Skip Navigation

Cardiovascular Research 1998 37(3):618-626; doi:10.1016/S0008-6363(97)00247-2
© 1998 by European Society of Cardiology
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Shimada, T.
Right arrow Articles by Yoshikawa, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shimada, T.
Right arrow Articles by Yoshikawa, J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 1998, European Society of Cardiology

Long acting calcium antagonist amlodipine prevents left ventricular remodeling after myocardial infarction in rats

Takehiro Shimadaa, Minoru Yoshiyamaa,*, Kazuhide Takeuchia, Takashi Omuraa, Yasuhiko Takemotoa, Shokei Kimb, Hiroshi Iwaob and Junichi Yoshikawaa

aFirst Department of Internal Medicine, Osaka City University Medical School, Osaka 545, Japan
bDepartment of Pharmacology, Osaka City University Medical School, Osaka 545, Japan

* Corresponding author. Tel. (+81-6) 645 2106; Fax (+81-6) 645 2107.

Received 3 June 1997; accepted 19 September 1997


   Abstract
Top
 Abstract
1 Introduction
 2 Materials and methods
 3 Results
 4 Discussion
 5 Study limitations
 6 Summary
 References
 
Objective: The purpose of this study was to examine the effect of amlodipine, a long-acting calcium antagonist, on the left ventricular remodeling, including systolic and diastolic dysfunction, the change of cardiac gene expression in the myocardial infarcted rats (MI). Methods: On the first day after myocardial infarction, the animals were randomly assigned to amlodipine treatment (n=8) or untreated groups (MI; n=9). We then performed Doppler-echocardiographic examinations and measured the hemodynamics at four weeks after myocardial infarction. Following these measurements, their cardiac mRNA was analyzed. Results: Left ventricular end-diastolic pressure (LVEDP) and central venous pressure (CVP) increased to 22±1 mmHg and 5±1 mmHg. Amlodipine reduced LVEDP and CVP to 15±1 mmHg (P<0.01) and 3±0 mmHg (P<0.01). The weight of right ventricle in MI was significantly larger than in the control rats (Control; 0.48±0.01 g/kg, MI; 0.79±0.04 g/kg, P<0.01). Left ventricular end-diastolic dimension (LVDd) in MI increased to 10.3±0.3 mm (P<0.01) (Control; 6.2±0.3 mm). Amlodipine prevented an increase of the weight of right ventricle (0.62±0.03 g/kg, P<0.01) and LVDd (7.9±0.2 mm, P<0.01 to MI). The rats in MI showed systolic dysfunction shown by the decreased fractional shortening (Control; 31±2% versus MI; 15±1%, P<0.01), and diastolic dysfunction shown by E wave deceleration rate (Control; 18.1±2.0 m/s2, MI; 32.6±2.1 m/s2, P<0.01). Amlodipine significantly prevented systolic and diastolic dysfunction. The increases in β-MHC, {alpha}-skeletal actin, and ANP mRNAs in the non-infarcted left ventricle and right ventricle at four weeks after the myocardial infarction were all significantly suppressed by the treatment with amlodipine. On the other hand, depressed {alpha}-MHC was restored to normal levels by amlodipine in both regions. Conclusions: Amlodipine prevents the left ventricular remodeling process accompanied by systolic and diastolic dysfunction, and inhibits abnormal cardiac gene expression after myocardial infarction.

KEYWORDS Ventricular remodeling; Myocardial infarction; Calcium channel antagonists; Echocardiography; Gene expression


   1 Introduction
Top
 Abstract
 1 Introduction
2 Materials and methods
 3 Results
 4 Discussion
 5 Study limitations
 6 Summary
 References
 
The global alterations of left ventricular architecture characterizing left ventricular postinfarct remodeling consist of ventricular dilatation accompanied by hypertrophy, which occurs in the course of weeks to months [1, 2]. Although this process probably constitutes a compensatory response to acute loss of myocardial mass, it is associated with progressive chamber dysfunction and an increased incidence of sudden death and congestive heart failure [3]. The administration of angiotensin-converting enzyme inhibitor has been shown to prevent left ventricular remodeling and to prolong survival in experimental myocardial infarction and in patients after myocardial infarction [4–7]. However, other vasodilator agents, including calcium channel antagonists, do not clearly show the same beneficial effects on left ventricular remodeling after myocardial infarction.

Amlodipine, so called third generation of calcium channel antagonists, appears to have fewer negative inotropic effects than previous other calcium antagonists [8–10]. Its slow onset of action and plasma half-life of more than 30 h do not activate the neurohumoral system [11]. Recently, amlodipine has reported to improve the prognosis of non-ischemic heart failure [12]. Amlodipine is expected to become a representative calcium channel antagonist for the treatment of ischemic heart disease and also have other benefits for the treatment of cardiovascular disease. The purpose of this study was to assess the effect of amlodipine on left ventricular remodeling after myocardial infarction in the rat. Left ventricular geometry and cardiac function were assessed by Doppler-echocardiography and cardiac gene expression of contractile protein and collagen in non-infarcted left ventricle and right ventricle by Northern blot analysis.


