(Circulation. 1995;92:3568-3573.)
© 1995 American Heart Association, Inc.
Articles |
Effects of ACE Inhibitors on Circulating Versus Cardiac Angiotensin II in Volume OverloadInduced Cardiac Hypertrophy in Rats
From the Hypertension Unit, University of Ottawa Heart Institute, Ontario, Canada.
Correspondence to Dr Frans H.H. Leenen, Hypertension Unit Room H360, University of Ottawa Heart Institute, 1053 Carling Ave, Ottawa, Ontario, K1Y 4E9 Canada.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Cardiac volume overload by an aortocaval shunt increases left ventricular end-diastolic pressure (LVEDP) and plasma and cardiac renin activity and results in LV hypertrophy. To a similar extent, the angiotensin-converting enzyme (ACE) inhibitors enalapril and quinapril prevent the increase in LVEDP. However, only quinapril attenuates the development of LV hypertrophy. We hypothesize that a low affinity of enalapril for cardiac ACE results in continuing generation of cardiac angiotensin II and thus hypertrophic growth of cardiomyocytes.
Methods and Results In the present study, we assessed plasma and cardiac angiotensins I and II 1 and 7 days after aortocaval shunt and the effects of enalapril and quinapril started 3 days before surgery on plasma and cardiac angiotensin I and II at the same time points. Aortocaval shunt increased plasma angiotensin II at 1 day by 180%, but only a small increase (by 40%) persisted at 7 days. Aortocaval shunt increased LV angiotensin II by 100% and 65% at 1 and 7 days, respectively. Both blockers similarly prevented the increase in plasma angiotensin II by aortocaval shunt at both time points. In contrast, only quinapril prevented the rise in LV angiotensin II induced by shunt at 1 and 7 days.
Conclusions Aortocaval shunt increases LVEDP and plasma and cardiac angiotensin II and results in LV hypertrophy. Only prevention of the increase in LVEDP and in plasma and cardiac angiotensin II attenuates the development of LV hypertrophy, consistent with the concept that angiotensin II is involved in the development of cardiac hypertrophy by aortocaval shunt by both hemodynamic and cardiac trophic effects. This study is the first to show that differences in affinity for cardiac ACE may determine the effect of ACE inhibitors on cardiac angiotensin II and therefore cardiac hypertrophy.
Key Words: angiotensin • enzymes • cardiac volume • hypertrophy
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Stretch of cardiomyocytes in vitro results in Ang II release and increased protein synthesis.1 2 Ang II appears to mediate this hypertrophic response because the Ang II receptor blocker losartan prevents it.1 Whether in vivo release of angiotensin II by cardiomyocytes in response to stretch also represents the "initiating" mechanism for hypertrophic growth of cardiomyocytes has not yet been evaluated.
In previous studies, we showed that an aortocaval shunt increases LVEDP and plasma and cardiac renin activity and results in LV eccentric hypertrophy and right ventricular hypertrophy.3 The Ang II receptor blocker losartan and the ACE inhibitors enalapril and quinapril attenuate to a similar extent the rise in LVEDP in response to aortocaval shunt and similarly decrease LVPSP.3 4 However, only losartan and quinapril prevent LV hypertrophy and dilation.3 4 The similar effects of quinapril and enalapril on resting LVEDP and LVPSP and a similar blockade of pressor responses to Ang I by the two blockers indicate a similar degree of blockade of plasma or endothelial ACE.4 In these studies, however, changes in plasma Ang II induced by aortocaval shunt and the effects of the two ACE inhibitors on actual plasma Ang II levels were not assessed.
Whereas blockade of circulatory ACE by different ACE
inhibitors differs mostly in duration,5 ACE
inhibitors show major differences in their affinity for
cardiac (and other tissues) ACEs.5 6 In doses
equipotent
for plasma ACE, enalapril shows minimal (by 
20%) and short (1 hour)
inhibition of cardiac ACE compared with marked (by 60%) inhibition
lasting 8 hours by quinapril, fosinopril, and
zofenopril.5 6 However, whether these differences in
affinity for cardiac ACE between ACE inhibitors result in
different levels of cardiac Ang II in vivo has not yet been assessed.
We hypothesized that a low affinity of enalapril for cardiac ACE
compared with quinapril, for example, may result in continuing
generation of cardiac Ang II and thus hypertrophic growth of
cardiomyocytes.
