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(Circulation. 1995;92:3105-3112.)
© 1995 American Heart Association, Inc.
Articles |
Expression of Renin-Angiotensin System Components in the Heart, Kidneys, and Lungs of Rats With Experimental Heart Failure
From the Hypertension-Endocrine Branch (Z.A.A., H.R.K.), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md; and Centro di Fisiologia Clinica e Ipertensione (F.P.), Ospedale Maggiore, Universita' di Milano, Italy.
Correspondence to Zaid A. Abassi, PhD, Hypertension-Endocrine Branch, National Heart, Lung, and Blood Institute, Bldg 10, Room 8C103, 10 Center Drive, MSC-1754, Bethesda, MD 20892-1754.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Chronic activation of the renin-angiotensin system (RAS) plays an important role in the pathogenesis of heart failure. Increasing evidence indicates that other than the circulating RAS, a local RAS exists in several tissues, including the heart. The present study was carried out to quantify cardiac, renal, and pulmonary mRNA levels of renin, angiotensin-converting enzyme (ACE), and types 1 and 2 angiotensin II receptors (AT-1 and AT-2), in rats with different severities of heart failure.
Methods and Results Heart failure was induced by the creation of an aortocaval fistula below the renal arteries. Rats with aortocaval fistula either compensate and maintain a normal sodium balance or decompensate and develop severe sodium retention. Six days after placement of the aortocaval fistula, heart weight (normalized to body weight) increased 35% (P<.05) in compensated and 65% in decompensated rats compared with control rats. Plasma renin activity increased 45% (P<.05) in rats in sodium balance and 127% in sodium-retaining rats. Total RNA was extracted from the heart, kidneys, and lungs, followed by reverse transcription–quantitative polymerase chain reaction. Renin mRNA levels in the heart, after 40 cycles, increased 68% (P<.01) and 140% in rats with either compensated or decompensated heart failure, respectively. Renal renin-mRNA levels also increased 130% (P<.05) in decompensated and only 52% (P<.05) in compensated animals. ACE-mRNA increased in a similar pattern in the heart but not in either the kidneys or lungs. Moreover, pulmonary, renal, and cardiac ACE immunoreactivity levels, assessed by Western blot analysis, showed the same trend. AT-1 receptor mRNA levels decreased 54% (P<.05) only in the myocardium of decompensated rats, whereas AT-2 receptor mRNA did not change in any tissue studied.
Conclusions The development of heart failure is associated with a remarkable increase in the expression of a local RAS in the heart, which may contribute to the pathogenesis of this clinical syndrome.
Key Words: heart failure • renin-angiotensin system
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The RAS plays an important role in the control of cardiovascular and renal homeostasis, affecting both blood pressure and fluid volume.1 Originally, the RAS was viewed solely as an endocrine system, in which angiotensinogen of hepatic origin is secreted into the systemic circulation and cleaved by renin and ACE to produce the active peptide Ang II. Increasing evidence, however, suggests that an RAS, complete with respect to all the components of the enzymatic pathway, may reside within several individual organs or tissues, such as kidney, lung, heart, and vascular smooth muscle cells, where it is believed to act in a functionally independent paracrine/autocrine fashion.2 3 4 Furthermore, the presence of the appropriate receptors and signal transducers, necessary to postulate that Ang II is locally active, has been demonstrated.5 Ang II exerts its biological effects via binding to at least two different receptor subtypes, AT-1 and AT-2.6 7
HF is, perhaps, the most recognized cardiovascular condition in which aberrations in the RAS have been found. The low cardiac output and renal hypoperfusion induce a series of compensatory mechanisms in HF, including activation of several neural and hormonal systems, ie, RAS, sympathetic nervous system, ANP, endothelins, and vasopressin.8 9 10 11 12 13 14 15 In particular, activation of the RAS is detrimental in HF because Ang II promotes peripheral vasoconstriction, aldosterone and vasopressin secretion, and sodium and water retention, leading to further deterioration of ventricular function.16 In addition, Ang II, of either local or circulatory origin, may play a significant role in the development of cardiac hypertrophy and in mediating the fibrogenic response to tissue injury after myocardial infarction.17 18 19 20 Furthermore, Ang II stimulates heart rate and contractility both directly and indirectly by facilitating adrenergic neurotransmission in the heart.21 22 The result is a decrease in coronary flow and arrhythmias.23 In support of these findings are the well-established beneficial effects of ACE inhibitors in patients with HF, ie, improved cardiac function and prolonged survival.24 25 26 27 28 29
Nevertheless, the status of the tissue RAS has not been comprehensively investigated in HF of different severities. Previously, it was shown that rats with an ACF, an experimental model of HF, either develop progressive sodium retention (decompensated HF) or compensate and maintain normal sodium balance (compensated HF).13 30 31 With this model, we studied the expression of renal, pulmonary, and cardiac mRNAs encoding renin, ACE, and Ang II receptors (types AT-1 and AT-2) in rats with HF of different degrees of severity.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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In Vivo Protocol
Experiments were conducted in accordance with the National Institutes of Health "Guide for the Care and Use of Laboratory Animals." Studies were performed on male Sprague-Dawley rats weighing
300 g (Harlan Farms). Animals were kept in
temperature-controlled rooms, with a 6:00 A.M.-to-6:00
P.M. light/dark cycle and fed standard rat chow containing
170 mEq/kg sodium (Agway). Tap water and rat chow were provided ad
libitum. An ACF was created between the abdominal aorta and the
inferior vena cava according to the method of Stumpe et
al.32 Briefly, on the day of the surgery, the animals were
anesthetized with pentobarbital sodium (40 mg/kg), and the vena
cava and aorta were exposed via a midline abdominal incision. A
side-to-side (1.2 to 1.4 mm) surgical anastomosis was created
between the two blood vessels distal to the origin of the renal
arteries. Animals that underwent a sham operation served as controls.