   2 Materials and methods
Top
 Abstract
 1 Introduction
 2 Materials and methods
3 Results
 4 Discussion
 5 Study limitations
 6 Summary
 References
 
Each animal received human care in compliance with the Principles of Laboratory Animal Care of the National Society of Medical Research and the Guide for the Care and Use of Laboratory Animals of the National Academy of Sciences.

2.1 Experimental protocol
Male Wistar rats, weighing 290–310 g (Clea Japan, Osaka, Japan) were used in the present experiments. Rats were anesthetized by intraperitoneal injection of pentobarbital sodium (35 mg/kg, i.p.) and xylocaine (10 mg/kg, i.p.), and following intratracheal intubation, a left thoracotomy was performed under volume-controlled mechanical ventilation (tidal volume 3.0 ml, respiration rate 60 cycle/min). The heart was accessed from the thorax, and a ligature with a 6-0 prolene suture was placed around the proximal left anterior descending coronary artery. The chest was then closed. The same surgical procedures were also performed in sham-operated rats (n=7), except that the suture around the coronary artery was not tied. About ten percent of rats died during operation and about five percent died for 24 h after operation. The rate of rats with more than 20% myocardial infarct size was about 90% in all myocardial infarcted rats. Rats with myocardial infarction surviving the operation for 24 h were randomly separated into amlodipine treated and untreated groups. Amlodipine caused dose-related reductions in blood pressure and the dosage of 10 mg/kg/day of amlodipine produced a substantial antihypertensive effect in SHRs with established hypertension [13], and we used 10 mg/kg/day of amlodipine to myocardial infarcted rats.

The rats of the treated group were administered amlodipine orally (10 mg/kg), in a volume of 2 ml/kg, by gastric gavage once per day for four weeks (n=8). The untreated group received a vehicle (5% gum arabic solution) in the same manner as the amlodipine (n=9). The left ventricular remodeling progresses with time and cardiac morphological alterations, including left ventricular cavity dilatation, expansion of infarct zone and the hypertrophy of non-ischemic myocardium, become apparent at 4 weeks after MI and these changes are still ongoing [14]. We considered that analyzing cardiac function and gene expressions is suitable for hearts at 4 weeks after MI. Before the treatment, body weight and blood pressure in these groups did not differ significantly. Systolic blood pressure of the conscious rats was measured by the tail-cuff method using a sphygmomanometer before starting treatment (Riken Development, Tokyo, Japan)

2.2 Doppler-echocardiographic studies
Litwin reported the Doppler-echocardiographic method in the experimental model of MI in rats in detail [15]. We describe the method of Doppler-echocardiographic studies briefly.

Rats were lightly anesthetized with intraperitoneal ketamine HCl (25 mg/kg to 50 mg/kg) and xylazine (5 mg/kg to 10 mg/kg). Echocardiograms were performed using a commercially available echocardiographic system equipped with a 7.5 MHz phased-array transducer (Hewlett Packard, Andover, Mass). A two-dimensional short-axis view of the left ventricle was obtained at the level of the papillary muscles. M-mode tracings were recorded through the anterior and posterior left ventricular walls at a paper speed of 100 mm/s. The anterior and posterior end-diastolic and end-systolic wall thickness and left ventricular internal dimensions and parameters of cardiac functions were measured by the leading-edge method of the American Society for Echocardiology (ASE) from at least three consecutive cardiac cycles on the M-mode tracings.

Pulsed-wave Doppler spectra of mitral inflow were recorded from the apical four-chamber view, with the sample volume placed near the tips of the mitral leaflets and adjusted to the position at which velocity was maximal and the flow pattern laminar. The sample volume was set at the smallest size available. The left atrium was then examined with pulsed-wave Doppler for the presence of mitral regurgitation. All Doppler spectra were recorded on paper at 100 mm/s and analyzed off-line as previously described. The numbers represent the mean of at least three consecutive cardiac cycles.

2.3 Hemodynamic studies
One day after the echocardiogram, the rats were anesthetized by intraperitoneal injection of ketamine HCl (25–50 mg/kg) and xylazine (5–10 mg/kg). Amlodipine was administered about 6 h before hemodynamics in rats were measured. Aortic and left ventricular pressure were recorded by inserting a polyethylene tubing catheter (0.58 mm internal diameter, PE-50) into the right carotid artery and advanced into the aorta and then into the left ventricle. Central venous pressure was measured by cannulating the right external jugular vein with a PE-50 tubing catheter. Water-filled catheters were connected to the polyethylene tubing (0.76 mm internal diameter, PE-60) connected to a water-filled pressure transducer (Model P23 ID, Gould, California, USA). With rats breathing spontaneously, pressures were recorded on a physiological recorder (Polygraph MIC-9800 and Thermal Recorder RF-85, Fukuda Denshi, Tokyo, Japan). Heart rate was determined from the tracing of aortic pressure.

