(Hypertension. 1999;33:961-968.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Effects of Candesartan and Cilazapril on Rats With Myocardial Infarction Assessed by Echocardiography
From the First Department of Internal Medicine (M.Y., K.T., T.O., H.Y., I.T., M.T., K.A., J.Y.) and Department of Pharmacology (S.K., H.I.), Osaka City University Medical School, Osaka, Japan.
Correspondence to Minoru Yoshiyama, MD, First Department of Internal Medicine, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan. E-mail myoshiyama{at}med.osaka-cu.ac.jp
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Abstract |
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Abstract—The purpose of this study was to compare the angiotensin II type 1 receptor antagonist candesartan cilexitil (candesartan) and the angiotensin-converting enzyme inhibitor cilazapril on cardiac function, assessed by Doppler echocardiography and cardiac gene expression associated with cardiac remodeling, in rats with myocardial infarction. Candesartan or cilazapril was administered after myocardial infarction. At 1 and 4 weeks after myocardial infarction, cardiac function and mRNA expression in noninfarcted myocardium were analyzed. Candesartan and cilazapril equally prevented increases in hypertrophy in noninfarcted myocardium, left ventricular dilatation, and ejection fraction at 4 weeks. The E-wave/A-wave velocity ratio and the rate of E-wave deceleration, measures of diastolic function, increased to 9.2±0.6 and 26.3±2.6 m/s2 at 1 week after myocardial infarction. Candesartan and cilazapril, administered at a dose of 1 mg/kg per day, prevented increases in E-wave/A-wave velocity ratio and E-wave deceleration at 1 and 4 weeks. Candesartan and cilazapril significantly suppressed increased mRNA expression of ß-myosin heavy chain,
-skeletal
actin, and atrial natriuretic peptide in noninfarcted
ventricle at 1 and 4 weeks and expression of collagen I and III at 4
weeks to a similar extent. When given at a dose of 10 mg/kg per day,
both candesartan and cilazapril prevented cardiac dysfunction and gene
expression to the same extent as when given at 1 mg/kg per day. In
conclusion, Doppler echocardiography showed
that candesartan and cilazapril equally improved systolic and
diastolic function and that ventricular
remodeling accompanied modulation of cardiac gene expression.
Key Words: ventricular remodeling • myocardial infarction • receptors, angiotensin • echocardiography • genes • diastole
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Introduction |
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Angiotensin-converting enzyme (ACE) inhibitors reduce morbidity and mortality in patients with chronic heart failure and left ventricular dysfunction as well as in patients who have had a myocardial infarction (MI).1 2 3 4 ACE inhibitors may exert a cardioprotective effect by decreasing afterload and preload and by inhibiting the cardiac renin-angiotensin system. Orally active, nonpeptide angiotensin II type 1 (AT1) receptor antagonists, such as losartan or candesartan cilexitil, can block this receptor specifically.5 6 Raya et al7 compared the long-term effects of the ACE inhibitor captopril with the direct blockade induced by losartan in a rat model of MI, and both drugs caused similar hemodynamic changes. Several other investigators have made similar comparisons in dog and rat models of MI.8 9 10 11 12 13 14 In some of these studies, the ACE inhibitor seemed to be superior to the AT1 receptor antagonist in preventing ventricular remodeling and hypertrophy,9 12 13 whereas in others the two seemed similar.7 8 10 11 13 14 Recently, investigators in the Evaluation of Losartan in the Elderly (ELITE) study found that losartan was, contrary to expectations, associated with lower mortality than captopril in patients with heart failure.15 On the other hand, in the RESOLVD study, a trial comparing candesartan with enalapril in patients with heart failure, no difference in effects on clinical events or death between the two drugs was shown.16 A comparison of the effects of AT1 receptor antagonists and ACE inhibitors on heart failure has not been performed.
Two-dimensional echocardiography allows visualization of the entire heart through multiple tomographic planes in real time and has become the noninvasive method of choice for evaluating chamber size and function. Pulsed-wave Doppler recordings of atrioventricular valve flow provide valuable information about diastolic filling of the heart,17 and transthoracic Doppler echocardiography has become a powerful noninvasive method that has been used to provide information about systolic and diastolic function in small-animal studies.18 19 The present study was undertaken to compare the effects of an AT1 receptor antagonist (candesartan cilexitil) and an ACE inhibitor (cilazapril) on cardiac dysfunction in rats after MI. For this purpose, we measured cardiac function by using Doppler echocardiography and ventricular mRNA expression of several genes associated with cardiac hypertrophy.
