(Circulation. 2001;103:148.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Effects of Combination of ACE Inhibitor and Angiotensin Receptor Blocker on Cardiac Remodeling, Cardiac Function, and Survival in Rat Heart Failure
From the Department of Pharmacology (S.K., Y.I., H.K., M.K., Y.Z., H.I.) and Department of Medicine, Division of Cardiology (M.Y.), Osaka City University Medical School, Osaka, Japan.
Correspondence to Shokei Kim, MD, PhD, Department of Pharmacology, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan. E-mail kims{at}med.osaka-cu.ac.jp
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Abstract |
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Background—The mechanism and treatment of diastolic heart failure are poorly understood. We compared the effects of an ACE inhibitor, an angiotensin receptor blocker (ARB), and their combination on diastolic heart failure in Dahl salt-sensitive (DS) rats.
Methods and Results—DS rats fed an 8% NaCl diet from 7 weeks of age were treated with benazepril 10 mg/kg alone, valsartan 30 mg/kg alone, or combined benazepril and valsartan at 5 and 15 mg/kg, respectively, or at 1 and 3 mg/kg, respectively. At 16 weeks of age, DS rats exhibited prominent concentric left ventricular (LV) hypertrophy and diastolic dysfunction with preserved systolic function, as estimated by echocardiography. Despite comparable hypotensive effects among all drug treatments, the combination of benazepril 5 mg/kg and valsartan 15 mg/kg improved diastolic dysfunction and survival in DS rats more effectively than ACE inhibitor or ARB alone. Furthermore, the increase in LV endothelin-1 levels and hydroxyproline contents in DS rats was significantly suppressed only by combined benazepril and valsartan, and LV atrial natriuretic peptide mRNA upregulation in DS rats was suppressed to a greater extent by the combination therapy than monotherapy.
Conclusions—The combination of ACE inhibitor and ARB, independently of the hypotensive effect, improved LV phenotypic change and increased LV endothelin-1 production and collagen accumulation, diastolic dysfunction, and survival in a rat heart failure model more effectively than either agent alone, thereby providing solid experimental evidence that the combination of these 2 agents is more beneficial than monotherapy for treatment of heart failure.
Key Words: heart failure • angiotensin • survival
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Accumulating evidence supports the notion that angiotensin AT1 receptor blockers (ARBs) have nearly the same favorable effects as ACE inhibitors on cardiac hypertrophy, remodeling, and function or heart failure.1 2 3 4 5 However, pharmacological profiles are substantially different between ARB and ACE inhibitors, because ARB can inhibit the action of angiotensin II (Ang II) generated through not only ACE but also the alternative pathways,6 whereas ACE inhibitors block the breakdown of bradykinin.7 Thus, combination therapy with ACE inhibitor and ARB may offer benefits beyond those of either agent alone. In fact, combined administration of ACE inhibitor and ARB is shown to decrease blood pressure in hypertensive rats8 9 and normotensive volunteers10 and improve cardiac function or hemodynamic status in pacing-induced pig heart failure11 and postischemic rat heart failure12 more than either intervention alone. Furthermore, several recent pilot clinical studies suggest that the combination of ACE inhibitor and ARB may be more beneficial in heart failure than either agent alone.13 14 15 As yet, however, the usefulness of combination therapy with these 2 agents in heart failure has not been demonstrated, and the pharmacological mechanism underlying the benefit of the combination therapy is not defined.
