© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Roles of renin–angiotensin and endothelin systems in development of diastolic heart failure in hypertensive hearts
aDepartment of Internal Medicine and Therapeutics (First Department of Medicine), Osaka University Graduate School of Medicine (A8), 2-2 Yamadaoka, Suita 565-0871, Japan
bGenome Information Research Center, Osaka University, Suita, Japan
* Corresponding author. Tel.: +81-6-6879-6612; fax: +81-6-6879-6613 masuyama{at}medone.med.osaka-u.ac.jp
Received 8 February 2000; accepted 18 April 2000
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Abstract |
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Objective: Although interest in diastolic heart failure is growing because of its clinical frequency, little is known about this type of heart failure. Our laboratory recently developed a diastolic heart failure model using Dahl salt-sensitive rat. In this model, gene expression of angiotensin-converting enzyme and endothelin (ET) system in the left ventricle was enhanced at heart failure stage without downregulation of angiotensin type 1a receptor mRNA level. However, the roles of these humoral systems in the transition to diastolic failure remain unclear. Methods: Subdepressor doses of angiotensin II type 1 (AT1) receptor and ET type A (ETA) receptor antagonists were administered in this model just after onset of hypertension, and their effects were investigated. Results: Neither AT1 nor ETA receptor blockade inhibited the early (13 weeks) compensatory left ventricular (LV) hypertrophy. This form of compensatory hypertrophy is associated with subnormal LV end-systolic stress, which was normalized by AT1 receptor blockade but not by ETA receptor blockade. Progression of LV hypertrophy and fibrosis and transition to heart failure (19 weeks) in the untreated rats were prevented by both antagonists, resulting in normalization of LV end-diastolic pressure and lung weight. AT1 receptor blockade, but not ETA receptor blockade, normalized time constant of LV relaxation. Enhanced gene expression for ET system in the left ventricle observed in the untreated rats was suppressed with AT1 receptor antagonist administration. ETA receptor blockade slightly but significantly elevated the AT1a receptor mRNA level as compared with the untreated rats. Conclusions: RAS and ET system contribute to the transition to diastolic heart failure through the development of excessive hypertrophy and ventricular fibrosis in hypertensive heart diseases, however, neither RAS nor ET system is mandatory for normal compensation for pressure overload. RAS apparently causes such diastolic effects at least partly through the ET system.
KEYWORDS Angiotensin; Endothelins; Heart failure; Hypertension; Hypertrophy
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1 Introduction |
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The prevalence of congestive heart failure is increasing and congestive heart failure is called the new ‘epidemic of cardiovascular disease’ [1]. Heart failure is not based on a sole pathogenesis and represents various types. Heart failure without moderate to severe left ventricular (LV) systolic dysfunction is often due to diastolic dysfunction. Diastolic heart failure comprises 30–50% of heart failure in clinical practice, and hypertensive heart disease is a major cause of this type of heart failure [2]. Neurohumoral regulation in the ventricle is considered to characterize each type of heart failure and to be a target for therapeutic strategy. The contribution of hormonal factors to this type of heart failure remains unclear partly because of an absence of proper animal models.
Our laboratory recently demonstrated that Dahl salt-sensitive (Dahl-S) rats fed on high salt diet from 7 weeks develop diastolic heart failure around 19 weeks following hypertension and compensated LV hypertrophy [3]. In this model, gene expression of angiotensin converting enzyme (ACE) and angiotensin II type 1a (AT1a) receptor was slightly enhanced in the left ventricle at a compensatory hypertrophic stage, but prepro-endothelin-1 (ppET-1) and ET converting enzyme-1 (ECE-1) mRNA levels were not increased [4]. At a decompensated stage with diastolic failure the gene expression of ACE was further enhanced without downregulation of AT1a receptor. In contrast to the compensatory stage, the decompensated stage was associated with the coordinated upregulation of gene expression of ppET-1, ECE-1 and ET receptors [4].
