(Circulation. 1995;92:2690-2696.)
© 1995 American Heart Association, Inc.
Articles |
Cardiac Renin-Angiotensin System in the Hypertrophied Heart
From the First Department of Internal Medicine, Shiga University of Medical Sciences, Tsukinowa Seta, Ohtsu-city, Shiga-ken, Japan.
Correspondence to Naoharu Iwai, MD, First Department of Internal Medicine, Shiga University of Medical Sciences, Tsukinowa Seta, Ohtsu-city 520-21, Shiga-ken, Japan.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background The cardiac renin-angiotensin system (RAS) has been suggested to play an important role in heart failure and cardiac hypertrophy. In the present study, we evaluated the expression of each component of the RAS in hypertrophied heart induced by aortocaval shunt.
Methods and Results The expression levels of renin,
angiotensinogen, angiotensin-converting
enzyme (ACE), and angiotensin II type Ia and Ib receptor
(AT1aR and AT1bR) mRNA were determined by the reverse
transcription–polymerase chain reaction method owing to the
relatively low expression levels of these mRNAs in the ventricle. The
expression level of renin or angiotensinogen mRNA in the
ventricle was very low, more than 1000-fold lower than that in the
kidney or liver, respectively. The expression of ACE mRNA in the
ventricle was relatively abundant and was increased in the
hypertrophied ventricle in this model, whereas no significant increases
in the expression levels of AT1aR and AT1bR mRNA were observed.
Administration of lisinopril attenuated the development of
left and right ventricular hypertrophy in this
model and was accompanied by an attenuation of the upregulation of the
ACE, collagen type I-
, and vimentin mRNAs. Because the activity of
the circulating RAS in the aortocaval shunt rats was not higher than
that in the sham-operated rats, the effects of
lisinopril in attenuating the ventricular
hypertrophy may be due to inhibition of the increased ACE
in the ventricle.
Conclusions The present study supports the importance of ACE expressed in the ventricle in the development of hypertrophy induced by aortocaval shunt.
Key Words: angiotensin • renin • receptors • genes, hypertrophy
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The favorable effects of ACE inhibitors on heart failure and cardiac hypertrophy have stimulated interest in the possibility that the cardiac RAS plays an important role in these conditions.1 2
Many studies have suggested that angiotensins are produced not only in the circulation but also in local tissues, including kidney, adrenal gland, brain, and heart and in the peripheral vasculature.1 2
The involvement of a cardiac RAS in the pathophysiology of cardiac hypertrophy has been based primarily on the results in a cardiac hypertrophy model by pressure overloading. Increased expression of ACE mRNA has been reported in pressure-overload hypertrophy.3 4 The increased expression of ACE has been suggested to increase the generation of angiotensin II in the hypertrophied ventricle because the administration of converting enzyme inhibitor attenuated the development of ventricular hypertrophy.5 6
The involvement of a cardiac RAS in the pathophysiology of cardiac remodeling after myocardial infarction has also been suggested. Increased expressions of ACE mRNA,7 8 AGT mRNA,9 and AT1R8 have been reported in the scar or the intact part of the infarcted heart. The favorable effects of ACE inhibitors in attenuating ventricular dilatation after myocardial infarction10 may reflect the functional importance of these RAS components expressed in the infarcted heart.
In the present study, we evaluated the expression of each component of the RAS in a hypertrophied heart induced by volume overload. We selected this model because the circulating RAS was supposed not to be activated in this model. In this model, it may be possible to dissociate the systemic hemodynamic effects of ACE inhibition on the left ventricle from the effects of blockade of cardiac ACE. Increased expression of ACE mRNA in the ventricles of the heart was found in this volume-overload model, and the favorable effects of an ACE inhibitor on ventricular weight suggest that this increased ACE expression may have some functional significance.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Animals
Male Sprague-Dawley rats (Charles River) weighing 250 to 300 g at the time of surgery were kept at a controlled room temperature under a 12-hour light regimen of 6 AM to 6 PM and fed regular pelleted rat chow and tap water ad libitum.