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Methods |
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Experimental Protocol
All procedures were in accordance with institutional guidelines for animal research. Male Wistar rats weighing 290 to 310 g were purchased from Clea Japan, Inc (Osaka, Japan). MI was produced by ligation of the left anterior descending coronary artery as previously described.20 21 The same surgical procedures were performed on a control group of rats (1 week, n=8; 4 weeks, n=8) except that the suture around the coronary artery was not tied. Rats that survived 24 hours after surgery were randomly separated into treated and untreated groups (MI groups: 1 week, n=9; 4 weeks, n=8). Treated rats were orally administered candesartan cilexitil (candesartan) (1 or 10 mg/kg) or cilazapril (1 or 10 mg/kg) in a volume of 2 mL/kg by gastric gavage once per day for 1 or 4 weeks after MI (candesartan, 1 mg/kg: 1 week, n=10; 4 weeks, n=9; candesartan, 10 mg/kg: 1 week, n=11; 4 weeks, n=10; cilazapril, 1 mg/kg: 1 week, n=10; 4 weeks, n=10; cilazapril, 10 mg/kg: 1 week, n=9; 4 weeks, n=10). Untreated rats were administered vehicle (5% gum arabic solution) in the same manner (1 week, n=9; 4 weeks, n=8).
Doppler Echocardiographic and Hemodynamic
Studies
Transthoracic Doppler
echocardiography was performed on each rat by
modifying the method described by Litwin et al.18
End-diastolic area was defined as the largest left
ventricular area and end-systolic as the smallest;
calculations of ventricular chamber size were previously
published by Scherrer-Crosbie et al.22 Ejection fraction
was measured by modifying Simpson's method, which uses 2- and
4-chamber views (Figure 1).23 The
hemodynamic studies are described in detail
elsewhere.24 Myocardial infarct size was measured as
previously described.21 Rats with an infarct size of
<20% were excluded from analysis. After determination of
infarct size, the left ventricle was divided into 3 parts, the
infarcted region, myocardium around the infarcted zone in
the free left ventricle (adjacent noninfarcted myocardium),
and septal myocardium (remote noninfarcted
myocardium). The infarct induced by ligation of the
descending coronary artery in the rat occurred in the free wall
of the left ventricle.
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Northern Blot Hybridization
The method of Northern blot hybridization used is described in
detail elsewhere.25
Statistics
Results are mean±SE. Statistical significance was determined
using ANOVA and Duncan's multiple range test. Differences were
considered significant at P<0.05.
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Results |
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Effects of Candesartan and Cilazapril on Hemodynamics and Heart Weight
As shown in Table 1, both candesartan and cilazapril significantly lowered mean blood pressure and left ventricular systolic pressure (LVSP) in rats with MI. The 10-mg/kg per day doses of candesartan and cilazapril decreased mean blood pressure and LVSP more than the 1-mg/kg per day doses. However, there was no significant difference in hypotensive effects among the 4 groups. Left ventricular end-diastolic pressure (LVEDP) and central venous pressure (CVP) were significantly higher in rats with MI at 1 and 4 weeks than in controls. In treated rats, LVEDP and CVP decreased to a similar extent. Right ventricular weight (0.78±0.03 g/kg, P<0.01) was significantly higher in rats with MI than in controls (0.56±0.03 g/kg) at 4 weeks. Left ventricular weight was lower in rats with MI than in controls at 1 week and was the same in both controls and rats with MI at 4 weeks, which means that scar formation in the infarcted region decreased left ventricular weight at 1 week and canceled the weight increased by cardiac hypertrophy of the noninfarcted regions at 4 weeks (1 week: control, 2.12±0.05 g/kg; MI, 1.99±0.04 g/kg; P<0.05; 4 weeks: control, 2.14±0.05 g/kg; MI, 2.15±0.07 g/kg; NS). Candesartan and cilazapril significantly prevented an increase in heart weight at 4 weeks. There was no significant difference in heart weights among the 4 treated groups.