These findings suggested that renin–angiotensin system (RAS) and ET system are activated in the transition to diastolic heart failure in hypertensive heart disease. Our preliminary study demonstrated that AT1 receptor blockade prevented the development of diastolic heart failure in our model [5]. Several in vitro studies demonstrated that AT II provides its effects through the ET system [6,7]. Thus, these systems are likely to play crucial roles in diastolic heart failure in a similar manner as demonstrated in systolic heart failure models [8,9]. However, the pathogenesis of diastolic failure is not consistent with that of systolic failure. For example, AT1 receptor is downregulated in systolic failure [10,11] but not in diastolic failure [4]. Thus, investigations of roles of RAS and ET system in diastolic heart failure in hypertensive heart disease are valuable, particularly to establish therapeutic strategies which are considered to be different from those for systolic heart failure [12]. Because the regulation of these systems changes from the compensatory hypertrophic stage to the decompensated diastolic failure stage [4], roles of these systems may not be consistent throughout the process of the development of diastolic failure.
In the current study, roles of local RAS and ET system in the heart in the transition to diastolic heart failure were investigated in the Dahl-S rat model by chronic administration of subdepressor doses of an AT1 receptor antagonist and an ET type A (ETA) receptor antagonist.
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2 Methods |
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This study conforms to the guiding principles of Osaka University Graduate School of Medicine with regard to animal care and to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health.
2.1 Subjects
Laboratory chow containing 0.3% NaCl was fed to weaning male Dahl-S rats (DIS/Eis, Eisai, Tokyo, Japan) until the diet was switched to laboratory chow containing 8% NaCl at 7 weeks. The diet and tap water were provided ad libitum throughout the experiment. These rats were divided into following groups: rats with oral administration of AT1 receptor antagonist (Candesartan Cilexetil) at 1 mg/kg/day (n=6) or 10 mg/kg/day (n=5) from 8 weeks, rats with oral administration of ETA receptor antagonist (TA-0201 [13]) at 0.3 mg/kg/day (n=6) or 10 mg/kg/day (n=5) from 8 weeks, rats without receptor blocker treatment (n=6). The male Dahl-S rats continuously fed the 0.3% NaCl chow were used as age-matched control (n=6). A mean value of tail cuff systolic blood pressure was 161 mmHg at 8 weeks in the rats with high-salt diet and was 130 mmHg in the age-matched control rats. Candesartan cilexetil was a gift of Takeda and TA-0201 was a gift of Tanabe Seiyaku.
Echocardiographic studies were performed at 13 and 19 weeks. At 19 weeks, a hemodynamic study and a harvest of the heart followed the echocardiographic study. These schedules were decided according to the results of our previous study [3]. Systolic blood pressure was measured at 7, 13, 15, 17 and 19 weeks with a tail cuff system (BP-98A, Softron, Tokyo, Japan).
2.2 Echocardiographic study
Transthoracic echocardiographic recordings were obtained as previously described [3]. Specifically, rats were anesthetized with intraperitoneal administration of ketamine HCl (50 mg/kg) and xylazine HCl (10 mg/kg), and were held in the half left-lateral position with spontaneous breathing. A commercially available echocardiographic machine equipped with a 7.5 MHz transducer (Sonos 2000, Hewlett-Packard, Andover, MA, USA) was used to measure LV inner diameter and wall thickness. LV fractional shortening and LV mass were calculated as previously described [3]. LV mass corrected for body weight was determined as LV mass index. LV mid-wall fractional shortening was calculated with a Shimizu's model [14] to avoid the overestimation of the systolic function in hypertrophied heart.
2.3 Hemodynamic study
Following the echocardiographic study at 19 weeks, a 1.5 F high-fidelity manometer-tipped catheter (SPR-407, Millar Instruments, Houston, TX, USA) was introduced through the right carotid artery into the left ventricle after the manometer was calibrated relative to atmospheric pressure [3]. Tracings of LV pressure and electrocardiogram were digitized to determine LV end-diastolic pressure and to calculate the time constant of isovolumic LV pressure fall (
) using a non-zero asymptote method as previously described [15]. LV end-systolic stress was calculated following Douglas's method [16].
2.4 Tissue sampling
After the hemodynamic studies, blood was sampled from the right carotid artery for measurement of plasma ET-1 and AT II, and the heart was quickly harvested as previously described [3]. Samples of the left ventricle for the measurement of the amount of mRNAs were weighed, immediately placed in liquid nitrogen and stored at –80°C. The other section was weighed and immersed in a cold 4% paraformaldehyde solution for 16–24 h. The lung was also harvested and weighed.