Despite advances in pharmacological therapy for congestive heart failure, mortality due to heart failure remains high. Diastolic heart failure in particular, which is caused by left ventricular (LV) diastolic dysfunction without systolic dysfunction and constitutes 30% to 50% of heart failure,16 has a poor prognosis.17 A specific therapeutic strategy for diastolic heart failure has not yet been established. Dahl salt-sensitive (DS) rats are shown to develop not only hypertension18 but also heart failure19 20 by a high-salt loading. A recent study showed that DS rats fed an 8% NaCl diet from 7 weeks of age develop LV diastolic dysfunction with preserved systolic function and die of congestive heart failure.20 In the present study, using this model, we compared in detail the effects of ACE inhibitor, ARB, and a combination of the 2 on diastolic heart failure. We obtained evidence that the combination of ACE inhibitor and ARB may be a potent therapeutic strategy for treatment of diastolic heart failure.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Experimental Animals and Protocol
All procedures were in accordance with institutional guidelines for animal research. DS rats (DIS/Eis, Eisai, Tokyo, Japan) were used in the present study. After weaning, DS rats were fed a 0.3% NaCl (low-salt) diet until 7 weeks of age. At 7 weeks of age, they were switched to an 8% NaCl diet. The rats were divided into 5 groups and treated with (1) vehicle (0.5% carboxymethylcellulose solution), (2) benazepril 10 mg · kg-1 · d-1, (3) valsartan 30 mg · kg-1 · d-1, (4) combined benazepril 5 mg · kg-1 · d-1 and valsartan 15 mg · kg-1 · d-1, and (5) combined benazepril 1 mg · kg-1 · d-1 and valsartan 3 mg · kg-1 · d-1. All drugs were given to DS rats orally by gastric gavage once a day until 16 weeks of age. Systolic blood pressure of conscious rats was periodically measured by the tail-cuff method at 4 to 5 hours after oral dosing, when these drugs exhibited the maximal hypotensive effects. At 10 and 14 weeks of age, DS rats were housed individually in metabolic cages, and 24-hour urine was collected in a flask containing 6N HCl for measurement of catecholamine concentrations. At 16 weeks of age, under ether anesthesia, arterial blood was immediately collected via the abdominal aorta, and plasma was collected by centrifugation and stored at -80°C until use. The heart was immediately excised, the LV was separated from the atria and the right ventricle, and they were weighed, immediately frozen in liquid nitrogen, and stored at -80°C until use.
Echocardiographic Study
Transthoracic echocardiographic studies were
performed on 16-week-old DS rats with an echocardiographic system
equipped with a 12.0-MHz phased-array transducer (SONOS 5500; Agilent
Technology) as previously described in
detail.21 In brief, rats
were lightly anesthetized with intraperitoneal injection of ketamine
HCl (25 to 50 mg/kg) and xylazine (5 to 10 mg/kg). M-mode tracings were
recorded through the anterior and posterior LV walls at the papillary
muscle level to measure LV end-diastolic dimension, fractional
shortening, LV anterior wall thickness at end diastole, and posterior
wall thickness at end diastole. To calculate LV end-diastolic volume
and LV ejection fraction, end-diastolic and end-systolic areas were
obtained from the 4-chamber view, as
described.21 Pulse-wave
Doppler spectra (E and A waves) of mitral inflow were recorded from the
apical 4-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.
RNA Preparation and Northern Blot
Analysis
All procedures were performed as described in detail
in our previous
reports.9 22 In
brief, 20 µg of total RNA samples from individual LVs were subjected
to 1% agarose gel electrophoresis and transferred to nylon membranes,
and hybridization was carried out with
[32P]dCTP-labeled cDNA probe for atrial
natriuretic peptide (ANP), brain natriuretic peptide (BNP), collagen
type I, GAPDH, or with an oligonucleotide probe complementary to
-myosin heavy chain (MHC) (5'-TTGTGGGATAGCAACAGCGA-3').
The densities of an individual mRNA band were measured with a
bioimaging analyzer (BAS-2000, Fuji Photo Film
Co).
Measurement of Cardiac Endothelin-1
Levels
LV endothelin-1 (ET-1) contents were measured by a
minor modification of the method of Iwanaga et
al.23 In brief, LV tissue
was homogenized with a Polytron homogenizer in 10 volumes of 1 mol/L
acetic acid containing 0.1% Triton-X, boiled for 7 minutes, and
centrifuged at 20 000g for 30
minutes at 4°C. ET-1 peptide was extracted from the resulting
supernatant with a Sep-Pak C18 cartridge and measured by means of a
sandwich enzyme immunoassay kit (Immuno-Biological Laboratories). The
sensitivity of this enzyme immunoassay kit was 0.78 pg/mL, and the
cross-reactivities with ET-3 and big ET-1 were both
<0.1%.