The objectives of the present study were to assess whether the increases in plasma and cardiac renin activity induced by aortocaval shunt are associated with parallel increases in plasma and cardiac Ang II, to evaluate whether the similar hemodynamic effects of enalapril and quinapril are indeed associated with similar changes in plasma Ang II, and to assess whether the differences in affinity for cardiac ACE between enalapril and quinapril in vitro result in different levels of cardiac Ang II in vivo and therefore may be relevant for the prevention of cardiac hypertrophy.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Animals, Treatments, and Surgery
Male Wistar rats weighing 200 to 225 g were obtained from Charles River Breeding Laboratories (Montreal, Quebec, Canada). Rats were housed two per cage, given food and water ad libitum, and kept on a 12-hour light-dark cycle. After an acclimatization period of at least 3 days, they were randomized into six groups: control, control plus enalapril, control plus quinapril, shunt, shunt plus enalapril, and shunt plus quinapril. Treatment with enalapril (250 mg/L in drinking water)3 7 8 and quinapril (200 mg/L in drinking water)9 started 3 days before the shunt or sham surgery and continued for 1 or 7 days. Aortocaval shunt was induced by an 18-gauge needle as described by Garcia and Diebold.10 Control (treated and untreated) rats were subjected to similar surgical procedures with the exception of puncturing the big vessels. On the day of the shunt or sham surgery or 6 days later, under a halothane–nitrous oxide–oxygen anesthesia, a PE-50 catheter (Clay Adams) filled with heparinized saline (100 U/mL) was inserted into the right common carotid artery. Catheters were exteriorized on the neck of the animals. LV and right ventricular weights and plasma and LV Ang I and II were assessed 1 and 7 days after the surgery (Fig 1
).
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Blood Samples for Assessment of Plasma Ang I and II
On the
day of the experiment (ie, 1 and 7 days after the shunt
or sham surgery) at approximately 10 AM after a 30-minute
acclimatization period, 2 mL arterial blood was collected
from conscious, unrestrained rats into chilled
microcentrifuge tubes containing EDTA-Na2 and
1,10-phenantroline at final concentrations of 5 and 1.25 mmol/L in
saline.11 Blood samples were centrifuged at
3000g for 5 minutes, and plasma for assessment of Ang I and
II was immediately extracted on a SepPak C 18 cartridge
(Millipore).
Cardiac Tissue Sampling for Assessment of Ang I and
II
After the collection of blood samples, rats were killed by
arterial injection of 1 mol/L KCl. The chest cavity was
opened, and the heart was rapidly excised and washed in ice-cold
saline. After removal of the atria and great vessels, the ventricles
were blotted dry, and the right ventricle was dissected along its
septal insertion from the rest of the ventricular mass. The
left ventricle was then weighed and placed into boiling 1 mol/L acetic
acid.12 13 The whole procedure, from KCl injection
until
placement of the left ventricle into boiling acetic acid, was practiced
extensively and did not last >45 seconds. Tissue samples were boiled
for 20 minutes, homogenized with a Polytron
homogenizer (Brinkmann Instruments) for 1 minute, and
centrifuged for 15 minutes at 7000g.
Plasma and supernatants from the LV homogenates were applied to methanol and water–preconditioned SepPak C 18 cartridges. Cartridges were washed twice with 4 mL of 0.1% trifluoroacetic acid. Angiotensin peptides were eluted by 2 mL of methanol:water:trifluoroacetic acid 80:19.9:0.1. Extracts were evaporated to dryness in a Savant SpeedVac concentrator.
Assessment of Ang I and II
Plasma and LV angiotensins were
assessed by RIA
after separation on HPLC. For this, plasma and LV samples were
dissolved in mobile phase and centrifuged, and supernatant was
injected. Angiotensins were separated on a
CSC-Spherisorb-ODS2 C18 column, 15x0.46 cm with a 5-µm particle size
(CSC), in a gradient system consisting of Waters 510 HPLC pumps
controlled by a Waters workstation (Millipore), Rheodyne 7125 injector,
and Spectra/Chrom CF-1 fraction collector (Spectrum). The mobile phase
was 0.05 mol/L sodium acetate, pH 5.6, and methanol with a linear
gradient from 40% to 80% methanol in 24 minutes from injection at a
flow rate of 1.4 mL/min. Elution times for Ang II, III, and I were
10.0, 13.0, and 17.5 minutes, respectively. Fractions were collected
every 0.5 minutes into polypropylene tubes containing 50 µL of 10%
glycerol and 100 µL of 0.05 mol/L Tris buffer, pH 7.4. Subsequently,
fractions were dried overnight in a SpeedVac
concentrator.14
The tubes were divided into two pools
containing the peaks of Ang II
and III for Ang II RIA and the peak of Ang I for Ang I RIA (Fig
2).