In experiments to investigate the effects of drugs on the development of ventricular hypertrophy induced by shunt, hydralazine (10 mg/kg) and lisinopril (10 mg/kg) were dissolved in water and administered orally once a day for 7 days.
AC rats were prepared according to Garcia and Diebold.11 Briefly, the aorta was punctured at the union of a segment two-thirds caudal to the renal artery and one-third cephalic to the aortic bifurcation with an 18-gauge disposable needle. The needle was advanced into the aorta, perforating its adjacent wall and penetrating the vena cava. After the aorta was clamped, the needle was withdrawn, and a drop of cyanoacrylate glue was used to seal the aortic puncture point. The patency of the shunt was verified visually by swelling of the vena cava and mixing of arterial and venous blood. The patency of the fistula shunt was verified the next day with a stethoscope by shunt murmur at the abdomen.
On the day of analysis (1, 7, or 40 days after the operation), rats were anesthetized with pentobarbital, and a PE-50 catheter filled with heparinized saline was inserted into the aorta through the right common carotid artery. Catheters were exteriorized on the necks of the animals. After a 4-hour recovery period, blood pressure was assessed, and blood was collected through the catheter for biochemical analyses.
RNA Isolation and Analysis
RNA was isolated as previously
reported.12 The
quality of RNA analyzed in the present study was confirmed
by ethidium bromide staining and Northern blot analysis of the
expression level of GAPDH, as previously reported.12 The
rat vimentin and collagen type 1- cDNA fragments were isolated from
the cDNA library of fetal rat ventricle by a differential screening
method.13 The expression levels of the renin, AGT, ACE,
and AT1aR and AT1bR mRNAs were determined by the RT-PCR method because
of relatively low expression levels of these mRNAs in the ventricle of
the heart. The expression levels of AT1Rs12 and
renin14 mRNAs were determined as previously described.
Rat
AGT cDNA15 was synthesized by PCR with the following
two primers: 5'-GACCGCGTATACATCCACCCCTTTCATCTC-3'
(nucleotides 73 through 102, exon 2) and
5'-GTCCACCCAGAACTCATGGAGCCCAGTCAG-3' (nucleotides
882 through 853, exon 3). The synthesized rat AGT cDNA fragment was
subcloned into the EcoRV site of pBluescript II KS (+). The
resulting plasmid, designated plasmid A, was cut with BamHI,
blunt-ended with a Klenow fragment of DNA polymerase, and then cut
with Kpn I, which released a Kpn I (in
vector)–BamHI (nucleotide 427, blunt-ended)
cDNA fragment. This cDNA fragment was subcloned into the Kpn
I– and Bal I–cut plasmid A. The resulting plasmid,
designated plasmid B, contained a rat AGT cDNA fragment that lacked a
region from nucleotide 248 to 425. From this plasmid B, a
deletion-mutated cRNA for rat AGT was synthesized with T3 RNA
polymerase as previously reported.12 A known amount
(5x103 molecules) of the deletion-mutated cRNA for rat
AGT was mixed with a sample RNA (1 µg), and this mixture was
converted to cDNAs by RT with random primers. The resulting cDNA
mixture was amplified PCR with the primers described above. An aliquot
of [32P]dCTP was included in the PCR reaction.
Fragments of 810 and 733 bp should be synthesized by PCR from the
native rat AGT mRNA and the deletion-mutated cRNA,
respectively.