Biochemical Measurement
To estimate cardiac collagen content, tissue
hydroxyproline content was determined by hydrolysis of the sample with
HCl followed by high-performance liquid chromatography (HPLC). Urinary
catecholamines were measured by HPLC with an automated HPLC
analyzer.
Effect on Survival Rate
To examine the effect on survival, 7-week-old DS rats
were fed an 8% NaCl diet and were subjected to each drug treatment, as
described in Results. Animals were carefully monitored, and deaths were
recorded every day. Survival rates were compared among groups at 20
weeks after the start of drug treatment.
Statistics
Results were expressed as mean±SEM. The data on
blood pressure were analyzed by 2-way ANOVA, and the differences
between each group at each time point were determined by the
least-squares mean test. For other data, statistical significance was
determined by 1-way ANOVA followed by Duncan’s multiple range test.
Survival was analyzed by the standard Kaplan-Meier analysis with
log-rank test and 
2 analysis. In all
tests, differences were considered statistically significant at a value
of
P<0.05.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Blood Pressure and Cardiac Weight
As shown in Figure 1
, DS rats fed a high-salt diet (8% NaCl) from 7
weeks of age progressively developed hypertension. All drug treatments
reduced blood pressure of DS rats to only a slight extent and to a
comparable degree.
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As shown in
Table 1, LV weight in 16-week-old DS rats fed a
high-salt diet was larger than in those fed a low-salt diet
(P<0.01). LV weight, corrected
for body weight, of DS rats was significantly reduced by all drug
treatments
(P<0.01).
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Cardiac Phenotype–Related Gene
Expression
As shown in
Figure 2, LV -MHC mRNA levels in DS rats fed a high-salt
diet were significantly decreased, and this decrease was normalized by
the drug treatments, except for benazepril 10 mg/kg. LV ANP mRNA levels
in DS rats fed a high-salt diet were 33-fold
(P<0.01) larger than in those
fed a low-salt diet. All drug treatments significantly reduced LV ANP
mRNA levels in DS rats. However, the combination of benazepril 5 mg/kg
and valsartan 15 mg/kg suppressed the upregulation of LV ANP to a
greater extent than any other drug treatments
(P<0.05). LV BNP mRNA levels
in DS rats were increased by 3.2-fold by a high-salt diet, and this
increase was significantly
(P<0.01) and comparably
inhibited by all drug treatments.
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P<0.05, *P<0.01 vs Veh.
Cardiac Collagen Gene Expression and
Hydroxyproline Content
As shown in
Figure 3A, LV collagen type I mRNA levels were increased in
DS rats fed a high-salt diet, which was significantly decreased by all
drug treatments.
Figure 3B indicates that LV hydroxyproline contents in DS
rats fed a high-salt diet were 2.4-fold higher than those fed a
low-salt diet (3.69±0.46 versus 1.56±0.12 µmol/g tissue,
P<0.01). Only the combination
of benazepril 5 mg/kg and valsartan 15 mg/kg significantly decreased LV
hydroxyproline contents in DS rats (2.34±0.28 µmol/g tissue,
P<0.05).
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Cardiac ET-1 Content
Figure 4 indicates LV ET-1 levels in each group of DS rats.
Sixteen-week-old DS rats fed a high-salt diet had 2.2-fold higher LV
ET-1 levels than those fed a low-salt diet (1085±71 versus 485±43
pg/g tissue, P<0.01). This
increase in LV ET-1 levels was significantly suppressed only by the
combination of benazepril 5 mg/kg and valsartan 15 mg/kg (812±50 pg/g
tissue,
P<0.05).
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Echocardiographic Analysis
As shown in
Figure 5, E/A in 16-week-old DS rats fed a high-salt diet
was 5.4-fold greater than those fed a low-salt diet (7.63±0.75 versus
1.41±0.06, P<0.01). All drug
treatments significantly prevented the increase in E/A
(P<0.01). However, the
normalization of E/A by combined benazepril 5 mg/kg and valsartan 15
mg/kg (1.86±0.20) was greater than that by any other drug treatments.