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Doppler Echocardiographic Assessment of Left
Ventricular Geometry and Function
Left ventricular cavity size significantly increased
in rats with MI at 1 and 4 weeks (1 week: control, 6.0±0.6 mm;
MI, 8.2±0.4 mm; P<0.01; 4 weeks: control,
6.7±0.3 mm; MI, 10.3±0.7 mm; P<0.01) (see Table 2). Rats with MI had significant
systolic dysfunction, as evidenced by decreased fractional
shortening (control, 38±4%; MI, 20±2%; P<0.05) at 1
week. Left ventricular posterior wall thickness was not
changed at 1 week and had decreased at 4 weeks. Candesartan and
cilazapril significantly prevented left ventricular cavity
dilatation and decreases in ejection fraction and fractional shortening
at 4 weeks (Figure 2A). There was no
significant difference in improvement of systolic function
among the 4 treated groups.
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Examples of pulsed-wave Doppler recordings of mitral inflow from control rats and from untreated, candesartan-treated (1 mg/kg per day), and cilazapril-treated (1 mg/kg per day) rats with MI at 1 week are shown in Figure 2B. At 1 week, peak early diastolic filling (E-wave) velocity increased (control, 56±4 cm/s; MI, 110±10 cm/s; P<0.01) and deceleration of the E wave became more rapid (control, 16.0±2.3 m/s2; MI, 26.3±2.6 m/s2; P<0.01). Atrial filling (A-wave) velocity decreased (control, 33±4 cm/s; MI, 13±2 cm/s; P<0.01), resulting in a marked increase in the ratio of E-wave to A-wave velocity (E/A) (control, 1.9±0.2; MI, 9.2±0.6; P<0.01). Candesartan and cilazapril significantly prevented worsening of diastolic dysfunction, as evidenced by E/A and the deceleration rate of the E wave at 1 and 4 weeks. There was no significant difference in improvement of diastolic function among the 4 treated groups.
Gene Expression of Contractile Proteins, Atrial
Natriuretic Peptide, and Collagens
The results of cardiac gene expression at 1 and 4 weeks are shown
in Figure 3 and Tables 3 and 4. At
1 week after MI, ß-myosin heavy chain (ß-MHC), -skeletal actin,
atrial natriuretic peptide (ANP), and collagen I and III
mRNA expression increased 4.5-, 3.1-, 9.4-, 14.3-, and 8.4-fold
(P<0.01), respectively, in the adjacent noninfarcted
myocardium. Gene expression increased significantly in the
remote noninfarcted left ventricle (septum) and right ventricle. These
genes were predominantly expressed in the adjacent noninfarcted
myocardium rather than the remote noninfarcted left
ventricle and right ventricle. At 1 week, candesartan and cilazapril
significantly prevented mRNA expression of ß-MHC, -skeletal actin,
and ANP in the adjacent and remote noninfarcted left ventricles and
right ventricle but did not affect mRNA expression of collagens I and
III in any region. At 4 weeks, ß-MHC, -skeletal actin, ANP, and
collagen I and III mRNA expression remained increased. Both candesartan
and cilazapril prevented these increases significantly in all regions.
There was no significant difference in prevention of cardiac gene
expression among the 4 treated groups.
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Figure 4 shows hearts from control rats and from untreated, candesartan-treated (10 mg/kg per day), and cilazapril-treated (10 mg/kg per day) rats at 12 weeks after MI. Both the AT1 antagonist and ACE inhibitor apparently prevented enlargement of a typical remodeled heart at 12 weeks after MI.
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Discussion |
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As expected, our study showed that treatment with candesartan or cilazapril attenuates left ventricular dilatation and cardiac hypertrophy in the noninfarcted region and improves ejection fraction (measured by the modified Simpson's method), fractional shortening, and left ventricular wall thickening at 4 weeks after MI. A variety of ways to calculate volumes have been proposed. Measuring ejection fraction with the modified Simpson's method is the most reliable way to assess systolic function using echocardiographic parameters because it minimizes the effect of geometric shape for calculating volumes. Left ventricular weight in the untreated infarct group was the same as in the control group at 4 weeks despite the presence of infarcts and considerable loss of myocardium (which was replaced by a thin wall of scar tissue), which suggests that reactive hypertrophy of the noninfarcted left ventricle occurred. Consequently, the reduced left ventricular weights of the candesartan- and cilazapril-treated groups indicate that reactive hypertrophy was prevented. Relatively little improvement of systolic function was induced by candesartan or cilazapril, but this increase coincided with a decrease in LVEDP, suggesting that the pumping ability of the left ventricle was significantly improved.