The rat ACE cDNA16 fragment was synthesized
by use of the
following two primers: 5'-CCTGATCAACCAGGAGTTTGCAGAG-3'
(nucleotides 279 through 303, exon 2) and
5'-GCCAGCCTTCCCAGGCAAACAGCAC-3' (nucleotides 595 through
571, exon 4). The resulting cDNA fragment was subcloned into the
EcoRV site of pBluescript II KS(+). The resulting plasmid
was cut with Avr II, blunt-ended with Klenow treatment,
and self-ligated. The resulting plasmid contained a rat ACE cDNA
fragment that lacked the Avr II site (nucleotide
400). From this plasmid, a mutated cRNA for rat ACE mRNA was
synthesized as previously reported.12 A known amount
(1.5x106 molecules) of the mutated cRNA for rat ACE
was mixed with a sample RNA (1 µg), and this mixture was converted to
cDNAs by RT with random primers used as a primer. The resulting cDNA
mixture was amplified by PCR with the primers described above.
Fragments of 317 and 321 bp should be synthesized by PCR from the
native rat ACE mRNA and the mutated cRNA, respectively. An aliquot of
[32P]dCTP was included in the PCR. The PCR
products were purified by ethanol precipitation and digested with
Avr II restriction enzyme. Digestion of the PCR product
from the native ACE mRNA should give 195- and 122-bp fragments.
The PCR amplification profile for AGT and ACE included an initial denaturing step at 94°C for 1 minute and 35 cycles for AGT and 31 cycles for ACE at 94°C for 1 minute, 58°C at 1 minute, and 74°C at 2 minutes. The PCR products were electrophoresed on 5% polyacrylamide gel. The expression levels of the mRNAs were calculated according to the following formula:
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where IN and IM represent the intensity of the PCR product from the native mRNA and the mutated cRNA, respectively, and CN and CM represent the content of dCTP in the PCR product from the native mRNA and the mutated cRNA, respectively. The intensity of the PCR products was determined from autoradiography with a densitometer.
Statistical Analysis
Results are expressed as mean±SD.
Statistical analyses
were performed with a one- or two-way ANOVA. Linear regression
analysis was used to study the relations between variables.
Differences were considered statistically significant if
P<.05.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Ventricular Hypertrophy by AC
The LV/W and RV/W in the AC rats were significantly higher than those in the sham-operated rats on days 7 and 40 after the operation (Table 1
). The plasma renin activity and
plasma aldosterone concentration in the AC rats were not
significantly different from those in the sham-operated rats (Table
1). The mean blood pressure in the AC rats was significantly
lower than
that in the sham-operated rats on days 1 and 40. The plasma ANP
concentration was significantly higher in the AC rats than in the
sham-operated rats from day 1. The plasma ACE activities in the AC
rats were not significantly higher than those in the sham-operated
rats.
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Expression Levels of mRNAs for the RAS Components
The
expression levels of the mRNAs for renin, AGT, ACE, and AT1aR
and AT1bR were examined in the left and right ventricles of AC and
sham-operated rats.
Fig 1 shows typical analyses of the
expression
levels of renin, AGT, ACE, and AT1R mRNA in the left ventricles of the
AC and sham-operated rats. The quality of RNA was confirmed by
ethidium bromide staining, in which no degradation of 28s or 18s
ribosomal RNA was observed (data not shown).
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Table 2
gives the expression levels of the mRNA of the
RAS components in the ventricles of the AC and sham-operated rats.
No significant differences in the expression levels of renin, AGT, or
AT1R mRNA were observed between the AC and sham-operated rats on
days 1, 7, and 40. However, the expression levels of ACE mRNA in the
left ventricles of AC rats were significantly higher than those in the
sham-operated rats from day 7. On day 40, the expression levels of
ACE mRNA in the left ventricles of the AC rats were about 3.3 times
higher than those in the sham-operated rats. Fig 2
shows the correlations between the LV/W and expression levels of mRNA
for renin, AGT, ACE, and AT1R in rats on day 7. A significant
correlation was observed only between the expression level of ACE mRNA
and LV/W.
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,
sham-operated rats; 
, AC rats.The expression levels of mRNAs of the RAS components in the right ventricles were also assessed. Again, only the expression levels of ACE mRNA in the AC rats were significantly higher than those in the sham-operated rats on day 7. The expression levels of AGT mRNA in the right ventricles were significantly higher than those in the left ventricles (P=.025, paired t test).