Table 2 indicates that there was no difference in LV
end-diastolic dimension, fractional shortening, LV end-diastolic
volume, or LV ejection fraction among all groups of DS rats. Anterior
and posterior wall thicknesses at end diastole in DS rats were
increased by a high-salt diet, and this increase was not affected by
any drug treatments.
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Urinary Catecholamine Excretions
At 10 weeks of age, 24-hour urinary norepinephrine and
epinephrine excretions were not different between DS rats fed a
high-salt and a low-salt diet and were not affected by any drug
treatments (data not shown). However, as shown in
Figure 6, 14-week-old DS rats fed a high-salt diet had a
1.7-fold greater urinary norepinephrine excretion than those fed a
low-salt diet (2.25±0.35 versus 1.33±0.10 µg/d,
P<0.01). This increase in
norepinephrine excretion was significantly and similarly prevented by
all drug treatments. There was no difference in 24-hour urinary
epinephrine excretion among all groups of DS rats at 14 weeks of
age.
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Survival Rate
Survival rate was analyzed at 20 weeks (140 days) after
start of drug treatment
(Figure 7). All vehicle-treated DS rats fed a high-salt diet
died of congestive heart failure between 49 and 120 days. The
Kaplan-Meier survival analysis showed that all drug treatments
statistically significantly prolonged survival rate of DS rats, and
there was no significant difference in improvement of survival among
benazepril alone at 2 or 10 mg/kg, valsartan alone at 6 or 30 mg/kg,
and combined benazepril 1 mg/kg and valsartan 3 mg/kg. However, the
combination of benazepril 5 mg/kg and valsartan 15 mg/kg improved
survival of DS rats more significantly than all monotherapies with
benazepril 2 (P<0.01) or 10
(P<0.01) mg/kg or valsartan 6
(P<0.01) or 30
(P<0.05) mg/kg and the
combination of benazepril 1 mg/kg and valsartan 3 mg/kg
(P<0.05).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Our present work provided solid experimental evidence that combination therapy with ACE inhibitor and ARB is more beneficial than each agent alone for treatment of heart failure.
It has been well established that DS rats fed 8% NaCl diet develop overt heart failure and die of congestive heart failure.19 20 Interestingly, the initiation of 8% NaCl diet in DS rats from 7 weeks of age produces diastolic heart failure with preserved systolic function.20 Although heart failure due to diastolic dysfunction often occurs in humans, the mechanism of diastolic heart failure is poorly understood.16 17 Despite the poor prognosis, a useful and specific therapeutic strategy for diastolic heart failure has not yet been established.24 Therefore, in this study, to investigate whether the combination of ACE inhibitor and ARB is beneficial for treatment of diastolic heart failure, we used DS rats fed a high-salt diet from 7 weeks of age.
As indicated by echocardiography, despite the lack of
systolic dysfunction or LV dilatation, DS rats had significant
diastolic dysfunction, as shown by the significant increase in E/A, and
died of congestive heart failure. The present findings are in good
agreement with the previous
report.20 In this study, we
found that either ACE inhibitor or ARB significantly improved E/A and
prolonged survival in heart failure of DS rats. Notably, despite there
being no additive hypotensive effect, the combination of ACE inhibitor
and ARB improved E/A to a greater extent than monotherapy with either
agent, being associated with more improvement of survival by the
combination therapy
(Figure 7
). Thus, our present work supports the theory that
combination therapy with these 2 agents is a useful therapeutic
strategy for treatment of congestive heart failure.
In this study, we found that DS rats with diastolic
dysfunction exhibited not only concentric LV hypertrophy but also
myocyte phenotypic modulation, as shown by the upregulation of fetal
genes such as ANP and BNP and the reciprocal downregulation of -MHC
(adult isoform of MHC). Interestingly, the combination therapy
suppressed LV ANP mRNA expression to a larger extent than monotherapy,
suggesting that the combination therapy may be more effective for
normalization of cardiac phenotypic modulation in pathological cardiac
hypertrophy.