Following these measurements rats were decapitated and the heart removed. The size of the myocardial infarct was measured, as previously described [16]. LVEDP did not increase in rats with infarct size less than 20% and these were excluded from the experiments. Rats with less than 20% of infarct size were excluded from analysis. Following determination of infarct size, the left ventricle was divided into the non-infarcted left ventricle portions and other portions, including the scar tissue. After weighing, the tissues were rapidly frozen in liquid nitrogen and stored at –80°C. All procedures were carried out within three min.

2.4 Oligonucleotide and cDNA probes
We used synthetic oligonucleotide probes complementary to the unique 3' untranslated regions of the two MHC and the two {alpha}-actin mRNAs, as previously described [17]. The sequence of the oligonucleotide probes used were as follows:

{alpha}-MHC, 5'-TTGTGGGATAGCAACAGCGA-3';
β-MHC, 5'-GTCTCAGGGCTTCACAGG-3';
{alpha}-skeletal actin, 5'-GCAACCATAGCACGATGGTC-3';
{alpha}-cardiac actin, 5'-TGCACGTGTGTAAACAAACT-3'.
In addition, to monitor the RNA content of the various lanes, we hybridized the blots with 24-base oligonucleotide complementary to rat 18S ribosomal RNA. The oligonucleotide probes were labeled with (g-32P)-ATP (6000 Ci/mM) at the 5' end using T4 polynucleotide kinase, and the labeled probes were purified by chromatography on the Bio-Spin 6 column (Bio-Rad, Richmond, CA).

The cDNA probes used were rat a1 (I) collagen cDNA (1.3 kb PstI/BamHI fragment) [18], mouse a1 (III) collagen cDNA (1.8 kb EcoRI/EcoRI fragment) [19], rat ANP cDNA (0.825 kb fragment) [17]. The cDNA probes were labeled with (32P)-dCTP (specific activity 3000 Ci/mM, New England Nuclear, Boston, MA) by the random primer extension method, using a Random Primer DNA Labeling Kit (Takara, Kyoto, Japan).

2.5 Northern blot hybridization
The method of RNA extraction was previously described in detail [20]. The RNA concentration was spectrophotometrically determined at 260 nm. Twenty µg of total RNA was denatured by incubating it with 1 M deionized glyoxal and 50% dimethyl sulfoxide at 50°C for 1 h, electrophoresed on 1% agarose gel and transferred to a nylon membrane (GeneScreen Plus, E.I. du Pont de Nemours, NEN products, Boston, USA), as previously described [20]. The 28S and 18S ribosomal RNAs in gels were stained with ethidium bromide to demonstrate the integrity of applied RNA and verify that the same amount of RNA was applied to each lane. The method of Northern blot analysis using the oligonucleotide probe and a specific cDNA probe was previously described [17].

2.6 Quantification of mRNA
To evaluate mRNA levels, an optical scanner (EPSON GT-8000, Seiko, Tokyo, Japan) was utilized for digitizing autoradiograms. The autoradiogram bands in the digitized image were measured for their density with the use of the public domain NIH image program and a computer (Macintosh LC-III, Apple Computer, USA), as described. For all RNA samples, the density of an individual mRNA band was divided by that of the 18S ribosomal RNA band, to correct for differences in RNA loading and/or transfer.

2.7 Statistics
Results were expressed as mean ± SE. Statistical significance was determined using ANOVA and Duncan's multiple range test. Differences were considered statistically significant at a value of P<0.05.


   3 Results
Top
 Abstract
 1 Introduction
 2 Materials and methods
 3 Results
4 Discussion
 5 Study limitations
 6 Summary
 References
 
3.1 Effect of amlodipine on hemodynamics
Table 1 shows no significant differences in body weight and heart rate between the control rats (Control) and rats with myocardial infarction treated with either the vehicle (MI) or amlodipine. Amlodipine decreased MAP, LVSP, LVEDP and CVP to 99±2 mmHg (P<0.01 to MI) and 114±3 mmHg (P<0.05 to MI), 15±1 mmHg (P<0.01 to MI) and 3±0 mmHg (P<0.01 to MI), respectively. The right ventricular weight was significantly higher than that in Control. The left ventricular weight in MI was not different from that in Control, which means that the weight increased by cardiac hypertrophy of the non-infarcted region was cancelled by scar formation of the infarcted region.


View this table:
[in this window]
[in a new window]

  		Table 1 Changes over time in organ weights and hemodynamics after myocardial infarction

 
During the treatment period, two myocardial infarcted rats died; one in the non-treated and one in the amlodipine-treated group. There was, therefore, no difference in mortality during the treatment period. The number of myocardial infarct-size<20% rats in non-treated and amlodipine treated group was one and two, respectively.

Fig. 1 and Table 2 show Doppler-echocardiographic assessments of left ventricular geometry and function for three groups of rats. Rats in MI showed significant systolic dysfunction, evident by decreased fractional shortening (FS) (Control; 31±2%, MI; 15±1%, P<0.01). Amlodipine prevented the increase of LVDd (7.9±0.2 mm, P<0.01 to MI) and the decrease of FS (21±1%, P<0.05 to MI). Fig. 2 shows examples of pulsed wave Doppler recordings of mitral inflow from Control and MI. MI caused profound and progressive alterations of LV diastolic filling characterized by increased early filling velocity (E wave), rapid deceleration of the early filling wave (E wave), and decreased atrial filling velocity (A wave).Fig. 3.


