardiac remodeling was prevented by chronic treatment with a long-acting third-generation calcium antagonist, amlodipine, but not with nifedipine. The present results support the clinical usefulness of amlodipine in hypertension. However, further investigation is necessary to clarify the precise molecular mechanisms by which amlodipine reduces cardiac remodeling that is produced by pressure overload.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by a grant-in-aid from the Ministry of Education, Science, Sports and Culture, Japan. We wish to thank Fumiko Harima, Makiko Iwata, and Mika Ono for technical assistance.
Received July 16, 1997; first decision August 14, 1997; accepted August 14, 1997.
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