Doppler echocardiography is currently the primary technique for evaluating left ventricular diastolic function.17 Increased E-wave velocity, decreased peak A-wave velocity (or absent A wave), and rapid E-wave deceleration were observed in our rats, and these flow patterns were similar to transmitral flow profiles observed in patients with heart failure with restrictive patterns. Both candesartan and cilazapril decreased the E/A ratio and E-wave deceleration rate at 1 and 4 weeks. Long-term ACE inhibitor therapy could prevent changes in left ventricular diastolic properties in patients with depressed ejection fraction.26 We recently reported that candesartan improved the diastolic filling pattern in rats with MI.27 Our data showed that candesartan and cilazapril prevented abnormal diastolic filling before systolic dysfunction after MI. This effect of ACE inhibitors has been already reported.28 Improvement of diastolic filling is caused by preload, afterload reduction, improvement in left ventricular relaxation, or decrease in passive elastic properties. Our data do not directly answer the difficult question of whether the changes in left ventricle filling are due to changes in myocardial properties, changes in left ventricle loading conditions, or both. However, when viewed in the context of previous studies using isolated muscle preparations from the same model of heart failure,29 30 the improvements in diastolic filling that accompany inhibition of the renin-angiotensin system result from a combination of effects on left ventricular preload and afterload as well as left ventricular chamber properties.
During the early phase of MI, the heart attempts to provide
hemodynamic compensation at the expense of
ventricular dilatation (Frank-Starling law).31
Chronic, continued hemodynamic stress leads to
pathological hypertrophy and progressive dilatation. We
have noted that MI occurs in the free wall in rats; therefore, the
marginal zone of the infarcted region (myocardium adjacent
to infarct region) is located in the left ventricular free
wall. Thus, we must examine the left ventricular free wall
and septum to analyze the properties of the whole noninfarcted
left ventricle. Left ventricular remodeling after MI is
known to be accompanied by severe hypertrophy of the
myocyte and dysfunction of regions adjacent to the infarct. We
previously reported that fetal genes (ß-MHC, -skeletal actin, and
ANP) are predominantly expressed in adjacent noninfarcted
myocardium. However, the pattern of fetal gene expression
did not differ between adjacent and remote noninfarcted
myocardium.24 In the present study,
candesartan and cilazapril equally prevented fetal gene expression at 1
and 4 weeks and collagen gene expression at 4 weeks, indicating that
both the AT1 receptor antagonist and the ACE
inhibitor attenuate remodeling of the myocyte and
nonmyocyte compartments to a similar extent after MI. Although
candesartan and cilazapril inhibited increased mRNA expression of
collagens I and III at 4 weeks, neither drug did so at 1 week.
AT1 receptor antagonists and ACE
inhibitors are reported to suppress
interstitial fibrosis in noninfarcted
myocardium.11 We believe the reason is that
the half-life of collagen is 80 to 120 days,32 which would
make it difficult to detect a change in gene expression after 1 week of
treatment.