Figure 1
View larger version (52K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Examples of M-mode echocardiograms from sham-operated (Control), myocardial-infarcted rats (MI) and myocardial-infarcted rats treated with amlodipine. AW indicates anterior wall; and PW indicates posterior wall. Note the left ventricular cavity dilatation, thinning, and akinesis of the anterior wall in rats with MI. Amlodipine prevented LV dilatation.

 

View this table:
[in this window]
[in a new window]

  		Table 2 Doppler echocardiographic measurements in Sham-operated rats, rats with myocardial infarction, and amlodipine-treated rats

 

Figure 2
View larger version (50K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Examples of the pulsed-wave Doppler spectra of the mitral inflow pattern from sham-operated (Control), myocardial-infarcted rats (MI) and myocardial-infarcted rats treated with amlodipine. Compared with Control, the mitral inflow pattern from the infarcted rat shows increased peak E wave velocity, rapid deceleration of the E wave, and decreased peak A wave. MI rats treated with amlodipine visually show a relatively normal transmitral flow pattern.

 

Figure 3
View larger version (46K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Typical autoradiograms of Northern blot analysis of the non-ischemic left ventricular mRNAs for {alpha}-myosin heavy chain ({alpha}-MHC), β-myosin heavy chain (β-MHC), {alpha}-cardiac actin, {alpha}-skeletal actin, atrial natriuretic polypeptide (ANP), collagen types I and III, and 18S ribosomal RNA at four weeks after myocardial infarction. Control: sham-operated rats; MI: myocardial-infarcted rats; Am: myocardial-infarcted rats treated with amlodipine.

 
E wave increased in MI following operation (Control; 73±3 cm/s, MI; 104±3 cm/s, P<0.01), and deceleration rate of E wave was more rapid in rats four weeks after operation (Control; 18.1±2.0 m/s2, MI; 32.6±2.1 m/s2, P<0.01). A wave decreased (Control; 47±4 cm/s, MI; 15±2 cm/s, P<0.01), resulting in a marked increase in the ratio of E wave to A wave (Control; 1.6±0.2, MI; 7.7±1.0, P<0.01) in MI.

3.2 Amlodipine improved these parameters
Gene expression of contractile proteins, ANP, and collagens after myocardial infarction and effects of amlodipine on these expressions.

Fig. 4 shows that β-MHC mRNA levels of non-infarcted LV and RV increased 2.0-fold and 1.9-fold, respectively, in rats four weeks after MI (P<0.01). While {alpha}-MHC mRNA in the non-infarcted LV and RV decreased 0.5-fold (P<0.01) and 0.7-fold (P<0.05). {alpha}-Skeletal actin mRNA levels in the non-infarcted LV and RV increased 2.4-fold (P<0.01) and 2.0-fold (P<0.01). On the other hand, {alpha}-cardiac actin was unchanged. ANP mRNA level at non-infarcted LV and RV increased 8.7-fold (P<0.01) and 2.5-fold (P<0.01). Collagen I and III mRNA levels of non-infarcted LV increased 4.0-fold (P<0.01) and 7.1-fold (P<0.01), respectively. The mRNA level in the RV increased 1.6-fold (P<0.01) and 2.3-fold (P<0.01), respectively, in MI.


Figure 4
View larger version (25K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 4 The non-ischemic left ventricular and right ventricular mRNA expression for {alpha}-myosin heavy chain ({alpha}-MHC), β-myosin heavy chain (β-MHC), {alpha}-cardiac actin, {alpha}-skeletal actin, atrial natriuretic polypeptide (ANP), collagen types I and III RNA at four weeks after myocardial infarction.

 
The increased expression of β-MHC, {alpha}-skeletal actin, ANP, collagen I and III mRNAs in non-infarcted LV and RV, described above, was significantly suppressed by treatment with amlodipine (non-infarcted LV; β-MHC 0.9-fold: P<0.01, {alpha}-skeletal actin 1.6-fold: P<0.01, ANP 5.4-fold: P<0.01, collagen I 2.6-fold: P<0.01, collagen III 3.9-fold, P<0.01, RV; β-MHC 1.4-fold: P<0.05, {alpha}-skeletal actin 1.3-fold: P<0.01, ANP 0.7-fold: P<0.01, collagen I 0.9-fold: P<0.01, collagen III 1.2-fold: P<0.01). Amlodipine did not alter {alpha}-cardiac actin mRNA levels during the experiments. On the other hand, depressed {alpha}-MHC was restored to a normal level by amlodipine both in non-infarcted LV and RV.