The rats were placed in individual metabolic cages for
daily monitoring of urine output and electrolyte excretion. One week
after the operation, rats with ACF were divided into two groups
according to their daily urinary excretion of sodium (UNaV), ie, rats
with UNaV of <200 µmol/24 h (decompensated) and rats with UNaV of
>1400 µmol/24 hr (compensated). Rats with UNaV of >200 µmol/24
hr
and <1400 µmol/24 hr (5% to 10% of total rats with ACF) were
excluded from this study. Postmortem examination revealed that
decompensated rats developed additional signs of HF, ie, ascites,
edema, enlarged liver, pleural effusions, and hypertrophy
of the heart. In addition, these rats displayed a profound activation
of the RAS (see "Results") and severe dyspnea, whereas these
signs were mild or absent in compensated rats. Seven days after placement of the ACF, normal rats (n=9) and animals with either compensated (n=5) or decompensated HF (n=5) were anesthetized with 100 mg/kg Inactin i.p. (BYK-Golden, Konstanz, Germany) and prepared for studies of renal function. The animals were placed on a heated table, and a tracheostomy was performed. Polyethylene catheters (PE-50) were inserted into the right carotid artery for blood pressure monitoring (blood pressure analyzer, Micro Med) and to obtain blood samples, into the jugular vein for infusions, and into the bladder for urine collections. Glomerular filtration rate was determined via inulin clearance calculated from the concentration of [methoxy-3H]inulin in 10-µL samples of urine and plasma as measured with a liquid scintillation counter (Beckman model LS 9000) using Hydrofluor (National Diagnostic Inc). The concentration of sodium in plasma and urine was measured with an ion-selective electrode (Synchron EL-ISE, Electrolyte System, Beckman Instruments). Separate groups of normal rats (n=15) and animals with either compensated (n=15) or decompensated (n=12) HF were decapitated, and their kidneys, lungs, and hearts were removed, immediately placed into liquid nitrogen, and kept frozen at -70°C until analysis. At the same time, blood was collected into precooled tubes containing potassium EDTA and immediately centrifuged at 4°C. Plasma samples were stored at -70°C until analysis for PRA, PAC, ANP, and ACE activity. PRA was measured with a radioimmunoassay for Ang I and expressed as nanograms of ang I formed per milliliter of plasma generated during a 1-hour incubation. PAC was measured in unextracted samples with a commercially available radioimmunoassay (Endocrine Sciences). Plasma levels of ANP were determined by Nichols Institutes using a specific commercial radioimmunoassay kit. ACE activity was determined by a spectrophotometric method based on incubation of plasma samples, dialyzed to remove EDTA, with an artificial peptide substrate (Endocrine Sciences).
In Vitro Protocol
RNA was extracted from the frozen kidneys,
lungs, and cardiac
tissue from both ventricles of control (n=5), compensated (n=5),
and
decompensated (n=5) rats, as described by Chomczynski and
Sacchi,33 after homogenization in a
commercial solution (RNAzol B, Tel-Test Inc) and quantified by
absorbance spectrophotometry at 260 nm. Because we were unable to
detect RNA encoding renin, Ang II receptor subtypes, and ACE by
standard Northern blotting with 20 µg of total RNA on each lane,
quantitative RT followed by quantitative PCR was applied.
RT Followed by Quantitative PCR
cDNAs for renin, ACE, AT-1,
and AT-2 were synthesized from 2
µg total RNA with the use of specific
primers34 35 36 37 38
(Table 1
). Avian myeloblastosis virus reverse
transcriptase (8 units/reaction, Promega) was used for RT, with the
reaction mixture recommended by the enzyme manufacturer in a volume of
20 µL. PCR was applied with 2 µL of the resulting cDNA and the
GeneAmp kit (Cetus Perkin Elmer), using both the upstream primer and
the downstream primer for RT. Each PCR reaction mixture contained 200
µmol/L dATP, dGTP, and dTTP; 100 µmol/L unlabeled dCTP, and 0.8
µCi 32P-labeled dCTP (NEN). Primers were chosen to span
introns to distinguish by size PCR products derived from cDNA from
those derived from genomic DNA contaminants.