LV collagen contents were significantly increased in DS rats with diastolic dysfunction. Given that collagen accumulation is responsible for cardiac stiffness,25 diastolic dysfunction in DS rats seems to be explained at least in part by the increased LV collagen accumulation. It is noteworthy that only the combination of ACE inhibitor and ARB significantly decreased LV collagen contents in DS rats. This reduction of LV collagen contents seems to be due to the change in the synthesis rate or the degradation rate rather than the transcription rate, because LV collagen mRNA levels were comparably reduced by all drug treatments, and either the synthesis rate or the degradation rate plays an important role in the metabolism of LV collagen.26 Therefore, more improvement of heart failure by the combination therapy may be mediated in part by the reduction of LV collagen accumulation. However, further study is needed to demonstrate our proposal.
Iwanaga et al23 produced DS rats with systolic heart failure by starting a high-salt diet from 6 weeks of age and examined the role of LV ET-1 in systolic heart failure of DS rats. These investigators demonstrated that LV ET-1 plays a critical role in the development of systolic heart failure in DS rats fed a high-salt diet from 6 weeks of age. Furthermore, LV ET-1 is also involved in the development of heart failure induced by myocardial infarction or hemodynamic overload.27 Therefore, in the present study, we measured LV ET-1 levels in DS rats with diastolic LV dysfunction. We found that as in DS rats with the phenotype of systolic heart failure,23 LV ET-1 contents were significantly increased in DS rats with the phenotype of diastolic heart failure. Very importantly, this increase in LV ET-1 was significantly prevented only by the combination of ACE inhibitor and ARB. These findings, taken together with the fact that ET-1 has toxic effects on cardiac myocytes,28 induces cardiac fetal gene expression,29 and stimulates cardiac collagen synthesis,30 support the notion that the reduction of LV ET-1 levels by the combination therapy in this study may be involved in the amelioration of heart failure.
Solid evidence indicates that Ang II directly stimulates LV ANP gene expression,31 ET-1 production,32 and collagen accumulation33 via AT1 receptor independently of its hypertensive effect, as reviewed.2 Therefore, in this study, the mechanism underlying the greater suppression of LV ANP gene expression, ET-1 production, and collagen accumulation in DS rats by combined ACE inhibitor and ARB than by either agent alone may be explained by more potent inhibition of Ang II–mediated AT1 receptor activation itself by the combination therapy. However, ACE inhibitor is well known to increase tissue bradykinin accumulation, and bradykinin has antigrowth effects and reduces vasomotor tone.7 Therefore, the possibility cannot be excluded that the accumulation of bradykinin by ACE inhibitor might participate in the present beneficial effects of the combination therapy in DS rats. Conversely, unlike ACE inhibitor, ARB increases circulating Ang II levels, leading to the stimulation of AT2 receptor, which has antigrowth effects.1 34 However, unlike treatment with ARB alone, the combination with ACE inhibitor suppresses plasma Ang II elevation induced by ARB,8 indicating that AT2 receptor activation caused by ARB alone is nullified by the combination with ACE inhibitor. Therefore, it is unlikely that AT2 receptor might contribute to the beneficial effects of the combination therapy in the present study. However, further work is needed to elucidate more detailed mechanisms responsible for the beneficial effects of the combination therapy in heart failure.