   4 Discussion
Top
 Abstract
 1 Introduction
 2 Materials and methods
 3 Results
 4 Discussion
5 Study limitations
 6 Summary
 References
 
The present study demonstrated (1) that amlodipine prevented the left ventricular cavity dilatation, the increased heart weight, systolic and diastolic dysfunction in myocardial infarcted rats, and (2) that it reduced the gene expression of fetal contractile protein and collagen mRNA expression in non-infarcted left and right ventricular myocardiums. These results suggest that amlodipine can prevent ventricular remodeling accompanied by cardiac dysfunction after myocardial infarction.

Calcium channel antagonists are theoretically effective in the prevention of left ventricular remodeling because of their actions as arteriolar dilators and anti-ischemic agents. Although all three classes of calcium channel antagonists now available, phenylalkylamine (e.g., verapamil), benzothiazepenes (e.g., diltiazem) and dihydropyridines (e.g., nifedipine, nimodipine, nitredipine), are effective vasodilators, none has been shown to produce a sustained improvement in symptoms in heart failure patients with predominant systolic ventricular dysfunction. Indeed, these drugs appear to worsen symptoms and may actually increase mortality in patients with systolic dysfunction [21–23]. The reason for these adverse effects of calcium channel antagonists in heart failure is unclear. It may be related to the known negative inotropic effects of these drugs, reflex neurohumoral activation, direct sympathetic nerve stimulation, activation of the renin–angiotensin system, or to a combination of these effects.

In this study, amlodipine decreased mean blood pressure, left ventricular systolic pressure, and left ventricular end-diastolic pressure. The afterload and preload reduction may contribute to prevent left ventricular remodeling after myocardial infarction. Moreover, amlodipine did not increase heart rate, which may not be deleterious to the progress of left ventricular remodeling. On the contrary, the prevention of remodeling by amlodipine may protect the worsening of hemodynamics. Amlodipine may break the vicious circle of the progressive cardiac dysfunction and worsening of hemodynamics during the left ventricular remodeling process.

The left ventricular remodeling is affected by hemodynamic failure and neurohumoral activation. Amlodipine has been reported to increase exercise time and to reduce symptoms and plasma norepinephrine concentration in heart failure [24]. In this study, we did not test the hypothesis that amlodipine would decrease the norepinephrine level and the sympathetic response to baroreflex stimulation in myocardial infarcted rats. Moreover, the oxidative stress may be related to worse heart failure [25, 26]and amlodipine has an antioxidant activity [27]. The prevention of the progressive cardiac dysfunction may partially be due to this effect. We presume that the effect of amlodipine on sympathetic or an oxidant activity may contribute to prevent the left ventricular remodeling after myocardial infarction.

Implicit in the physiological definition of heart failure is that it can be caused by an abnormal systolic function leading to a defect in the expulsion of blood (i.e., systolic heart failure), or by an abnormal diastolic function leading to a defect in ventricular filling (i.e., diastolic heart failure). The former is the more familiar — classic heart failure caused by an impaired inotropic state. Less familiar, but perhaps just as important, is diastolic heart failure in which the ability of the ventricle to accept blood is impaired [28, 29]. Many aspects of diastolic function have been inferred from the pattern of transmitral flow velocity seen on pulsed-wave Doppler [30, 31]. Increased peak E wave velocity, decreased peak A velocity (or absent A wave), and rapid E-wave deceleration were observed in our rats and amlodipine improved these parameters. Calcium antagonist, especially verapamil, have been shown to accelerate ventricular relaxation in patients with hypertrophic cardiomyopathy and have been reported to be useful in the treatment of diastolic dysfunction characteristic in this condition [32]. Amlodipine may improve diastolic dysfunction accompanied with preventing left ventricular remodeling. Moreover, diastolic dysfunction may be due to slowed or incomplete ventricular relaxation and amlodipine may improve it in non-infarcted myocardium directly.

Continued hypertrophy, inadequate for normalizing increased wall tension, activates an initially fetal program of gene expression exemplified by an increase in β-MHC and {alpha}-skeletal actin and accompanied by an increase in the expression of atrial natriuretic peptide [33–35]. β-MHC has low Ca2+-ATPase activity and therefore low energy consumption [36]. {alpha}-Skeletal actin is reported to have greater contractility than {alpha}-cardiac actin [37]. Myosin and actin isoform shifts improve cardiac muscle efficiency and correspond better to the new velocity of contraction. The reason that the decrease {alpha}-MHC and increase of β-MHC in the LV and RV in untreated infarcted rats is that the genes encoding MHC isoforms are regulated in an antithetical manner [34]. In addition, ANP is upregulated in the ventricle with increased work load [38], which probably contributes to the increased level of circulating peptide that in turn tends to decrease preload and afterload. Both phenotypic conversions and ventricular production of ANP may be compensative response to normalize the working conditions of the cardiac pump. However, these changes are not fully effective to prevent the transition from hypertrophy to failure. Moreover, we showed that collagen I and III gene expression increased in non-infarcted myocardium. It is reported that the collagen content increased in non-infarcted myocardium [39, 40]. The increased interstitial collagen content of the myocardium probably enhances organ stiffness and results in cardiac dysfunction eventually leading to heart failure [39, 41]. Amlodipine prevented the increased gene expression of phenotypic modulation, ANP and collagen I and III in both non-infarcted left and right ventricles. We only analyzed mRNA and did not examine protein level. We cannot comment on the property of myocardium. However, we presume that amlodipine can prevent the change of property of myocardium leading to cardiac dysfunction.