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In a preliminary study, we
found that the minimum number of PCR cycles
necessary to obtain a visible product on an acrylamide
gel for each component was 22 cycles for ß-actin in all tissues,
25 cycles for ACE in the lung and renin in the kidney, 30 cycles for
ACE in the heart and kidney and for AT-1 and AT-2 in all tissues, and
40 cycles for renin in the heart. We also verified that the quantity of
product yielded after the chosen number of PCR cycles was directly
proportional to the amount of cDNA used. Then, after an initial
denaturation step at 94°C for 3 minutes, appropriate cycles of
annealing at 56°C for 1 minute, elongation at 72°C for 1 minute,
and denaturation at 94°C for 1 minute were performed, using 10% of
the cDNA described above. The expected size of each PCR product is
listed in Table 1
. The RT-PCR product of the gene encoding
ß-actin served as a quantity control. Negative controls for the
PCR reaction included tubes lacking either template or AMV-RT. Eight
microliters of the PCR product were electrophoresed on a 4-20% TBE
gel (Novex). The resulting gel was exposed to radiographic
film for several hours until clear bands were visible. The ratios
between the mRNAs of renin, ACE, AT-1, and AT-2 to ß-actin mRNA
(standardized mRNA) were quantified via densitometric analysis
(NIH Image 1.55) for each rat.
Determination of ACE Immunoreactivity Levels by Western Blot
Analysis
Membranes were prepared from kidneys, lungs, and hearts of
sham-operated animals and rats with compensated or decompensated HF
as described by Maeda et al.39 Briefly, the organs were
minced and resuspended in 3 mL of 10 mmol/L sodium phosphate buffer, pH
7.4, containing 1 mmol/L MgCl2, 30 mmol/L NaCl,
0.02% sodium azide, 20 mg/L Bestatin, 20 mg/L leuopeptin, and 10
µg/L DNAse. Then, the tissues were homogenized for 30
seconds in a Polytron homogenizer (Brinkmann
Instruments) at a setting of 7.0. The homogenate was
layered on an equal volume of 41% (w/v) sucrose and
centrifuged at 100 000g for 30 minutes in an
ultracentrifuge (model L5-50B, Beckman). The buffer/sucrose
interface, which includes the membranal preparation, was collected and
washed twice with 10 mmol/L Tris, pH 7.4; resuspended in an appropriate
volume of the same buffer; and stored at -70°C until use. Prestained
molecular markers (Bio-Rad) were used to determine the molecular weight
of the immunoreactive products. Approximately 10 µL of membrane
preparations (80 µg protein) from each tissue of the different
experimental groups were treated with 20 µL of sample buffer (10%
sodium dodecyl sulfate, 50% glycerol, 1.0 mol/L Tris, 0.1%
Bromphenol blue, and 1 mol/L DTT, pH 6.8) and placed in boiling water
for 5 minutes. Then, samples were electrophoresed on sodium
dodecyl sulfate–4-16% polyacrylamide gel and
transferred electrophoretically to a nitrocellulose membrane (100 V for
1 hour). The nitrocellulose membrane was incubated with a monoclonal
ACE antibody (Biotrack), and bands were visualized by successive
incubation with goat anti-rabbit IgG/alkaline phosphatase conjugate
and alkaline phosphatase substrate.
Statistical Analysis
Differences in systemic, renal, and
hormonal
parameters shown in Tables 2 and 3 were
evaluated with one-factor ANOVA followed by
Fisher's test.
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For study of the expression of RAS components, the mRNA for each component was standardized against ß-actin for each animal in each group. The differences between either the compensated or the decompensated animals and the control animals were calculated. A one-group unpaired t test with a hypothesized null difference was used to compare changes of mRNA. A value of P<.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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In Vivo Protocol
Group characteristics. Six days after placement of the ACF, heart weight (hw), normalized to body weight, increased 35% (P=.02) in compensated and 65% (P=.0002) in decompensated animals compared with controls animals. Heart weight increased 23% (P=.03) in decompensated compared with compensated rats (Fig 1
). Mean arterial
pressure decreased 7% (P=.01) in compensated and 24%
(P<.0001) in decompensated animals compared with control
animals. Furthermore, mean arterial pressure decreased 18%
(P<.0001) in decompensated compared with compensated rats
(Table 2).
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P<.05
for decompensated vs compensated animals.
Renal function. Urine flow
rate did not differ among the
three groups. However, total and fractional sodium excretions were
decreased 83% and 75%, respectively (P<.05 for each), in
decompensated rats compared with control animals.
Glomerular filtration rate decreased 43%
(P<.0001) in compensated and 61% (P<.0001) in
decompensated animals compared with control animals. In addition, it
decreased 36% (P<.03) in decompensated compared with
compensated rats (Table 2).
Plasma activity levels of RAS hormones. PRA increased
45%
(P<.05) in compensated and 127% (P<.01) in
decompensated rats compared with control animals. Moreover, PRA
increased 56% (P<.02) in decompensated compared with
compensated rats (Table 2). PAC increased more than fivefold in
decompensated rats compared with control animals or compensated rats,
which did not differ (Table 2). Plasma ACE activity was
comparable in
all three groups. Plasma levels of ANP were increased 68% to 75%
(P<.05) in rats with either compensated or decompensated HF
compared with control animals (Table 2).
In Vitro Protocols
Each pair of specific oligonucleotide
primers
produced cDNA fragments of the expected size when cDNAs were amplified
from reverse-transcribed mRNA extracted from renal,
pulmonary, and cardiac tissues. No cDNA products were
discovered in the absence of either reverse transcriptase or mRNA.