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Both RIAs used the same buffer: 0.05 mol/L Tris, pH 7.4, with 1 mg/mL RIA-grade BSA and 0.02% sodium azide. Ang I and II standards (Sigma Chemical Co) were added to 700 µL or the mobile phase (with 100 µL buffer and 50 µL of 10% glycerol) and dried. For incubation, 200 µL RIA buffer, 100 µL antibody solution in RIA buffer, and 30 µL tracer (125I-Ang I or 125I-Ang II, both from Amersham) in RIA buffer (4000 to 5000 counts per minute) were subsequently added to the dried tube. The antisera (Ang I or II antibody) concentration was adjusted to yield 40% to 45% of specific binding after 24 hours of incubation at 4°C. Ang II antibody had 100% cross-reactivity with Ang II and III and <0.1% cross-reactivity with Ang I. After incubation, bound and free tracers were separated with dextran-coated charcoal (nonspecific binding <1%). The radioactivity of bound tracer was recorded for 4 minutes with a gamma counter (LKB Wallac).
Statistical Analysis
Results are expressed as
mean±SEM. Differences between groups
at a given treatment period were evaluated by ANOVA and Duncan's
multiple-range test. Differences were considered significant at
P<.05.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Assessment of Ang I and II
The sensitivity of detection of the method used to assess Ang I and II was 0.5 and 0.2 pg per tube, respectively. Recovery of angiotensins from plasma and tissue was determined by spiking of plasma or LV samples with 0 to 100 pg synthetic Ang I and II. Spiked samples were processed the same way as regular samples, including boiling, homogenization, SepPak extraction, HPLC, and RIA. Overall recoveries of Ang I and II were 60% to 80% from cardiac tissue and 80% to 100% from plasma. There was no significant difference in recovery between Ang I and II.
Plasma Ang I and II
Aortocaval shunt increased plasma Ang I
by 150%
(P<.05) 1 day after surgery compared with control rats
(Table 1). By 7 days after the shunt,
plasma Ang I in rats with aortocaval shunt had returned to close to the
values of control rats (Table 1). The time course of
changes in plasma Ang II in response to aortocaval shunt showed the
same trend as described for Ang I: plasma Ang II increased by 180%
at day 1 after the shunt surgery, but only a small increase (40%,
P<.05) persisted at 7 days after surgery compared with
control rats (Table 1).
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Enalapril and quinapril
increased plasma Ang I in control rats compared
with untreated control rats at both time points of follow-up (Table
1
). This increase in plasma Ang I by enalapril and
quinapril was more pronounced (P<.05) in rats with
aortocaval shunt at day 1 but was no longer pronounced at day 7 after
the shunt surgery compared with their respective treated control rats
(Table 1).
Enalapril and quinapril caused only small
(P=NS) changes in
plasma Ang II at days 1 and 7 in control rats (Table 1).
In contrast, both blockers completely prevented the increase in plasma
Ang II by aortocaval shunt at days 1 and 7 after the shunt surgery
(Table 1).
LV Ang I and II
Aortocaval shunt caused only small
(P=NS) increases in
LV Ang I at days 1 and 7 after surgery (Table 1). In
control rats, enalapril and quinapril similarly increased LV Ang I at
day 1 (Table 1). This increase persisted in
quinapril-treated but not enalapril-treated control rats at day
7 (Table 1). In rats with aortocaval shunt, enalapril
increased LV Ang I at both time points. Quinapril caused no significant
changes in LV Ang I at days 1 and 7 after the shunt surgery (Table
1).
Aortocaval shunt resulted in an increase in LV Ang
II of about 100%
(P<.05) and 65% (P<.05) at days 1 and 7 after
shunt surgery, respectively (Fig 3).
Enalapril and quinapril did not cause significant changes in LV Ang II
in control rats at either time point of follow-up (Fig 3).
Quinapril completely prevented the increase in LV
Ang II at days 1 and 7 after the shunt surgery. In contrast, enalapril
failed to prevent the increase in LV Ang II at day 1 after surgery (Fig
3). At 7 days after the shunt, enalapril resulted in a
minor (P=NS) decrease in LV Ang II compared with untreated
shunt rats (Fig 3).