2.5 Pathological study
The specimen immersed in 4% paraformaldehyde solution was embedded in paraffin. Transverse sections (2-µm thick) of the LV free wall at the papillary muscle level was microscopically examined with Azan Mallory stain at 100x magnification, and the percent area of fibrosis was determined as previously described [3].
2.6 RNA preparation and quantification of mRNA
Total RNAs were extracted from the left ventricle by using Isogen, and treated with RNase-free DNaseI (Nippon Gene, Japan). Reverse transcriptions of the 2 µg total RNA samples were carried out with oligo d(T)16 as a reverse primer by using GeneAmp RNA PCR kit (Perkin-Elmer, Foster, CA, USA). The expression of mRNAs for GAPDH [17], ppET-1 [18], ECE-1 [19], ET type A (ETA) receptor [20], ET type B (ETB) receptor [21], ACE [22], and AT1a receptor [23], was quantified with real-time quantitative PCR using Prism 7700 sequence detector (Perkin-Elmer) as previously described [4]. Sequences of all oligo-nucleotides used as forward primers, reverse primers and detection probes are summarized in Table 1. The amount of each measured mRNA was divided by that of GAPDH mRNA.
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2.7 Statistics
Results are expressed as mean±SEM. Differences at specific stages between groups were assessed using one-way ANOVA and Fisher's protected least significant difference test. A probability value of P<0.05 was considered statistically significant.
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3 Results |
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3.1 Transition to diastolic heart failure in this model
All echocardiographic and hemodynamic data of the untreated rats are summarized in Tables 2 and 3
. Their systolic blood pressure was significantly elevated at 13 and 19 weeks compared to the age-matched control. At 13 weeks, LV mass and LV mass index were greater and LV end-diastolic dimension and LV end-systolic stress were smaller in the untreated rats than in the control. At 19 weeks, the untreated rats showed signs of overt heart failure such as tachypnea, labored respiration and loss of activity. LV mass and mass index progressively increased from 13 to 19 weeks in the untreated rats, but there was no significant difference in LV end-diastolic dimension, mid-wall fractional shortening or LV end-systolic stress at 19 weeks between the untreated and the control rats. LV end-diastolic pressure and a ratio of lung weight to body weight (lung/weight) were higher and the area of fibrosis in the left ventricle was greater in the untreated rats than in the control (Fig. 1).
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3.2 Effects of different doses of AT1 receptor antagonist and ETA receptor antagonist
There was no significant difference in blood pressure, LV geometry and function between the rats treated with two different doses of AT1 receptor antagonist or between those with two different doses of ETA receptor antagonist (Tables 2 and 3
). Thus, the data obtained in rats treated with 1 mg/kg/day of candesartan cilexetil were used as those of an AT1 receptor antagonist-treated group, and the data obtained in rats treated with 0.3 mg/kg/day of TA-0201 were used as those of an ETA receptor antagonist-treated group in the following.
3.3 Effects of AT1 receptor antagonist
AT1 receptor antagonist administration did not decrease systolic blood pressure at 13 or 19 weeks in this study (Tables 2 and 3). Nevertheless, geometrical alteration occurred at 13 weeks (Table 2): LV end-diastolic dimension was enlarged to the level of the control rats with LV mass and LV mass index comparable to those of the untreated rats. As a result, LV end-systolic stress was normalized.
At 19 weeks, no rats treated with AT1 receptor antagonist showed signs of overt heart failure. LV end-diastolic dimension was not different among the rats treated with AT1 receptor antagonist, the untreated rats and the control (Table 3). AT1 receptor antagonist administration prevented a further increase in LV mass index from 13 to 19 weeks observed in the untreated rats. LV end-diastolic pressure, plasma ET-1 level, , lung/weight and the area of fibrosis were lower in the rats treated with AT1 receptor antagonist than in the untreated rats and were not different from those of the control. Mid-wall fractional shortening or LV end-systolic stress was not affected by the administration of AT1 receptor antagonist at 19 weeks.
The mRNA levels for ppET-1, ECE-1, ETA receptor, ETB receptor and ACE in the left ventricle were lower in the rats treated with AT1 receptor antagonist than in the untreated rats (Figs. 2–4). Administration of AT1 receptor antagonist decreased the mRNA levels for ppET-1, ECE-1, ETA receptor and ACE to the control level.