Effect of HF on cardiac RAS mRNA expression. Cardiac
renin
expression was detectable only after 40 cycles of amplification. Fig
2a shows a typical autoradiogram that
demonstrates the progressive increase of renin message in the hearts of
control, compensated, and decompensated rats. Densitometric
analysis demonstrated that cardiac renin mRNA levels increased
concomitantly with the severity of HF (Fig 2b). Cardiac renin
mRNA
levels increased 68% (P=.01) in compensated and 140%
(P=.002) in decompensated rats. In addition, renin mRNA
increased 56% (P=.003) in decompensated compared with
compensated rats. Similarly, cardiac ACE mRNA expression increased 56%
(P=.03) in compensated and 149% (P=.01) in
decompensated animals. Moreover, ACE mRNA increased 60%
(P=.01) in decompensated compared with compensated rats (Fig
2c and 2d). These latter results were confirmed
by Western blot
analysis in which a monoclonal antibody to rat ACE produced a
major band of 116 kDa. The intensity of this band in cardiac tissue
increased progressively from the control to the compensated situation
and therefore to the decompensated situation (see Fig 5).
Interestingly, the increases in cardiac expression of both renin and
ACE were accompanied by a 54% decrease (P=.02) in AT-1
receptor message in decompensated but not in compensated animals (Fig
2e and 2f). In contrast, AT-2 mRNA levels were
not significantly
affected by the induction of HF (Fig 2g and 2h).
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Effect of HF on renal RAS mRNA expression. As expected,
mRNA
levels of renin in renal tissue were more abundant than in the heart,
ie, detectable after only 25 cycles of amplification. Fig 3a
shows a representative
autoradiogram demonstrating that renin message in the
kidney increased concomitant with the severity of HF. Renal renin mRNA
levels increased 52% (P=.02) in compensated and 130% in
decompensated rats (P=.03) compared with control animals.
Furthermore, renin mRNA increased 51% (P<.05) in
decompensated compared with compensated rats (Fig 3b). The
expression
of ACE, AT-1, and AT-2 receptor mRNA was unchanged in rats with HF
compared with control animals (Fig 3c through 3h). Renal ACE
immunoreactivity levels were similar in all groups (see Fig 5).
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Effect of HF on pulmonary RAS mRNA expression. In
contrast to heart and kidney, the expression of renin in the lungs was
not observed even after 40 cycles. ACE message was more abundant in
lung than in either heart or kidney. Nevertheless, mRNA levels for ACE
and both Ang II receptor subtypes were unaffected by HF (Fig 4a
through
4f). Pulmonary ACE immunoreactivity levels were
similar in all groups (Fig 5).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Results of the present study demonstrate that in this model of HF, expression of the components of a local RAS is affected proportionally to the severity of the HF. This modulated coexpression of tissue RAS elements suggests an important role for this local system, primarily in the heart, in HF.
Rats with an ACF developed volume load–induced cardiac biventricular hypertrophy and HF. One week after the operation, we could separate the rats into two subgroups according to their daily sodium excretion. Compensated animals maintained normal sodium excretion, whereas decompensated rats developed severe and sustained sodium retention. The different severities of HF were also evident in the more profound reductions in MAP, glomerular filtration rate, and fractional sodium excretion in decompensated compared with compensated rats. Similarly, activation of the systemic RAS was more pronounced in decompensated rats, as shown by the higher levels of PRA and PAC observed in this group. In addition, animals with either compensated or decompensated HF displayed significant cardiac hypertrophy. Interestingly, the extent of cardiac hypertrophy was significantly greater in rats with severe HF than in compensated animals. The hemodynamic, renal, and hormonal alterations observed in animals with HF are very similar to those found in patients with this clinical syndrome.15 40
The existence and function of a local RAS independent of the circulating system have been extensively debated.41 42 Although several biochemical, physiological, and molecular biology studies have denied the presence of a complete local RAS, with anephric animals used to support their claim, other reports, using similar techniques, have demonstrated that various organs contain the crucial components of this system.43 44 45 46 47 48 49 Using the techniques of molecular biology, we were able to demonstrate the potential for the local synthesis of elements of the RAS in heart, lung, and kidney. In this way, we avoided activity measurements that can be influenced by circulatory uptake of these elements. On the other hand, the fact that cardiac renin mRNA was observed only after 40 cycles of PCR could raise some doubts about the physiological significance of this finding. In addition, we do not exclude the involvement of other aspartyl proteases in angiotensin formation, negating any absolute dependence on renin, of either circulatory or local origin. However, in the present study, we have shown that not only renin but also ACE mRNA levels are significantly increased in hypertrophied failing hearts. The most striking finding was that this increase was significantly greater in decompensated than in compensated rats. Because renin and ACE are the rate-limiting steps in the Ang II biosynthetic pathway, the observed upregulation of both renin and ACE expression in the heart would lead to increased local production of Ang II.50 51 Interestingly, the increase in PRA and Ang II levels may also lead to elevated ACE binding density in the cardiac tissue, as shown by Sun et al.20 52 Although the location of ACE in the different cardiac cells was not determined in the present study, there is strong evidence that ACE is localized mainly within the fibrosis induced by the exposure of the myocardium to high levels of Ang II or aldosterone.52 Taken together, these findings suggest that the RAS plays a crucial role in the remodeling of the myocardium.