The
expression level of renin mRNA in the ventricle was very low, about
1000-fold lower than that in the kidney (Table 3). The
expression level of AGT mRNA in the ventricle was also very low, about
4000-fold lower than that in the liver (Table 3). On the other
hand,
the expression level of ACE mRNA in the ventricle was relatively high,
only about 20- to 40-fold lower than that in the lung (Table
3). The
expression level of AT1R (AT1a+AT1b) mRNA in the ventricle was also
only about 20-fold lower than that in the liver (Table 3).
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The expression levels of renin mRNA in the kidneys of the AC rats were
not significantly different from those of the sham-operated rats on
day 7 (Table 3
).
Effects of an ACE Inhibitor on LVH
The above results
indicated that the expression levels of ACE mRNA
were increased in AC rats and that circulating RAS activity was not
increased. To investigate the possible functional role of this
increased ACE expression, the effects of the ACE inhibitor
lisinopril on the development of ventricular
hypertrophy by AC were examined (Table 4,
top). The 7-day administration of lisinopril
beginning 1 day after the operation markedly reduced the development of
LVH and RVH (P<.05). Another antihypertensive drug,
hydralazine, had no attenuating effects on the development of
LVH or RVH. No significant differences were observed in the blood
pressure levels among the three groups. Lisinopril had no
significant effects on ventricular weight in the
sham-operated control rats (Table 4, bottom).
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The
upregulation of the expression of ACE, collagen type 1-, and
vimentin mRNA, which was observed in the AC rats, was significantly
attenuated by treatment with an ACE inhibitor (Fig 3 and Table
5). Thus, attenuation of the
development of ventricular hypertrophy in AC
rats by treatment with lisinopril was accompanied by an
attenuation of the upregulation of
hypertrophy-associated genes.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The expression level of ACE mRNA in the ventricle increased with the introduction of AC, although the activity of the circulating RAS was not increased. Administration of the ACE inhibitor lisinopril attenuated the development of LVH induced by AC. These results may be strong evidence of the importance of increased ACE expressed in the hypertrophied ventricle. However, we should evaluate our current results more closely to assess the possible role of a cardiac RAS.
Characteristics of AC Rats
The characteristics of AC rats may
depend on the size of the
AC.17 Notable features of the AC rats in the present
study were that RVH and LVH were evident on day 7, plasma ANP levels
were markedly increased from day 1, and neither plasma renin activity
nor plasma aldosterone concentration was increased, even on
day 40. These characteristics of the AC rats in the present study
indicate that our model reflected stable compensated
hypertrophy and not decompensated heart failure.
Expression Levels of mRNAs of RAS Components
Although the
local generation of angiotensins was
demonstrated previously,1 it remains unclear whether
angiotensins are produced by locally synthesized components
or plasma-borne components of the RAS. It is also unclear which
components of the RAS are rate-limiting in the generation of
angiotensins in peripheral tissues. The
expressions of each component of the RAS (renin, AGT, ACE, AT1aR, and
AT1bR) in the ventricle were confirmed by
others3 9 12 18
and the present study. However, the expression level of renin or
AGT mRNA in the ventricle was very low, <1000-fold lower than that in
the kidney or liver. Therefore, it is unlikely that locally synthesized
renin or AGT influences the local concentration of these substances. In
fact, we recently demonstrated that plasma-derived, but not locally
synthesized, renin contributes to the generation of
angiotensins in the peripheral
vasculature.19 Moreover, Jan Danser et al20
recently reported that angiotensin production in
the ventricle depends on plasma-derived renin and
plasma-derived AGT stored in the interstitial fluid.
The lack of any significant modulation of these genes in hypertrophied
ventricle by AC suggests that these components synthesized in the
ventricles may not play a primary role in the initiation and
maintenance of ventricular hypertrophy
in this model.