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Rn (fluorescent emission) was plotted against cycle numbers. As the smaller amount of the standard sample was applied, the significant
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3.4 Effects of ETA receptor antagonist
The administration of ETA receptor antagonist slightly decreased systolic blood pressure at 13 weeks but the effect was no longer evident at 19 weeks (Tables 2 and 3
). At 13 weeks, LV end-diastolic dimension of the rats treated with ETA receptor antagonist was greater than that of the untreated rats but was smaller than that of the control rats. LV mass and LV mass index at 13 weeks were not different between the rats treated with ETA receptor antagonist and the untreated rats (Table 2). LV end-systolic stress was subnormal as in the untreated rats.
At 19 weeks, the rats treated with ETA receptor antagonist presented no signs of overt heart failure without a difference in LV end-diastolic dimension, mid-wall fractional shortening or end-systolic stress as compared with the untreated rats (Table 3). Administration of ETA receptor antagonist prevented the further increase in LV mass index from 13 to 19 weeks and kept LV end-diastolic pressure, plasma ET-1 level, lung/weight and area of fibrosis at the control level. However, was not shortened by ETA receptor antagonist administration compared with the untreated rats.
The mRNA level for ACE in the left ventricle was lower in the rats treated with ETA receptor antagonist than in the untreated rats but higher than in the control (Fig. 4). Administration of ETA receptor antagonist slightly but significantly increased the AT1a receptor mRNA level (Fig. 4).
3.5 Effects of AT1 receptor antagonist versus ETA receptor antagonist
At 13 weeks, LV end-diastolic dimension was enlarged by administration of any of the antagonists, but AT1 receptor antagonist was more potent than ETA receptor antagonist. LV mass index was not decreased by either antagonist. As a result, LV end-systolic stress was normalized in the rats treated with AT1 receptor antagonist but was subnormal in those treated with ETA receptor antagonist. At 19 weeks, the effects on LV end-diastolic dimension, LV mass index, LV end-systolic stress, LV end-diastolic pressure, and area of fibrosis were equivalent between both antagonists. The value was shortened by AT1 receptor antagonist administration but not by ETA receptor antagonist administration. Administration of AT1 receptor antagonist decreased LV mRNA levels for ppET-1, ECE-1 and ETA and ETB receptors (Figs. 2 and 3), while ETA receptor antagonist administration increased the AT1a receptor mRNA level (Fig. 4). Administration of either antagonist decreased the ACE mRNA level but the decrease was greater for AT1 receptor antagonist than for ETA receptor antagonist (Fig. 4).
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4 Discussion |
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TopAbstract1 Introduction2 Methods3 Results4 Discussion5 ConclusionsReferences |
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Chronic administration of subdepressor dose of AT1 receptor antagonist or ETA receptor antagonist after the onset of hypertension prevented the transition to overt diastolic heart failure in the hypertensive heart model. Such preventive effects were not provided through their effects on LV systolic function. Neither AT1 receptor antagonist nor ETA receptor antagonist administration hampered the development of the early compensatory component of LV hypertrophy. AT1 receptor blockade completely prevented the decrease in LV end-diastolic dimension at 13 weeks, but such effect of ETA receptor antagonist was incomplete. Administration of either antagonist prevented the further progression of LV hypertrophy from 13 to 19 weeks and the development of myocardial fibrosis. The
value was normalized by AT1 receptor blockade but not by ETA receptor blockade. AT1 receptor blockade suppressed enhancement of gene expression for ET system in the left ventricle. In contrast, ETA receptor blockade slightly enhanced mRNA level of AT1a receptor and suppressed the ACE mRNA expression to the lesser degree than AT1 receptor blockade.
4.1 RAS and ET system in the development of ventricular hypertrophy and fibrosis
The in vitro studies showed that both AT II and ET-1 play crucial roles in induction of myocyte hypertrophy [6,7,24,25]. However, a recent study showed that LV hypertrophy is induced by aorta-banding even in AT1a receptor knockout mice [26]. Because AT II induces myocyte hypertrophy through ET system in vitro [6,7], roles of RAS and ET system in the pressure-overloaded heart are presently controversial.