It is currently believed that the biological actions of Ang II in the heart are mediated through activation of two different receptor subtypes, AT-1 and AT-2.53 In the present study, we found that AT-1 receptors in cardiac tissue were downregulated in decompensated rats but not in compensated animals, whereas AT-2 receptors were unchanged. Most likely, the observed downregulation of AT-1 receptors stems from the chronic elevation in circulating Ang II, as demonstrated by Sun and Weber.54 In addition, Lopez et al55 have shown that the AT-1 receptor was strongly downregulated in isolated, pressure-overload hypertrophied hearts. However, these authors did not measure AT-2 receptors directly but inferred that the predominant receptor subtype changed from AT-1 to AT-2 in these hearts, findings that require further elaboration. Taken together, these findings suggest that activation of local Ang II may provoke reciprocal changes in Ang II receptor subtypes. It is known that AT-1 receptors mediate the systemic and cardiac effects of Ang II, whereas the role of AT-2 receptors remains unclear. Nevertheless, Ardaillou56 suggested that AT-2 receptors generally mediate effects opposite those of AT-1 receptors, such as natriuresis and inhibition of cell proliferation. Therefore, it is tempting to speculate that a shift in Ang II receptor subtypes, ie, AT-1 downregulation and AT-2 upregulation, could be a locally protective mechanism for the failing heart. Nevertheless, it should be noted that other authors have reported opposite results in different models of cardiac dysfunction, such as renovascular hypertension and coronary ligation, where upregulation of the AT-1 receptor was observed.57 58 These differences may be due to variations in the severity of heart failure, characteristics of the cardiac hypertrophy induced, or duration of the study.
The elevated levels of PRA in rats with HF were associated with remarkable increases in the renal renin message that were proportional to the severity of HF. This increase most likely reflects the expected systemic activation of the RAS. Nevertheless, there is evidence that the kidney contains a RAS capable of synthesizing Ang II locally and independent of the circulating RAS.59 Therefore, the observed increase in the expression of renal renin-mRNA in animals with HF may contribute to the pathophysiology of this syndrome by enhancing sodium and fluid retention via either direct tubular effects or local hemodynamic changes.60 On the other hand, the fact that renal ACE mRNA levels did not change is not surprising. Several studies have shown that large amounts of ACE exist on the brush border of proximal tubular cells. This is confirmed by the high immunoreactive levels of ACE found in the kidneys of all animals in the present study. Thus, it can be assumed that a further increase in ACE synthesis and activity in the kidney would not be required for increased activity of the renal RAS. Similar findings have been reported by Huang et al61 in a model of HF induced by coronary ligation.
Analysis of the Ang II receptor subtypes in the kidney revealed that mRNA levels were similar in rats with either compensated or decompensated HF and in control animals. Recent reports suggest that the main physiological actions of Ang II in the kidney are mediated by AT-1 receptors. In pathological conditions, AT-2 receptors, which are more abundant in fetal kidney, might be involved in renal remodeling and tissue repair in an attempt to balance the harmful hemodynamic effects mediated by AT-1 receptors.56 62 The lack of significant changes in the renal messages for the Ang II receptor subtypes in the present study could be attributed to several factors: the short duration of the study, the activation of feedback mechanisms by Ang II production, or the fact that we extracted RNA from the whole kidney, whereas the distribution and function of the receptor subtypes varies according to their intrarenal location.63
Renin message was not detectable in the lung by PCR even after 40 cycles of amplification, indicating that this organ is not a major site of local production of this enzyme. On the other hand, it is well known that pulmonary endothelial cells are the main source of ACE and are responsible for the conversion of circulating Ang I to Ang II. Pulmonary ACE mRNA was easily detected after only 25 cycles, and it did not differ between control animals and animals with HF. Huang et al61 reported a decrease in pulmonary ACE activity and mRNA levels in rats in HF. However, it should be emphasized that in their study, the rats were killed 3 months after the initiation of HF compared with 1 week in our study. Thus, the altered ACE expression could have been caused by local hemodynamic factors that may alter endothelial cell function. Such time-related endothelial dysfunction has been shown to be associated with the release of various vasoactive mediators and even of ACE, as documented by high levels of plasma ACE activity.61 In contrast, in our experimental model with a shorter duration, plasma ACE activity was unchanged in animals with HF compared with control animals.
In summary, our findings provide further evidence for a local RAS that is activated in the heart and kidneys of rats with HF. Strikingly, the magnitude of RAS activation in these tissues was proportional to the severity of HF. The widely accepted therapeutic use of ACE inhibitors has been shown to be highly beneficial even in the early stages of HF and independent of activation of the systemic RAS.64 65 66 Intracoronary administration of ACE inhibitors provided strong evidence of the importance of the local RAS in the ventricular dysfunction of HF.67 Because AT-2 receptors are believed to mediate beneficial effects, it would be of special interest to determine whether activation of AT-2 receptors in association with inhibition of AT-1 receptors is more effective than treatment with either ACE inhibitors or AT-1 blockers.68 69 70 71 Thus, future studies aimed at the development of specific agonists and antagonists for each Ang II receptor subtype will improve our understanding of their role in HF and may provide highly selective therapeutic agents.
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Selected Abbreviations and Acronyms |
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Received April 5, 1995; revision received June 28, 1995; accepted July 5, 1995.
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References |
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TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Sealy JE, Laragh JH. The renin-angiotensin-aldosterone system for normal regulation of blood pressure and sodium and potassium homeostasis. In Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis and Management, 2nd ed. New York, NY: Raven Press; 1995:1763-1796.