On the other hand, the expression level of ACE mRNA in the ventricles was relatively high. In addition, the expression level of ACE mRNA was increased in hypertrophied ventricle by AC. However, this does not necessarily mean that the modulation of ACE expression affects the generation of angiotensins in the ventricle. It has been claimed that the quantity of ACE is vast and is not likely to be rate-limiting. Indeed, plasma angiotensin I is readily converted to angiotensin II in a single pass through the pulmonary circulation. In local tissues, however, the expression level of ACE is not necessarily excessive, and modulation of the expression of ACE may affect the generation of angiotensin II locally. Indeed, Schunkert et al3 reported that an increased cardiac ACE expression caused by pressure overloading of the ventricle by aortic stenosis resulted in an increased intramyocardial conversion of angiotensin I to angiotensin II.
Measuring the angiotensin II
concentration in the
hypertrophied ventricle might provide a definitive answer as to whether
increased ACE in the ventricles of AC rats affects the local generation
of angiotensin II. However, this might prove technically
difficult to accomplish.21 Therefore, as an alternative,
we investigated the effects of lisinopril on the
development of LVH induced by AC. Administration of
lisinopril attenuated the development of LVH and RVH and
was accompanied by the attenuation of upregulation of
hypertrophy-associated genes, such as collagen type
I- and vimentin. No significant reduction in blood pressure was
observed with the administration of lisinopril. The plasma
renin activity and plasma aldosterone concentration in AC
rats were not higher than those in sham-operated rats. No
significant effects of lisinopril on heart weight were
observed in sham-operated rats. Therefore, it is tempting to
speculate that the attenuating effect of lisinopril on
ventricular hypertrophy occurs through the
inhibition of the increased ACE in the ventricles of AC rats. The
increased expression of ACE in the hypertrophied ventricle by AC may
lead to increased angiotensin II generation or bradykinin
degradation and may contribute to the maintenance of
hypertrophy by AC.
No significant increases in the expression levels of the AT1aR and AT1bR mRNAs were observed in the hypertrophied ventricle in the present model. This finding may be in contrast to those observed in a hypertrophied ventricle caused by pressure overloading, in which the increased expression of AT1aR has been reported.22 The expression level of AT1aR mRNA was reportedly higher in cardiac fibroblast than in cardiomyocyte.23 The AC in the present study may not have been sufficient to cause enough fibrosis in the hypertrophied ventricles to increase AT1R mRNA levels.
ACE in Cardiac Tissue and Hypertrophy
Cells responsible for
ACE expression in the cardiac tissue of
infarcted ventricles have been identified as predominantly
fibroblastlike cells that can produce type I collagen.24
Many studies confirmed that ACE binding or activity is anatomically
coincident with connective tissue
formation.8 24 25 Thus,
marked upregulation of ACE mRNA in the AC rats on day 40 may reflect a
progression of fibrosis in the ventricle.
Treatment with lisinopril
markedly attenuated the
development of ventricular hypertrophy in the
AC rats and was accompanied by attenuation of the upregulation of ACE,
collagen type I-, and vimentin mRNA. This indicates that
lisinopril may prevent the proliferation of the
fibroblastlike cells that are responsible for the increased ACE
expression. Angiotensin II is not only a vasoactive peptide
but also a growth-promoting factor and has been reported to promote
fibroblast proliferation.26 27 Bradykinin, on the
other
hand, has been reported to reduce collagen synthesis and augment
collagenase activity in adult cardiac
fibroblast.28 Because angiotensin II
antagonist has been reported to be effective in attenuating
hypertrophy by shunt,17 the mechanism by which
lisinopril attenuates hypertrophy by shunt may
involve primarily its effects in blocking angiotensin II
generation rather than in potentiating bradykinin. In the tissue RAS or
the tissue angiotensin II–generating system, it is not yet
clear what the rate-limiting component is for
angiotensin II generation. The fact that
lisinopril attenuated hypertrophy in the
present AC model in which only the expression levels of ACE mRNA
were increased strongly suggests that increased ACE in the
hypertrophied ventricle may be rate-limiting or at least may have
some effect on the generation of angiotensin II in
situ.