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Hemodynamics
Because changes in central and peripheral
hemodynamics are the primary determiners of the
hypertrophic response of the heart, we show previously published
results on hemodynamics. Aortocaval shunt decreased
LVPSP at days 1 and 7 after surgery (Table 2). Enalapril and
quinapril decreased
LVPSP in control rats by 10 mm Hg but had no effect on LVPSP in rats
with aortocaval shunt (Table 2).
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Aortocaval shunt
increased LVEDP at both days 1 and 7 after surgery
compared with control rats (Table 2). Enalapril and
quinapril attenuated to a similar extent the increase in LVEDP in
response to aortocaval shunt (Table 2).
Body Weight and LV Weight
There were no differences in body
weight between the groups at 1
and 7 days after surgery (Table 2). Aortocaval shunt
increased LV weight compared with control rats by 20%. Enalapril
and quinapril caused only small (P=NS) decreases in LV
weight in control rats (Table 2). Rats with aortocaval
shunt receiving enalapril developed LV hypertrophy similar
to that in untreated rats. In contrast, quinapril significantly
attenuated the development of LV hypertrophy compared with
untreated rats with aortocaval shunt (Table 2).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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This study has the following primary findings. Aortocaval shunt increases plasma and LV Ang II. Enalapril and quinapril prevent to a similar degree the increase in plasma Ang II. In contrast, only quinapril prevents the increase in cardiac Ang II induced by aortocaval shunt.
Assessment of the Method Used to Evaluate Ang I and
II
Separation of angiotensins on HPLC and assessment of
angiotensins by RIA represent standard biochemical
techniques.12 13 14 15 16
The sampling part of the method, however,
is critical to preserve angiotensins at the level that most
likely reflects the (patho)physiological processes.
We eliminated the effect of anesthesia, decreased the total
time of cardiac ischemia to about 45 seconds, and stopped
ischemia-activated proteases linked to Ang I and II
generation or degradation by immediately placing tissue samples into
boiling acetic acid and collecting blood directly into chilled tubes
containing inhibitors. This approach resulted in recovery
of >80% plasma Ang I and II as assessed from spiking of plasma
samples with Ang I and II. These data are consistent with
others reporting similar recoveries for plasma Ang I and
II.17 18 Recoveries for LV Ang I and II were about
60% to
80%. These recoveries are lower compared with plasma, possibly
reflecting losses related to degradation of Ang I and II by tissue
proteases during boiling in acetic acid and to (technical) losses from
separation of supernatant and centrifugate after the
homogenization of the tissue. Campbell et
al16 showed recoveries for Ang I and II from cardiac and
other tissues of 40% to 60%. They did not boil the tissue samples
or use any other preventive measures from collection to
homogenization to prevent generation or degradation
of angiotensins. Our baseline levels for Ang I and II in
control rats showed only small variability (see the SEM) and high
reproducibility. Others reported similar data on plasma and cardiac Ang
I and II in rats under physiological
circumstances.15 19
Effects of Aortocaval Shunt on Plasma and LV Ang I and
II
Plasma
Aortocaval shunt increased both Ang I and II
at day 1 after
surgery. Both Ang I and II had decreased to close to control values at
7 days after the shunt. This time course of changes reflects the
changes in plasma renin activity that we previously reported: peak
values 1 day after surgery and then a gradual decrease.3
These increases in plasma Ang II appear to cause arteriolar
vasoconstriction and thus maintain blood pressure within the normal
range during the early stages of an aortocaval
shunt.20 21
Although the total peripheral resistance is reduced in
shunt animals,3 22 23 resistance is
increased in certain
vascular beds—at least in part—as a result of high levels of
Ang II.21 22 23 In addition, an increased
plasma Ang II could
contribute through its renal effects (eg, increases in renal sodium and
fluid reabsorption) to volume expansion and cardiac
output.23 We are not aware of any study on changes in
plasma Ang I and II in response to aortocaval shunt in rats.
In the doses used, enalapril and quinapril had similar effects on LVEDP and LVPSP4 and similarly shifted the pressure–Ang I dose-response curve to the right.4 Consistent with these findings, enalapril and quinapril prevented to a similar extent the increase in plasma Ang II by aortocaval shunt. As a result of the blockade of Ang I to II conversion, plasma renin activity3 and consequently Ang I increased in enalapril- and quinapril-treated animals.