2.
Lindpainter K, Ganten D. The cardiac
renin-angiotensin system: an appraisal of present
experimental and clinical evidence. Circ
Res. 1991;68:905-921.
3. Dostal DE, Baker KM. Evidence for a role of an intracardiac renin-angiotensin system in normal and failing hearts. Trends Cardivasc Med. 1993;3:67-74.
4. Dzau VJ. Circulating versus local renin-angiotensin system in cardiovascular homeostasis. Circulation. 1988;77(suppl I):I-4-I-13.
5. Peach M, Dostal DE. The angiotensin II receptor and the actions of angiotensin II. J Cardiovasc Pharmacol. 1990;16(suppl 4):S25-S30.
6. Chiu AT, Herblin WF, McCall DE, Ardeck RJ, Carini DJ, Duncia J, Pease LJ, Wong PC, Wexler R, Johnson AL, Timmermans PBMWM. Identification of angiotensin II receptor subtypes. Biochem Biophys Res Commun. 1989;165:196-203. [Medline] [Order article via Infotrieve]
7.
Inagami T, Harris RC. Molecular insights into
angiotensin II receptor subtypes. News
Physiol Sci. 1993;8:215-218.
8. Dzau VJ. Renal and circulatory mechanisms in congestive heart failure. Kidney Int. 1987;31:1402-1415. [Medline] [Order article via Infotrieve]
9. Riegger GAJ. Hormones in heart failure-regulation and counter-regulation. Eur Heart J. 1991;12:D190-D192.
10. Clavell A, Stingo A, Margulies K, Lerman A, Underwood D, Burnett JC. Physiological significance of endothelin: its role in congestive heart failure. Circulation. 1993;87(suppl V):V-45-V-50.
11. Raine AEG, Erne P, Burgisser E, Muller FB, Bolli P, Burkart F, Buhler FR. Atrial natriuretic peptide and atrial pressure in patients with congestive heart failure. N Engl J Med. 1986;315:533-537. [Abstract]
12.
Burnett JC, Kao PC, Hu DC, Heser HW, Heublein D,
Granger JP, Opgenorth TJ, Reeder GS. Atrial
natriuretic peptide elevation in congestive heart failure
in the human. Science. 1986;231:1145-1147.
13.
Winaver J, Hoffman A, Burnett JC, Haramati A.
Hormonal determinants of sodium excretion in rats with
experimental high-output heart failure. Am J
Physiol. 1988;254:R776-R784.
14. Mancia G. Sympathetic activation in congestive heart failure. Eur Heart J. 1990;11(suppl A):3-11.
15. Cody RJ, Covit AB, Schaer GL, Laragh JH, Sealey JE, Feldschuh J. Sodium and water balance in chronic congestive heart failure. J Clin Invest. 1986;77:1441-1452.
16.
Eiskjaer H, Bagger JP, Danielsen H, Jensen JD,
Jespersen B, Thomsen K, Sorensen SS, Pedersen EB. Mechanisms of
sodium retention in heart failure: relation to the
renin-angiotensin-aldosterone
system. Am J Physiol. 1991;260:F883-F889.
17.
Holubarsh C, Hasenfuss G, Schmidt-Schweda S, Knorr A,
Pieske B, Ruf T, Fasol R, Just H. Angiotensin I and
II exert inotropic effects in atrial but not in ventricular
human myocardium: an in vitro study under
physiological experimental conditions.
Circulation. 1993;88:1228-1237.
18. Morishita R, Gibbons GH, Ellison KE, Lee W, Zhang L, Yu H, Kaneda Y, Ogihara T, Dzau VJ. Evidence for direct local effect of angiotensin in vascular hypertrophy: in vivo gene transfer of angiotensin converting enzyme. J Clin Invest. 1994;94:9078-984.
19.
Sun Y, Cleutjens JPM, Diaz-Arias A, Weber KT.
Cardiac angiotensin converting enzyme and myocardial
fibrosis in the rat. Cardiovasc Res. 1994;28:1423-1432.
20.
Sun Y, Weber KT. Angiotensin II
receptor binding following myocardial infarction in the rat.
Cardiovasc Res. 1994;28:1623-1628.
21.
Urata H, Healy B, Stewart RW, Bumpus FM, Husain A.
Angiotensin II receptors in normal and failing
hearts. J Clin Endocrinol Metab. 1989;69:54-66.
22.
Sadoshima J, Izumo S. Molecular characterization
of angiotensin II induced hypertrophy of
cardiac myocytes and hyperplasia of cardiac fibroblasts: critical role
of the AT1 receptor subtype. Circ Res. 1993;73:413-423.
23. Seravalle G, Cattaneo BM, Giannattasio C, Perondi R, Saino A, Grassi G, Mancia G. RAA system and cardiovascular control in normal subjects, hypertensives and patients with congestive heart failure. J Hum Hypertens. 1993;7(suppl 2):S13-S18.
24. The CONSENSUS Trial Study Group. Effects of enalapril on mortality and severe congestive heart failure: results of the Cooperative North Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316:1429-1435. [Abstract]
25. SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart faiulure. N Engl J Med. 1991;325:293-302. [Abstract]
26. The SOLVD Investigators. Effect of enalapril on mortality in the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992;327:669-677. [Abstract]
27. Coats AJS, Adamopoulos S. Neurohumoral mechanisms and the role of angiotensin-converting enzyme (ACE) inhibitors in heart failure. Cardiovasc Drugs Ther. 1994;8:685-692. [Medline] [Order article via Infotrieve]
28.