Comparison With Other Studies on AC
Recently, Ruzicka et
al17 showed that the
angiotensin II receptor antagonist
losartan but not the ACE inhibitor enalapril
attenuated the development of ventricular
hypertrophy by AC and suggested the presence of an
alternative pathway for the generation of angiotensin II.
However, subsequent studies29 by the same authors showed
that the efficacy of ACE inhibitors in attenuating
ventricular hypertrophy by AC seems to depend
on their efficacy in cardiac ACE inhibition. Because enalapril shows
only minimal and short-lived inhibition of cardiac ACE, it failed
to attenuate the development of ventricular
hypertrophy by shunt. On the other hand, quinapril, which
markedly inhibits cardiac ACE, could attenuate the development of
hypertrophy by shunt, even though it has
hemodynamic effects similar to those of enalapril.
Because lisinopril has effects on the inhibition of cardiac
ACE that are almost identical to those of quinapril,30 our
finding that lisinopril was effective in attenuating
hypertrophy by shunt is consistent with those of
Ruzicka and Leenen.29
Study Limitations
As noted earlier regarding the
characteristics of the AC rats in
the present study, the model in the present study reflects
stable compensated hypertrophy, not decompensated heart
failure. In this AC fistula model of stable compensated
hypertrophy, only the expression of ACE mRNA was increased,
and no significant modulation of the expression of other RAS components
was observed. However, this may not apply to decompensated heart
failure or other types of ventricular
hypertrophy. In fact, the expression of renin mRNA was
temporarily markedly increased in the ventricles of
isoproterenol-induced myocardial necrosis (our unpublished
observation).
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by a grant-in-aid from the Japanese Ministry of Education, Science, and Culture.
Received November 30, 1994; revision received March 13, 1995; accepted May 25, 1995.
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References |
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TopAbstractIntroductionMethods Results Discussion References |
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W. S. Akers and L. A. Cassis Presynaptic modulation of evoked NE release contributes to sympathetic activation after pressure overload Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2151 - H2158. [Abstract] [Full Text] [PDF]
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C. E Huggins, A. A Domenighetti, T. Pedrazzini, S. Pepe, and L. M. Delbridge Elevated intracardiac angiotensin II leads to cardiac hypertrophy and mechanical dysfunction in normotensive mice Journal of Renin-Angiotensin-Aldosterone System, September 1, 2003; 4(3): 186 - 190. [Abstract] [PDF]
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D. Schultz, X. Su, C.-C. Wei, S. P. Bishop, P. Powell, G. H. Hankes, A. R. Dillon, P. Rynders, F. G. Spinale, G. Walcott, et al. Downregulation of ANG II receptor is associated with compensated pressure-overload hypertrophy in the young dog Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H749 - H756. [Abstract] [Full Text] [PDF]
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S. M. Dolgilevich, F. M. Siri, S. A. Atlas, and C. Eng Changes in collagenase and collagen gene expression after induction of aortocaval fistula in rats Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H207 - H214. [Abstract] [Full Text] [PDF]
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G. J. Perry, T. Mori, C.-C. Wei, X. Y. Xu, Y.-F. Chen, S. Oparil, P. Lucchesi, and L. J. Dell'Italia Genetic Variation in Angiotensin-Converting Enzyme Does Not Prevent Development of Cardiac Hypertrophy or Upregulation of Angiotensin II in Response to Aortocaval Fistula Circulation, February 20, 2001; 103(7): 1012 - 1016. [Abstract] [Full Text] [PDF]