The right ventricular weight appears to be a useful marker of the overload hypertrophy induced in this model [4]. In the present study, we examined the gene expression of the right ventricle and the effect of amlodipine on these changes. The ventricular weight and the gene expression of fetal contractile proteins and collagen increased and amlodipine prevented the increase of right ventricular weight and changes of the expression of these genes. Structural remodeling and interstitial fibrosis occurs in the right ventricle of rats with myocardial infarction [42]. Thus, amlodipine could prevent the changes of quantity and quality of right ventricular remodeling after myocardial infarction. Amlodipine can prevent not only the left ventricular remodeling but also right ventricular remodeling after myocardial infarction.


   5 Study limitations
Top
 Abstract
 1 Introduction
 2 Materials and methods
 3 Results
 4 Discussion
 5 Study limitations
6 Summary
 References
 
Echocardiograms were performed in rats anesthetized with intraperitoneal ketamine HCl and xylazine. These anesthetics may affect the cardiac function. In fact, these anesthetics invoke a decreasing heart rate. The heart rate lowering effect prevents the summation of E and A waves. However, if possible, we should measure cardiac function without anesthesia in humans. In future studies it will be necessary for us to assess left ventricular size and function by using anesthesia which does not affect cardiac function. Moreover, we did not show the relationship between mRNA and protein levels. mRNA levels may not be necessarily representative of protein levels and, therefore, they cannot provide sufficient data to analyze the mechanism of the progressive cardiac dysfunction after myocardial infarction.


   6 Summary
Top
 Abstract
 1 Introduction
 2 Materials and methods
 3 Results
 4 Discussion
 5 Study limitations
 6 Summary
References
 
In summary, our study showed that amlodipine prevents left ventricular remodeling, including systolic and diastolic dysfunction, and abnormal fetal gene expression in myocardial infarcted rats. It follows that an intriguing possibility exists that suitable amlodipine administration to postmyocardial infarction subjects may overcome abnormal cardiac gene expression and morphological remodeling, thereby altering the natural course towards heart failure.

Time for primary review 35 days.


   Acknowledgements
 
We would like to thank Dr. Iku Toda, Dr. Masakazu Teragaki and Dr. Kaname Akioka for invaluable help and advice, and Ms. Harumi Baba, Ms. Ayako Kobayashi and Ms. Hiroko Kajiwara for secretarial assistance.


   References
Top
 Abstract
 1 Introduction
 2 Materials and methods
 3 Results
 4 Discussion
 5 Study limitations
 6 Summary
 References
 