McDonald et al9 reported that ACE inhibitors, but not AT1 receptor antagonists, attenuate left ventricular remodeling in dogs after transmyocardial direct shock. Moreover, they showed a possible role of the bradykinin B2-receptor antagonist HOE 140 in the antiremodeling effect of ACE inhibitors in this model.33 Because ACE inhibitors block degradation of bradykinin and because candesartan and cilazapril have the same cardioprotective effect, we may interpret these data to indicate that the cardioprotective effect of ACE inhibitors is due to blockade of the conversion of angiotensin I to angiotensin II, not inhibition of kinin hydrolysis. However, the effect of the AT1 receptor antagonist may not be entirely due to blockade of the AT1 receptor. Angiotensin receptors comprise 2 major subtypes, AT1 and AT2.34 When the AT1 receptor is blocked, plasma renin and angiotensin increase; angiotensin may act on AT2 receptors, which could have an antitrophic effect either directly or via the release of autocoids, such as kinins35 36 and nitric oxide,37 38 and consequently may contribute to the therapeutic effect of AT1 receptor antagonist by a mechanism similar to that of kinins. Liu et al8 reported that the effect of the ACE inhibitor is mediated in part by kinins, whereas that of the AT1 receptor antagonist is triggered by activation of the AT2 receptor and is also mediated in part by kinins. Nunez et al39 showed that combination of an ACE inhibitor and AT1 receptor antagonist improved hemodynamics in association with reduced left ventricular mass in spontaneously hypertensive rats. However, additional studies are needed to verify that the release of autocoids by AT1 receptor antagonists has the same beneficial effects on systolic and diastolic function as those induced by inhibition of bradykinin degradation by an ACE inhibitor.
In summary, candesartan and cilazapril had equally beneficial effects on cardiac function, as assessed by Doppler echocardiography and cardiac gene expression, after MI.
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Acknowledgments |
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We thank Hiroko Kajiwara for Doppler echocardiographic examination, Emi Utsunomiya and Tinami Kobata for technical assistance, and Harumi Baba and Ayako Kobayashi for secretarial assistance.
Received July 7, 1998; first decision July 29, 1998; accepted December 11, 1998.
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T. Omura, M. Yoshiyama, S. Kim, R. Matsumoto, Y. Nakamura, Y. Izumi, H. Ichijo, T. Sudo, K. Akioka, H. Iwao, et al. Involvement of Apoptosis Signal-Regulating Kinase-1 on Angiotensin II-Induced Monocyte Chemoattractant Protein-1 Expression Arterioscler Thromb Vasc Biol, February 1, 2004; 24(2): 270 - 275. [Abstract] [Full Text]
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T. Backlund, E. Palojoki, A. Saraste, T. Gronholm, A. Eriksson, P. Lakkisto, O. Vuolteenaho, M. S Nieminen, L.-M. Voipio-Pulkki, M. Laine, et al. Effect of vasopeptidase inhibitor omapatrilat on cardiomyocyte apoptosis and ventricular remodeling in rat myocardial infarction Cardiovasc Res, March 1, 2003; 57(3): 727 - 737. [Abstract] [Full Text] [PDF]
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Y. Nakamura, M. Yoshiyama, T. Omura, K. Yoshida, Y. Izumi, K. Takeuchi, S. Kim, H. Iwao, and J. Yoshikawa Beneficial effects of combination of ACE inhibitor and angiotensin II type 1 receptor blocker on cardiac remodeling in rat myocardial infarction Cardiovasc Res, January 1, 2003; 57(1): 48 - 54. [Abstract] [Full Text] [PDF]
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 Yuejin Yang, Yida Tang, Yingmao Ruan, Yongli Li, Yanwen Zhou, Runlin Gao, Jilin Chen, and Zaijia Chen Comparative effects of cilazapril, carvedilol and their combination in preventing from left ventricular remodelling after acute myocardial infarction in rats Journal of Renin-Angiotensin-Aldosterone System, March 1, 2002; 3(1): 31 - 35. [Abstract] [PDF]
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L. Brown, A. Fenning, A. Shek, and D. Burstow Reversal of cardiovascular remodelling with candesartan Journal of Renin-Angiotensin-Aldosterone System, March 1, 2001; 2(1_suppl): S141 - S147. [Abstract] [PDF]
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S. Kim and H. Iwao Molecular and Cellular Mechanisms of Angiotensin II-Mediated Cardiovascular and Renal Diseases Pharmacol. Rev., March 1, 2000; 52(1): 11 - 34. [Abstract] [Full Text] [PDF]
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 L. A.M. Zornoff, S. A.R. Paiva, B. B. Matsubara, L. S. Matsubara, and J. Spadaro Combination Therapy with Angiotensin Converting Enzyme Inhibition and AT1 Receptor Inhibitor on Ventricular Remodeling After Myocardial Infarction in Rats Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2000; 5(3): 203 - 209. [Abstract] [PDF]
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