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H. Yamakawa, T. Imamura, T. Matsuo, H. Onitsuka, Y. Tsumori, J. Kato, K. Kitamura, Y. Koiwaya, and T. Eto Diastolic wall stress and ANG II in cardiac hypertrophy and gene expression induced by volume overload Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2939 - H2946. [Abstract] [Full Text] [PDF]
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P. A. Modesti, S. Vanni, I. Bertolozzi, I. Cecioni, G. Polidori, R. Paniccia, B. Bandinelli, A. Perna, P. Liguori, M. Boddi, et al. Early sequence of cardiac adaptations and growth factor formation in pressure- and volume-overload hypertrophy Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H976 - H985. [Abstract] [Full Text] [PDF]
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K. C Wollert and H. Drexler The renin-angiotensin system and experimental heart failure Cardiovasc Res, September 1, 1999; 43(4): 838 - 849. [Abstract] [Full Text] [PDF]
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A. T. Hirsch, J. A. Opsahl, M. M. Lunzer, and S. A. Katz Active renin and angiotensinogen in cardiac interstitial fluid after myocardial infarction Am J Physiol Heart Circ Physiol, June 1, 1999; 276(6): H1818 - H1826. [Abstract] [Full Text] [PDF]
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M. Nishimura, K. Ohtsuka, N. Iwai, H. Takahashi, and M. Yoshimura Regulation of brain renin-angiotensin system by benzamil-blockable sodium channels Am J Physiol Regulatory Integrative Comp Physiol, May 1, 1999; 276(5): R1416 - R1424. [Abstract] [Full Text] [PDF]
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K. Harada, I. Komuro, Y. Zou, S. Kudoh, K. Kijima, H. Matsubara, T. Sugaya, K. Murakami, and Y. Yazaki Acute Pressure Overload Could Induce Hypertrophic Responses in the Heart of Angiotensin II Type 1a Knockout Mice Circ. Res., April 20, 1998; 82(7): 779 - 785. [Abstract] [Full Text] [PDF]
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Y. Sumida, S. Umemura, K. Tamura, M. Kihara, S.-i. Kobayashi, T. Ishigami, M. Yabana, N. Nyui, H. Ochiai, A. Fukamizu, et al. Increased Cardiac Angiotensin II Receptors in Angiotensinogen-Deficient Mice Hypertension, January 1, 1998; 31(1): 45 - 49. [Abstract] [Full Text]
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M. van Bilsen Signal transduction revisited: recent developments in angiotensin II signaling in the cardiovascular system Cardiovasc Res, December 1, 1997; 36(3): 310 - 322. [Full Text] [PDF]
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J. Fareh, R. M. Touyz, E. L. Schiffrin, and G. Thibault Cardiac Type-1 Angiotensin II Receptor Status in Deoxycorticosterone Acetate–Salt Hypertension in Rats Hypertension, November 1, 1997; 30(5): 1253 - 1259. [Abstract] [Full Text]
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J. Pan, K. Fukuda, H. Kodama, S. Makino, T. Takahashi, M. Sano, S. Hori, and S. Ogawa Role of Angiotensin II in Activation of the JAK/STAT Pathway Induced by Acute Pressure Overload in the Rat Heart Circ. Res., October 19, 1997; 81(4): 611 - 617. [Abstract] [Full Text]
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E. Balcells, Q. C. Meng, W. H. Johnson Jr., S. Oparil, and L. J. Dell'Italia Angiotensin II formation from ACE and chymase in human and animal hearts: methods and species considerations Am J Physiol Heart Circ Physiol, October 1, 1997; 273(4): H1769 - H1774. [Abstract] [Full Text] [PDF]
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N. Iwai, M. Izumi, T. Inagami, and M. Kinoshita Induction of Renin in Medial Smooth Muscle Cells by Balloon Injury Hypertension, April 1, 1997; 29(4): 1044 - 1050. [Abstract] [Full Text]
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A. Luchner, T. L. Stevens, D. D. Borgeson, M. M. Redfield, J. E. Bailey, S. M. Sandberg, D. M. Heublein, and J. C. Burnett Angiotensin II in the Evolution of Experimental Heart Failure Hypertension, September 1, 1996; 28(3): 472 - 477. [Abstract] [Full Text]
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