  1. Weisman H.F., Bush D.E., Mannisi J.A., Bulkley B.H. Global cardiac remodeling after acute myocardial infarction: a study in the rat model. J Am Coll Cardiol (1985) 5:1355–1362.[Abstract]
  2. McKay R.G., Pfeffer M.A., Pasternak R.C., Markis J.E., Come P.C., Nakao S., Alderman J.D., Ferguson J.J., Safian R.D., Grossman W. Left ventricular remodeling after myocardial infarction: a corollary to infarct expansion. Circulation (1986) 74:693–702.[Abstract/Free Full Text]
  3. Pfeffer M.A., Braunwald E. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation (1990) 81:1161–1172.[Abstract/Free Full Text]
  4. Pfeffer M.A., Pfeffer J.M., Steinberg C., Finn P. Survival after an experimental myocardial infarction: beneficial effects of long-term therapy with captopril. Circulation (1985) 72:406–412.[Abstract/Free Full Text]
  5. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med (1987) 316:1429–1435.[Abstract]
  6. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med (1991) 325:293–302. (See comments).[Abstract]
  7. The SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. N Engl J Med (1992) 327:669–677. (See comments).[Abstract]
  8. Murdoch D., Heel R.C. Amlodipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cardiovascular disease [published erratum appeared in Drugs 1991 Jun;41(6):856]. Drugs (1991) 41:478–505.[Web of Science][Medline]
  9. Conti C.R. Use of calcium antagonists to treat heart failure [editorial]. Clin Cardiol (1994) 17:101–102.[Web of Science][Medline]
  10. Little W.C., Cheng C.P. Vascular versus myocardial effects of calcium antagonists. Drugs (1994) 4:41–45.
  11. Habeler G., Lenzhofer R., Pall H., Tomaschek A., Ziebart-Schroth A., Zirm B., Ganzinger U. Effectiveness and tolerance of amlodipine in treatment of patients with mild to moderate hypertension. Results of a long-term study with a new calcium antagonist. [German]. Wien Klin Wochenschr (1992) 104:16–20.[Web of Science][Medline]
  12. PRAISE. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Eng J Med (1996) 335:1107–1114.[Abstract/Free Full Text]
  13. Burges R.A., Dodd M.G., Gardiner D.G. Pharmacologic profile of amlodipine. Am J Cardiol (1989) 64:18I–20I.
  14. Yoshiyama M., Takeuchi K., Hanatani A., Kim S., Omura T., Toda I., Teragaki M., Akioka K., Iwao H., Yoshikawa J. Differences in expression of sarcoplasmic reticulum Ca2+ ATP ase and Na+-Ca2+ exchanger genes between adjacent and remote noninfarcted myocardium after myocardial infarction. J Mol Cell Cardiol (1997) 29:255–264.[CrossRef][Web of Science][Medline]
  15. Litwin S.E., Katz S.E., Morgan J.P., Douglas P.S. Serial echocardiographic assessment of left ventricular geometry and function after large myocardial infarction in the rat. Circulation (1994) 89:345–354.[Abstract/Free Full Text]
  16. Gay R.G. Early and late effects of captopril treatment after large myocardial infarction in rats. J Am Coll Cardiol (1990) 16:967–977.[Abstract]
  17. Kim S., Ohta K., Hamaguchi A., Yukimura T., Miura K., Iwao H. Angiotensin II induces cardiac phenotypic modulation and remodeling in vivo in rats. Hypertension (1995) 25:1252–1259.[Abstract/Free Full Text]
  18. Genovese C., Rowe D., Kream B. Construction of DNA sequences complementary to rat alpha 1 and alpha 2 collagen mRNA and their use in studying the regulation of type I collagen synthesis by 1,25-dihydroxyvitamin D. Biochemistry (1984) 23:6210–6216.[CrossRef][Web of Science][Medline]
  19. Liau G., Yamada Y., de C.B. Coordinate regulation of the levels of type III and type I collagen mRNA in most but not all mouse fibroblasts. J Biol Chem (1985) 260:531–536.[Abstract/Free Full Text]
  20. Kim S., Ohta K., Hamaguchi A., Omura T., Yukimura T., Miura K., Inada Y., Wada T., Ishimura Y., Chatani F., Iwao H. Role of angiotensin II in renal injury of deoxycorticosterone acetate-salt hypertensive rats. Hypertension (1994) 24:195–204.[Abstract/Free Full Text]
  21. MDPIT. The effect of diltiazem on mortality and reinfarction after myocardial infarction. The Multicenter Diltiazem Postinfarction Trial Research Group. N Engl J Med (1988) 319:385–392.[Abstract]
  22. Gibson R.S. Current status of calcium channel-blocking drugs after Q wave and non-Q wave myocardial infarction. Circulation (1989) VI:107–119.
  23. Goldstein R.E., Boccuzzi S.J., Cruess D., Nattel S. Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction. The Adverse Experience Committee; and the Multicenter Diltiazem Postinfarction Research Group. Circulation (1991) 83:52–60. (See comments).[Abstract/Free Full Text]
  24. Packer M., Nicoid P., Khandheria B.R., Costello D.L., Wasserman A.G., Konstam M.A., Weiss R.J., Moyer R.R., Pinsky D.J., Abittan M.H., Souhrada J.F. Randomized, multicenter, double-blind, placebo-controlled evaluation of amlodipine in patients with mild-moderate heart failure. J Am Coll Cardiol (1991) 17:274A.
  25. Packer M., Bristow M.R., Cohn J.N., Colucci W.S., Fowler M.B., Gilbert E.M., Shusterman N.H. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med (1996) 334:1349–1355. (See comments).[Abstract/Free Full Text]
  26. Khaper N., Singal P.K. Effects of afterload reducing drugs on pathogenesis of antioxidant changes and congestive heart failure in rats. J Am Coll Cardiol (1997) 29:856–861.[Abstract]
  27. Lupo E., Locher R., Weisser B., Vetter W. In vitro antioxidant activity of calcium antagonists against LDL oxidation compared with alpha-tocopherol. Biochem Biophys Res Commun (1994) 203:1803–1808.[CrossRef][Web of Science][Medline]