Ruzicka M, Leenen FHH. Relevance of blockade of
cardiac and circulatory angiotensin-converting enzyme
for the prevention of volume overload–induced cardiac
hypertrophy. Circulation. 1995;91:16-19.
29.
Bruckschlegel G, Holmer SR, Jandeleit K, Grimm D,
Muders F, Kromer EP, Riegger GAJ, Shunkert H. Blockade of the
renin-angiotensin system in cardiac
pressure-overload hypertrophy in rats.
Hypertension. 1995;25:250-259.
30.
Abassi ZA, Burnett JC, Grushka E, Hoffman A, Haramati
A, Winaver J. Atrial natriuretic peptide and renal
cGMP in rats with experimental heart failure. Am J
Physiol. 1991;261:R858-R864.
31. Abassi ZA, Kotob S, Golomb E, Pieruzzi F, Keiser HR. Pulmonary and renal reutral endopeptidase EC 3.4.24.11 in rats with experimental heart failure. Hypertension, in press.
32. Stumpe KO, Solle H, Klein H, Kruck F. Mechanism of sodium and water retention in rats with experimental heart failure. Kidney Int. 1973;4:309-317. [Medline] [Order article via Infotrieve]
33. Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987;162:156-159. [Medline] [Order article via Infotrieve]
34. Fukamizu A, Nishi K, Cho T, Saitoh M, Nakayama K, Ohkubo H, Nakanishi S, Murakami K. Structure of the rat renin gene. J Mol Biol. 1988;201:443-450. [Medline] [Order article via Infotrieve]
35. Koike G, Krieger JE, Jacob HJ, Mukoyama M, Pratt RE, Dzau VJ. Angiotensin converting enzyme and genetic hypertension: cloning of rat cDNAs and characterization of the enzyme. Biochem Biophys Res Commun. 1994;198:380-386. [Medline] [Order article via Infotrieve]
36. Murphy TJ, Alexander RW, Griendling KK, Runge MS, Bernstein KE. Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor. Nature. 1991;351:233-236. [Medline] [Order article via Infotrieve]
37. Mukoyama M, Nakajima M, Horiuchi M, Sasamura H, Pratt RE, Dzau VJ. Expression cloning of type 2 angiotensin II receptor reveals a unique class of seven-transmembrane receptors. J Biol C. 1993;268:24539-24542.
38.
Nudel U, Zakut R, Shani M, Neuman S, Levy Z, Yaffe D.
The nucleotide sequence of the rat cytoplamic
ß-actin gene. Nucleic Acids Res. 1983;11:1759-1771.
39. Maeda T, Balakrishinan K, Mehdi Q. A simple and rapid method for the preparation of plasma membranes. Biochim Biophys Acta. 1983;731:115-120. [Medline] [Order article via Infotrieve]
40. Dzau VJ. Renin-angiotensin system and renal circulation in clinical congestive heart failure. Kidney Int. 1987;31(suppl 20):S203-S209.
41.
von Lutterotti N, Catanzaro DF, Sealy JE, Laragh JH.
Renin is not synthesized by cardiac and extrarenal tissues: a
review of experimental evidence.
Circulation. 1994;89:458-470.
42.
Dzau VJ, Re R. Tissue angiotensin
system in cardiovascular medicine: a paradigm
shift? Circulation. 1994;89:493-498.
43.
Hirsh AT, Talsness CE, Shunkert H, Paul M, Dzau VJ.
Tissue-specific activation of cardiac
angiotensin converting enzyme in experimental heart
failure. Circ Res. 1991;69:475-482.
44.
Boer PH, Ruzicka M, Lear W, Harmsen E, Rosenthal J,
Leenen FHH. Stretch-mediated activation of cardiac renin
gene. Am J Physiol. 1994;267:H1630-1636.
45. Morgan K, Wharton J, Webb JC, Keogh BE, Smith PLC, Taylor KM, Oakley CM, Polak JM, Cleland JCF. Co-expression of renin-angiotensin system component genes in human atrial tissue. J Hypertens. 1994;12(suppl 4):S11-S19.
46.
Pinto YM, de Smet BGJL, van Gilst WH, Sholtens E,
Monnik S, de Graeff PA, Wesseling H. Selective and time related
activation of the cardiac renin-angiotensin system
after experimental heart failure: relation to ventricular
function and morphology. Cardiovasc Res. 1993;27:1933-1938.
47.
Shiota N, Miyazaki M, Okunishi H. Increase of
angiotensin converting enzyme gene expression in the
hypertensive aorta. Hypertension. 1992;20:168-174.
48. Studer R, Reinecke H, Muller B, Holtz J, Just H, Drexler H. Increased angiotensin-I converting enzyme gene expression in the failing human heart. J Clin Invest. 1994;94:301-310.
49.
Shunkert H, Jackson B, Tang SS, Schoen FJ, Smits JFM,
Apstein CS, Lorell BH. Distribution and functional significance
of cardiac angiotensin converting enzyme in hypertrophied
rat hearts. Circulation. 1993;87:1328-1339.