Left
Ventricle
The previously reported increases in LV renin activity 1 and
7
days after the shunt3 also suggested increases in LV
angiotensins. Indeed, LV Ang I and II increased by 50%
and 100%, respectively, at day 1 after the shunt. Although LV Ang I
returned to the level seen in control rats, LV Ang II remained
significantly increased compared with control rats. As for plasma Ang I
and II, the changes in LV angiotensins in response to
aortocaval shunt have not yet been assessed. However, similar increases
in LV Ang II after 7 days of isoproterenol infusion (4.2
mg·kg-1·d-1),
16.2±2.0 pg/g tissue in isoproterenol-treated rats compared with
7.3±0.8 pg/g tissue in control rats, were associated with LV
hypertrophy by 16%.15
In contrast to complete prevention of the increase in plasma Ang II 1 and 7 days after aortocaval shunt by both blockers, only quinapril also completely prevented the increase in LV Ang II at days 1 and 7 after aortocaval shunt. Because quinapril prevented the increase in both plasma and cardiac Ang II at both time points of follow-up, it appears that Ang II generation is driven by ACE rather than by nonspecific Ang II–forming enzyme(s). The nearly complete blockade of the increase in plasma Ang II by enalapril and lack of blockade of the increase in cardiac Ang II indicate a low affinity of enalapril for cardiac ACE. These results also suggest that regulation of Ang II generation in cardiac tissue can be independent of circulatory Ang II.
Relevance of LV Ang II for the Development of Cardiac
Hypertrophy
As results from this study show, aortocaval shunt
increases LVEDP
and plasma and cardiac Ang II and causes LV
hypertrophy.3 4 23 Attenuation of the
increase
in LVEDP and plasma and cardiac Ang II by quinapril or losartan
(blocker of Ang II receptors) attenuates the development of LV
hypertrophy.3 4 In contrast, this study also
shows that enalapril prevents an increase in LVEDP and plasma Ang II
but does not prevent an increase in cardiac Ang II or the development
of LV hypertrophy.3 4 These data are
consistent with the concept that Ang II is involved in the
development of cardiac hypertrophy in response to cardiac
volume overload by aortocaval shunt in two ways. First, plasma Ang II
is a determiner of cardiac preload (by venoconstriction and sodium and
water retention), cardiac afterload (by arterial
vasoconstriction), and LV function (ventricular
relaxation).3 23 24 25
Second, an increase in cardiac Ang II
mediates the hypertrophic response of cardiomyocytes to
cardiac volume overload because LV hypertrophy develops
when an increase in cardiac Ang II is not prevented (eg, by
enalapril).
This concept of the role of cardiac Ang II as a trophic factor in the development of cardiac hypertrophy in vivo is consistent with previously reported data by Sadoshima et al1 2 showing that Ang II released in vitro by cardiomyocytes in response to stretch mediates their hypertrophic response.
In the model of cardiac volume overload induced by an aortocaval shunt, enalapril and quinapril prevent an increase in plasma Ang II, but only quinapril prevents an increase in cardiac Ang II. These data reflect the effects of the two blockers at their peak (about 4 to 6 hours after the drinking period). The biological half-life of enalapril is substantially shorter (14 to 18 hours) and dissociates faster from the ACE active side compared with quinapril (30 to 36 hours).5 6 26 Because rats drink only 12 hours per day, quinapril probably provides adequate blockade of plasma and LV ACE at the end of the dosing interval, whereas enalapril provides neither of these. This may result in higher LVEDP and plasma and cardiac Ang II at the end of the dosing interval, changes that probably would contribute to the development or persistence of cardiac hypertrophy.
Possible Clinical Implications
This study is the first to
show that differences in
affinity for cardiac ACE between ACE inhibitors in
vitro5 6 result in different levels of cardiac Ang II
in
vivo. These differences in affinity for cardiac ACE between ACE
inhibitors appear to determine their effect on cardiac
hypertrophy when cardiac Ang II mediates or potentiates the
growth of cardiomyocytes. In patients with end-stage
renal disease, obese hypertensive patients, and patients who have had
myocardial infarction, cardiac volume overload clearly contributes to
the development of cardiac hypertrophy.27 28
If cardiac Ang II also mediates or potentiates the development or
maintenance of cardiac hypertrophy in these
patients, one may hypothesize that these patients would benefit more
from treatment with ACE inhibitors with high affinity for
cardiac ACE than from treatment with those showing low affinity for
cardiac ACE. This, however, remains to be assessed.