Study Limitations
DS rats fed a high-salt diet are a useful and unique
diastolic heart failure
model.20 However, the
characteristics of heart failure in DS rats are very complex, and
several study limitations are raised. Because E/A can be affected by
loading conditions as well as diastolic function, the improvement of
E/A by the drug treatments might be partially mediated by the
improvement of loading conditions. A high-salt diet significantly
reduced body weight of DS rats, and this decrease was prevented by the
drug treatments, which did not allow us to accurately estimate the
effect of drug therapy on cardiac hypertrophy. DS rats develop renal
dysfunction as well as heart failure. Therefore, the improvement of
survival by the drug treatments might be partially due to the
amelioration of renal dysfunction. Furthermore, a possible role of the
sympathetic nervous system cannot be completely excluded in the present
study, because urinary norepinephrine excretion in DS rats was
significantly reduced by the drug treatments, and the sympathetic
nervous system is responsible for the development of heart
failure.35
Conclusions
In conclusion, we examined the effects of ACE
inhibitor, ARB, and their combination on cardiac hypertrophy,
remodeling, gene expression, ET-1 levels, cardiac function, and
survival rate in a rat diastolic heart failure model. Our present study
provided evidence that either ACE inhibitor or ARB has beneficial
effects on diastolic heart failure but that their combination has more
beneficial effect than either agent alone. Thus, we propose that the
combination of ACE inhibitor and ARB may be a potent therapeutic
strategy for treatment of heart failure in
humans.
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Acknowledgments |
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This work was supported in part by a Grant-in-Aid for Scientific Research (09470527) from the Ministry of Education, Science, and Culture.
Received May 3, 2000; revision received July 18, 2000; accepted July 20, 2000.
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 L. J. Ellmers, N. J. A. Scott, S. Medicherla, A. P. Pilbrow, P. G. Bridgman, T. G. Yandle, A. M. Richards, A. A. Protter, and V. A. Cameron Transforming Growth Factor-{beta} Blockade Down-Regulates the Renin-Angiotensin System and Modifies Cardiac Remodeling after Myocardial Infarction Endocrinology, November 1, 2008; 149(11): 5828 - 5834. [Abstract] [Full Text] [PDF]
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M. Nishio, Y. Sakata, T. Mano, T. Ohtani, Y. Takeda, T. Miwa, M. Hori, T. Masuyama, T. Kondo, and K. Yamamoto Beneficial effects of bisoprolol on the survival of hypertensive diastolic heart failure model rats Eur J Heart Fail, May 1, 2008; 10(5): 446 - 453. [Abstract] [Full Text] [PDF]
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 R. Choudhary, A. Palm-Leis, R. C. Scott III, R. S. Guleria, E. Rachut, K. M. Baker, and J. Pan All-trans retinoic acid prevents development of cardiac remodeling in aortic banded rats by inhibiting the renin-angiotensin system Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H633 - H644. [Abstract] [Full Text] [PDF]
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 E. Yamamoto, K. Kataoka, H. Shintaku, T. Yamashita, Y. Tokutomi, Y.-F. Dong, S. Matsuba, H. Ichijo, H. Ogawa, and S. Kim-Mitsuyama Novel Mechanism and Role of Angiotensin II Induced Vascular Endothelial Injury in Hypertensive Diastolic Heart Failure Arterioscler Thromb Vasc Biol, December 1, 2007; 27(12): 2569 - 2575. [Abstract] [Full Text] [PDF]
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 E. Yamamoto, K. Kataoka, T. Yamashita, Y. Tokutomi, Y.-F. Dong, S. Matsuba, H. Ogawa, and S. Kim-Mitsuyama Role of Xanthine Oxidoreductase in the Reversal of Diastolic Heart Failure by Candesartan in the Salt-Sensitive Hypertensive Rat Hypertension, October 1, 2007; 50(4): 657 - 662. [Abstract] [Full Text] [PDF]
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 Y. Okura, Y. Nakashima, H. Tojo, E. Tashiro, and K. Saku Valsartan, an Angiotensin II Type-I Receptor Blocker, and Left Ventricular Diastolic Function: A Case Report Angiology, July 1, 2005; 56(4): 467 - 473. [Abstract] [PDF]