50.
Mizuno K, Nakamura M, Higushimori K, Inagami T.
Local generation of angiotensin II in
peripheral vascular tissue.
Hypertension. 1988;11:223-229.
51. Vicaut E, Hou X. Local renin-angiotensin system in the microcirculation of spontaneously hypertensive rats. Hypertension. 1994;24;70-76.
52. Sun Y, Ratajska A, Zhou G, Weber KT. Angiotensin-converting enzyme and myocardial fibrosis in the rat receiving angiotensin II or aldosterone. J Lab Clin Med. 1993;122;395-403.
53. Matsubara H, Kanasaki M, Murasawa S, Tsukaguchi Y, Nio Y, Inada M. Differential gene expression and regulation of angiotensin II receptor subtypes in rat cardiac fibroblasts and cardiomyocytes in culture. J Clin Invest. 1994;93:1592-160.
54. Sun Y, Weber KT. Angiotensin II and aldosterone receptor binding in rat heart and kidney: response to chronic angiotensin II or aldosterone administration. J Lab Clin Med. 1993;122:404-411. [Medline] [Order article via Infotrieve]
55.
Lopez JJ, Lorell BH, Ingelfinger JR, Wienberg EO,
Shunkert H, Diamant D, Tang SS. Distribution and function of
cardiac angiotensin AT1 and AT2 receptor subtypes in
hypertrophied rat hearts. Am J Physiol. 1994;267:H844-H852.
56.
Ardaillou R. Angiotensin II type 2
receptor: does it have a role in the normal diseased kidney?
Nephrol Dial Transplant. 1994;9:1364-1365.
57. Nio Y, Matsubara H, Murasawa S, Kanasaki M, Inada M. Regulation of gene transcription of angiotensin II receptor subtypes in myocardial infarction. J Clin Invest. 1995;95:46-54.
58.
Suzuki J, Matsubara H, Urakami M, Inada M. Rat
angiotensin II (type 1A) receptor mRNA regulation and
subtype expression in myocardial growth and
hypertrophy. Circ Res. 1993;73:439-447.
59.
Shunkert H, Tang SS, SLitwin SE, Diamant D, Riegger G,
Dzau VJ, Ingelfinger JR. Regulation of intrarenal and
circulating renin-angiotensin systems in severe heart
failure in the rat. Cardiovasc Res. 1993;27:731-735.
60. Schunkert H, Ingelfinger JR, Hirsch AT, Tang SS, Litwin SE, Talsness CE, Dzau VJ. Evidence for tissue-specific activation of renal angiotensinogen mRNA expression in chronic stable experimental heart failure. J Clin Invest. 1992;90:1523-1529.
61.
Huang H, Arnal JF, Ilorens-Cortes C, Challah M,
Alhenc-Gelas F, Corvol P, Michel JB. Discrepancy between plasma
and lung angiotensin-converting enzyme activity in
experimental congestive heart failure. Circ
Res. 1994;75:454-461.
62.
Keiser JA, Bjork FA, Hodges JC, Taylor DG Jr.
Renal hemodynamic and excretory responses to PD
123319 and losartan, nonpeptide AT-1 and AT-2
subtype-specific angiotensin II ligands.
J Pharmacol Exp Ther. 1992;262:1154-1160.
63. Edwards RM, Aiyar N. Angiotensin II receptor subtypes in the kidney. J Am Soc Nephrol. 1993;3:1643-1652. [Abstract]
64. Falkenhahn M, Gohlke P, Paul M, Stoll M, Unger T. The renin-angiotensin system in the heart and vascular wall: new therapeutic aspects. J Cardiovasc Pharmacol. 1994;24(suppl 2):S6-S13.
65. Dzau VJ. Cell biology and genetics of angiotensin in cardiovascular disease. J Hypertens. 1994;12(suppl 4):S3-S10.
66. Swales JD. The renin-angiotensin system as a target for therapeutic intervention. J Cardiovasc Pharmacol. 1994;24(suppl 2):S1-S5.
67.
Haber HL, Powers ER, Gimple LW, Wu CC, Subbiah K,
Johnson WH, Feldman MD. Intracoronary
angiotensin-converting enzyme inhibition improves
diastolic function in patients with left
ventricular hypertrophy.
Circulation. 1994;89:2616-2625.
68.
Crozier I, Ikram H, Awan N, Cleland J, Stephen N,
Dickstein K, Frey M, Young J, Klinger G, Makris L, Rucinska E, for the
Losartan Hemodynamic Study Group.
Losartan in heart failure: hemodynamic
and tolerability. Circulation. 1995;91:691-697.
69.
Abassi ZA, Kelly G, Golomb E, Klein H, Keiser HR.
Losartan improves the natriuretic response
to ANF in rats with high-output heart failure.
J Pharmacol Exp Ther. 1994;268:224-230.
70. Eberhardt RT, Kevak RM, Kang PN, Frishman WH. Angiotensin II receptor blockade: an innovative approach to cardiovascular pharmacotherapy. J Clin Pharmacol. 1993;33:1023-1038. [Abstract]
71. Timmermans PBMWM, Wong PC, Chiu AT, Herblin WF, Smith RD. New perspectives in angiotensin system control. J Hum Hypertens. 1993;7(suppl 2):S19-S31.
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