Blockade of AT1 receptor or ETA receptor did not prevent the development of compensatory component of LV hypertrophy in hypertensive hearts in this study. This result is partly compatible with the result obtained in pressure-overloaded AT1a receptor knockout mice; [26] however, the mice study failed to clarify whether development of pressure-overload LV hypertrophy leads to the occurrence of overt heart failure. We have expanded the previous study by demonstrating that AT1-receptor- and ETA-receptor-mediated signalings play crucial roles in the further progression of LV hypertrophy following early compensatory component of hypertrophy. Restraint of such further progression of LV hypertrophy was effective to prevent the transition to diastolic heart failure, suggesting that the AT1 receptor- and ETA receptor-mediated hypertrophy is not mandatory to the development of compensatory hypertrophy but is closely related to LV hypertrophy that is excessive and responsible for overt heart failure. This concept is also supported by the finding that LV end-systolic stress was normalized by LV hypertrophy in the rats treated with AT1 receptor or ETA receptor antagonist.
AT1 or ETA receptor blockade prevented myocardial fibrosis even at a dose without antihypertensive effects. Thus, RAS and ET system are likely to facilitate the transition to diastolic heart failure through the development of both fibrosis and excessive hypertrophy. This result is compatible with the data of the previous in vitro and in vivo studies in which RAS and ET system contributed to the development of fibrosis in the presence of pressure overload [25].
Effects of AT1 receptor and ETA receptor blockade on the development of LV hypertrophy and fibrosis were similar to each other in this study. We need not take account of the incompleteness of the receptor blockade, because administration of much higher doses of these antagonists provided the same results (Tables 2 and 3). AT1 receptor blockade reduced LV mRNA levels for ET system, while ETA receptor blockade increased a mRNA level of AT1a receptor. This finding suggests that RAS induces excessive component of hypertrophy and fibrosis at least partly through ET system, which is compatible with the previous in vitro studies [6,7]. Either blockade decreased the ACE mRNA level in association with the prevention of heart failure, but its degree was greater for AT1 receptor blockade than for ETA receptor blockade. The decrease in ACE mRNA level in the rats treated with either antagonist may have been provided through the prevention of heart failure, and the difference in the degree of the decrease in ACE mRNA level in spite of comparable hemodynamic effects may indicate that ET system is downstream of RAS. Alternatively, AT1 receptor-mediated signaling may directly upregulate ACE gene expression [27].
4.2 RAS and ET system in geometrical and functional changes
AT1 receptor blockade inhibited alterations in LV chamber geometry as well as pathological changes. At the compensatory hypertrophic stage (13 weeks), LV end-diastolic dimension was smaller in the untreated rats than in the control, however, it was normal in the rats treated with AT1 receptor antagonist. Ventricular cavity reduction contributes to a decrease in ventricular stress, and thus, such geometrical remodeling has been considered as a necessary process to adapt for pressure overload. However, the LV end-systolic wall stress was significantly lower at 13 weeks in the untreated rats than in the control (Table 2). The abnormally lowered LV end-systolic wall stress was normalized with the administration of AT1 receptor antagonist at 13 weeks. ETA receptor blockade incompletely prevented such geometrical change, and thus, LV end-systolic stress at 13 weeks was still lower than that of the control. Our previous study demonstrated that the expression of mRNA for ACE and AT1a receptor was slightly but significantly enhanced at the compensatory hypertrophic stage in this model [4]. Activation of RAS may work towards to alter LV geometry to concentric form, and such geometrical effect may not be mediated through ET system. Sugishita et al. showed that antihypertensive therapy with calcium channel antagonist, β-blocker and diuretics failed to inhibit progression of ventricular hypertrophy in hypertensive patients with subnormal end-systolic wall stress although they were effective in patients with normal end-systolic wall stress [28]. Considering their results and ours, RAS may be already activated in hypertensive hearts with ventricular hypertrophy, concentric LV geometry and subnormal end-systolic wall stress, where an inhibition of RAS rather than a sole reduction of blood pressure may be effective in hampering progressive LV hypertrophy.