  28. Iriarte M., Murga N., Sagastagoitia D., Molinero E., Morillas M., Salcedo A., Estella P., Etxebeste J. Congestive heart failure from left ventricular diastolic dysfunction in systemic hypertension. Am J Cardiol (1993) 71:308–312.[CrossRef][Web of Science][Medline]
  29. Gaasch W.H. Diagnosis and treatment of heart failure based on left ventricular systolic or diastolic dysfunction. JAMA (1994) 271:1276–1280. (See comments).[Abstract/Free Full Text]
  30. Giannuzzi P., Imparato A., Temporelli P.L., de-Vito F., Silva P.L., Scapellato F., Giordano A. Doppler-derived mitral deceleration time of early filling as a strong predictor of pulmonary capillary wedge pressure in postinfarction patients with left ventricular systolic dysfunction. J Am Coll Cardiol (1994) 23:1630–1637.[Abstract]
  31. Xie G.Y., Berk M.R., Smith M.D., Gurley J.C., DeMaria A.N. Prognostic value of Doppler transmitral flow patterns in patients with congestive heart failure. J Am Coll Cardiol (1994) 24:132–139. (See comments).[Abstract]
  32. Gilligan D.M., Chan W.L., Joshi J., Clarke P., Fletcher A., Krikler S., Oakley C.M. A double-blind, placebo-controlled crossover trial of nadolol and verapamil in mild and moderately symptomatic hypertrophic cardiomyopathy. J Am Coll Cardiol (1993) 21:1672–1679.[Abstract]
  33. Hanatani A., Yoshiyama M., Kim S., Omura T., Toda I., Akioka K., Teragaki M., Takeuchi K., Iwao H., Takeda T. Inhibition by angiotensin II type 1 receptor antagonist of cardiac phenotypic modulation after myocardial infarction. J Mol Cell Cardiol (1995) 27:1905–1914.[CrossRef][Web of Science][Medline]
  34. Chassagne C., Wisnewsky C., Schwartz K. Antithetical accumulation of myosin heavy chain but not alpha-actin mRNA isoforms during early stages of pressure-overload-induced rat cardiac hypertrophy. Circ Res (1993) 72:857–864.[Abstract/Free Full Text]
  35. Schiaffino S., Samuel J.L., Sassoon D., Lompre A.M., Garner I., Marotte F., Buckingham M., Rappaport L., Schwartz K. Nonsynchronous accumulation of alpha-skeletal actin and beta-myosin heavy chain mRNAs during early stages of pressure-overload—induced cardiac hypertrophy demonstrated by in situ hybridization. Circ Res (1989) 64:937–948.[Abstract/Free Full Text]
  36. Swynghedauw B. Developmental and functional adaptation of contractile proteins in cardiac and skeletal muscles. Physiol Rev (1986) 66:710–771.[Abstract/Free Full Text]
  37. Hewett T.E., Grupp I.L., Grupp G., Robbins J. Alpha-skeletal actin is associated with increased contractility in the mouse heart. Circ Res (1994) 74:740–746.[Abstract/Free Full Text]
  38. Izumo S., Nadal G.B., Mahdavi V. Protooncogene induction and reprogramming of cardiac gene expression produced by pressure overload. Proc Natl Acad Sci USA (1988) 85:339–343.[Abstract/Free Full Text]
  39. Weber K.T., Janicki J.S., Shroff S.G., Pick R., Chen R.M., Bashey R.I. Collagen remodeling of the pressure-overloaded, hypertrophied nonhuman primate myocardium. Circ Res (1988) 62:757–765.[Abstract/Free Full Text]
  40. Volders P.G., Willems I.E., Cleutjens J.P., Arends J.W., Havenith M.G., Daemen M.J. Interstitial collagen is increased in the non-infarcted human myocardium after myocardial infarction. J Mol Cell Cardiol (1993) 25:1317–1323.[CrossRef][Web of Science][Medline]
  41. Weber K.T., Sun Y., Tyagi S.C., Cleutjens J.P. Collagen network of the myocardium: function, structural remodeling and regulatory mechanisms. J Mol Cell Cardiol (1994) 26:279–292.[CrossRef][Web of Science][Medline]
  42. van K.C., Smits J.F., Cleutjens J.P., Debets J.J., Schoemaker R.G., Struyker B.H., Bosman F.T., Daemen M.J. DNA synthesis in the non-infarcted cardiac interstitium after left coronary artery ligation in the rat: effects of captopril. J Mol Cell Cardiol (1991) 23:1245–1253.[CrossRef][Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
A. Ogino, G. Takemura, H. Kanamori, H. Okada, R. Maruyama, S. Miyata, M. Esaki, M. Nakagawa, T. Aoyama, H. Ushikoshi, et al.
Amlodipine inhibits granulation tissue cell apoptosis through reducing calcineurin activity to attenuate postinfarction cardiac remodeling
Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2271 - H2280.
[Abstract] [Full Text] [PDF]

Home page
 J CARDIOVASC PHARMACOL THERHome page
B. I. Jugdutt and V. Menon
Beneficial Effects of Therapy on the Progression of Structural Remodeling During Healing After Reperfused and Nonreperfused Myocardial Infarction: Different Effects on Different Parameters
Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2002; 7(2): 95 - 107.
[Abstract] [PDF]

Home page
 J Am Coll CardiolHome page
B. I. Jugdutt, V. Menon, D. Kumar, and H. Idikio
Vascular remodeling during healing after myocardial infarction in the dog model: Effects of reperfusion, amlodipine and enalapril
J. Am. Coll. Cardiol., May 1, 2002; 39(9): 1538 - 1545.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
H. Kumamoto, H. Okamoto, M. Watanabe, H. Onozuka, K. Yoneya, I. Nakagawa, S. Chiba, S. Watanabe, T. Mikami, K. Abe, et al.
Beneficial effect of myocardial angiogenesis on cardiac remodeling process by amlodipine and MCI-154
Am J Physiol Heart Circ Physiol, April 1, 1999; 276(4): H1117 - H1123.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Shimada, T.
Right arrow Articles by Yoshikawa, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shimada, T.
Right arrow Articles by Yoshikawa, J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?