In conclusion, because enalapril fails to prevent an increase in cardiac Ang II and the development of cardiac hypertrophy in this model of volume overload, it appears that (1) besides the affinity for plasma ACE, affinity for cardiac ACE determines the effect of ACE inhibitors on cardiac hypertrophy when Ang II mediates or potentiates the growth of cardiomyocytes and (2) increases in both plasma and cardiac Ang II potentiate the hypertrophic response of the heart to cardiac volume overload by aortocaval shunt by both hemodynamic and direct trophic effects.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by an operating grant from the Heart and Stroke Foundation of Ontario and by Parke-Davis, Division of Warner-Lambert Co, Canada. Enalapril maleate was a generous gift from Merck, Sharp & Dohme, Kirkland, Quebec, Canada. Quinapril hydrochloride was a generous gift from Parke-Davis, Division of Warner-Lambert Co, Ann Arbor, Mich. Antibody against Ang I was provided by Dr D. Osmond, Toronto, Ontario, Canada. Antibody against Ang II was a generous gift from Dr P. Admiraal, University Hospital Dijkzigt, Rotterdam, the Netherlands.
Received May 10, 1995; revision received June 19, 1995; accepted August 8, 1995.
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References |
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N. S. Dhalla, M. R. Dent, P. S. Tappia, R. Sethi, J. Barta, and R. K. Goyal Subcellular Remodeling as a Viable Target for the Treatment of Congestive Heart Failure Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2006; 11(1): 31 - 45. [Abstract] [PDF]
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X. Wang, E. Sentex, D. Chapman, and N. S. Dhalla Alterations of adenylyl cyclase and G proteins in aortocaval shunt-induced heart failure Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H118 - H125. [Abstract] [Full Text] [PDF]
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J. L. Segar, G. B. Dalshaug, K. A. Bedell, O. M. Smith, and T. D. Scholz Angiotensin II in cardiac pressure-overload hypertrophy in fetal sheep Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2001; 281(6): R2037 - R2047. [Abstract] [Full Text] [PDF]
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F. H. H. Leenen, R. White, and B. Yuan Isoproterenol-induced cardiac hypertrophy: role of circulatory versus cardiac renin-angiotensin system Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2410 - H2416. [Abstract] [Full Text] [PDF]
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B. S. Huang, D. Ganten, and F. H. H. Leenen Responses to Central Na+ and Ouabain Are Attenuated in Transgenic Rats Deficient in Brain Angiotensinogen Hypertension, February 1, 2001; 37(2): 683 - 686. [Abstract] [Full Text] [PDF]
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W. C. De Mello and A. H. J. Danser Angiotensin II and the Heart : On the Intracrine Renin-Angiotensin System Hypertension, June 1, 2000; 35(6): 1183 - 1188. [Abstract] [Full Text] [PDF]
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C. A.M van Kesteren, J. J Saris, D. H.W Dekkers, J. M.J Lamers, P. R Saxena, M. A.D.H Schalekamp, and A.H.J. Danser Cultured neonatal rat cardiac myocytes and fibroblasts do not synthesize renin or angiotensinogen: evidence for stretch-induced cardiomyocyte hypertrophy independent of angiotensin II Cardiovasc Res, July 1, 1999; 43(1): 148 - 156. [Abstract] [Full Text] [PDF]
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F. H. H. Leenen, V. Skarda, B. Yuan, and R. White Changes in cardiac ANG II postmyocardial infarction in rats: effects of nephrectomy and ACE inhibitors Am J Physiol Heart Circ Physiol, January 1, 1999; 276(1): H317 - H325. [Abstract] [Full Text] [PDF]
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Y. Ishigai, T. Mori, T. Ikeda, A. Fukuzawa, and T. Shibano Role of bradykinin-NO pathway in prevention of cardiac hypertrophy by ACE inhibitor in rat cardiomyocytes Am J Physiol Heart Circ Physiol, December 1, 1997; 273(6): H2659 - H2663. [Abstract] [Full Text] [PDF]
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F. G. Spinale, M. de Gasparo, S. Whitebread, L. Hebbar, M. J. Clair, D. M. Melton, R. S. Krombach, R. Mukherjee, J. P. Iannini, and S.-J. O Modulation of the Renin-Angiotensin Pathway Through Enzyme Inhibition and Specific Receptor Blockade in Pacing-Induced Heart Failure : I. Effects on Left Ventricular Performance and Neurohormonal Systems Circulation, October 7, 1997; 96(7): 2385 - 2396. [Abstract] [Full Text]
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J. Diez, A. Panizo, M. Hernandez, and J. Pardo Is the Regulation of Apoptosis Altered in Smooth Muscle Cells of Adult Spontaneously Hypertensive Rats? Hypertension, March 1, 1997; 29(3): 776 - 780. [Abstract] [Full Text]
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