The value, a reference of LV relaxation, was prolonged at the heart failure stage in the untreated rats and was normalized in the rats treated with AT1 receptor antagonist. LV hypertrophy is known to prolong LV relaxation and the progression of LV hypertrophy following compensatory hypertrophy was hampered in the rats treated with AT1 receptor antagonist. However, our previous study showed the absence of further prolongation of from the compensatory hypertrophic stage to the heart failure stage [4]. In addition, was still prolonged in the rats treated with ETA receptor antagonist although they had LV hypertrophy comparable to the rats treated with AT1 receptor antagonist. Therefore, activation of RAS is likely to prolong LV relaxation independently of LV structural change and ET system. AT II may upregulate oxidative stress [29,30], resulting in endothelial dysfunction. Nitric oxide (NO) improves LV relaxation through cGMP-dependent pathway [31,32]. Thus, RAS-induced impairment of LV relaxation may be partly mediated by attenuated NO donation due to endothelial dysfunction induced by oxidative stress.
In the current study, ETA receptor blockade prevented excessive component of LV hypertrophy but did not alter LV fractional shortening or mid-wall fractional shortening. In the previous study, however, ETA receptor blockade prevented the transition to heart failure through the inhibition of systolic dysfunction but not through the inhibition of ventricular hypertrophy in rats with hypertensive hearts [33]. In contrast to our model, their model was associated with severe systolic dysfunction at heart failure stage. In addition, ETA receptor blockade was initiated after the development of compensatory hypertrophy in their study and soon after onset of hypertension in our study. Such difference in the type of heart failure and the timing of the initiation of ETA receptor blockade may at least partly explain the difference in the findings.
4.3 Study limitations
A failure in the prevention of the compensatory LV hypertrophy with AT1 or ETA receptor blockade may raise a question whether the administered doses of the antagonists were enough. Although we did not confirm a lack of effects of exogenous AT II or ET-1 during the administration of these antagonists, compensatory hypertrophy was not prevented even with much higher doses of these antagonists in this study (Table 2). Thus, our results cannot be explained by the low doses of the antagonists.
Second, blood pressure was slightly lower at 13 weeks in the rats treated with ETA receptor antagonist than in the untreated rats. If the lower blood pressure had influenced on our data, LV mass should have been lower in the rats treated with ETA receptor antagonist than in the untreated rats. Thus, the lower blood pressure cannot explain a failure in the prevention of compensatory LV hypertrophy by the ETA receptor blockade. Blood pressure after 13 weeks in the rats treated with the ETA receptor antagonist was almost similar to that of the untreated rats. Therefore, we believe that the difference in blood pressure at 13 weeks had little, if any, influence on our conclusions.
Third, effects of the ETB receptor blockade were not investigated in this study. Thus, the current study may overlook roles of ETB receptor-mediated signaling pathway which is a part of ET system.
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5 Conclusions |
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TopAbstract1 Introduction2 Methods3 Results4 Discussion5 ConclusionsReferences |
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We demonstrated that RAS and ET system contribute to the transition to diastolic heart failure through the development of excessive hypertrophy and ventricular fibrosis in hypertensive heart disease, and that neither the RAS nor the ET system is mandatory for compensation for pressure overload. The RAS is likely to provide such effects at least partly through ET system. Activation of the RAS also contributes to LV geometrical alteration toward concentric form and impairment of LV relaxation independently of ET system.
Diastolic heart failure was prevented even in the presence of compensatory component of hypertrophy in the current study, indicating that therapeutic target for diastolic heart failure due to hypertensive heart disease should be focused on the inhibition and/or regression of excessive hypertrophy. AT1 and ETA receptor antagonists may be effective for this purpose.
Time for primary review 22 days.
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Acknowledgements |
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This study was supported in part by research grants from the Ministry of Health and Welfare, Japan, the Ministry of Education, Japan, and the Research for the Future Program (JSPS-RFTF 97100402) supported by the Japanese Society for the Promotion of Science. The authors are grateful to Dr. Naoto Minamino at National Cardiovascular Center, Japan, for the advice on quantitative RT-PCR analysis, to Dr. Masami Imakita at National Cardiovascular Center, Japan, for the valuable comments on pathological data, and finally to Toru Koyama, MD, Ms. Haruka Kobayashi, Ms. Megumi Yoshida, Ms. Hisako Nagata, and Ms. Mayumi Shinzaki for technical assistance of the experiment.
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