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A. Pourdjabbar, T. G. Parker, Q. T. Nguyen, J.-F. Desjardins, N. Lapointe, J. N. Tsoporis, and J.-L. Rouleau Effects of pre-, peri-, and postmyocardial infarction treatment with losartan in rats: effect of dose on survival, ventricular arrhythmias, function, and remodeling Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1997 - H2005. [Abstract] [Full Text] [PDF]
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 H. Okada, Y. Watanabe, T. Kikuta, T. Kobayashi, Y. Kanno, T. Sugaya, and H. Suzuki Bradykinin Decreases Plasminogen Activator Inhibitor-1 Expression and Facilitates Matrix Degradation in the Renal Tubulointerstitium under Angiotensin-Converting Enzyme Blockade J. Am. Soc. Nephrol., September 1, 2004; 15(9): 2404 - 2413. [Abstract] [Full Text] [PDF]
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 Y.-H. Liu, X.-P. Yang, E. G. Shesely, S. S. Sankey, and O. A. Carretero Role of angiotensin II type 2 receptors and kinins in the cardioprotective effect of angiotensin II type 1 receptor antagonists in rats with heart failure J. Am. Coll. Cardiol., April 21, 2004; 43(8): 1473 - 1480. [Abstract] [Full Text] [PDF]
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J. Yoshida, K. Yamamoto, T. Mano, Y. Sakata, N. Nishikawa, M. Nishio, T. Ohtani, T. Miwa, M. Hori, and T. Masuyama AT1 Receptor Blocker Added to ACE Inhibitor Provides Benefits at Advanced Stage of Hypertensive Diastolic Heart Failure Hypertension, March 1, 2004; 43(3): 686 - 691. [Abstract] [Full Text] [PDF]
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 M. O. Boluyt, K. Converso, H. S. Hwang, A. Mikkor, and M. W. Russell Echocardiographic assessment of age-associated changes in systolic and diastolic function of the female F344 rat heart J Appl Physiol, February 1, 2004; 96(2): 822 - 828. [Abstract] [Full Text] [PDF]
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D. Jin, S. Takai, M. Yamada, M. Sakaguchi, K. Kamoshita, K. Ishida, Y. Sukenaga, and M. Miyazaki Impact of chymase inhibitor on cardiac function and survival after myocardial infarction Cardiovasc Res, November 1, 2003; 60(2): 413 - 420. [Abstract] [Full Text] [PDF]
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T. Nishikimi, F. Yoshihara, S. Horinaka, N. Kobayashi, Y. Mori, K. Tadokoro, K. Akimoto, N. Minamino, K. Kangawa, and H. Matsuoka Chronic Administration of Adrenomedullin Attenuates Transition From Left Ventricular Hypertrophy to Heart Failure in Rats Hypertension, November 1, 2003; 42(5): 1034 - 1041. [Abstract] [Full Text] [PDF]
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H. Sato, H. Yaoita, K. Maehara, and Y. Maruyama Attenuation of heart failure due to coronary stenosis by ACE inhibitor and angiotensin receptor blocker Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H359 - H368. [Abstract] [Full Text] [PDF]
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T. Sugie, Y. Kagaya, M. Takeda, H. Yahagi, C. Takahashi, J. Takahashi, M. Ninomiya, J. Watanabe, R. Ichinohasama, F. Tezuka, et al. Should increasing the dose or adding an AT1 receptor blocker follow a relatively low dose of ACE inhibitor initiated in acute myocardial infarction? Cardiovasc Res, June 1, 2003; 58(3): 611 - 620. [Abstract] [Full Text] [PDF]
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Y. Sakata, K. Yamamoto, T. Mano, N. Nishikawa, J. Yoshida, T. Miwa, M. Hori, and T. Masuyama Temocapril prevents transition to diastolic heart failure in rats even if initiated after appearance of LV hypertrophy and diastolic dysfunction Cardiovasc Res, March 1, 2003; 57(3): 757 - 765. [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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S. Kim, Y. Izumi, Y. Izumiya, Y. Zhan, M. Taniguchi, and H. Iwao Beneficial Effects of Combined Blockade of ACE and AT1 Receptor on Intimal Hyperplasia in Balloon-Injured Rat Artery Arterioscler Thromb Vasc Biol, August 1, 2002; 22(8): 1299 - 1304. [Abstract] [Full Text] [PDF]
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W. Zhang Old and new tools to dissect calcineurin's role in pressure-overload cardiac hypertrophy Cardiovasc Res, February 1, 2002; 53(2): 294 - 303. [Abstract] [Full Text] [PDF]
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