(Circulation. 1995;92:2666-2675.)
© 1995 American Heart Association, Inc.
Articles |
Long-term Treatment With Angiotensin I–Converting Enzyme Inhibitors Attenuates the Loss of Cardiac ß-Adrenoceptor Responses in Rats With Chronic Heart Failure
From the Department of Pharmacology, Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo, Japan.
Correspondence to Satoshi Takeo, PhD, Department of Pharmacology, Tokyo University of Pharmacy and Life Science, 1432-1, Horinouchi, Hachioji, Tokyo, 192-03 Japan.
 |
Abstract |
|---|
 Top Abstract IntroductionMethods Results Discussion References |
|---|
Background Cardiac contractile force in response to ß-adrenoceptor agonists and ß-adrenergic receptor density are decreased in failing human hearts. The effects of angiotensin I–converting enzyme (ACE) inhibitor on cardiac responsiveness to ß-adrenergic stimulation in failing hearts are not established. The present study was undertaken to determine whether ACE inhibitor may improve cardiac ß-adrenergic responsiveness in animals with chronic heart failure (CHF).
Methods and Results CHF was induced by left coronary artery ligation in rats. Cardiac output and stroke volume indices decreased 12 weeks after the operation. In sham-operated rats, dobutamine and isoprenaline increased cardiac output and stroke volume indices. In contrast, cardiac output and stroke volume responses to dobutamine and isoprenaline were severely blunted in the CHF rat. Cardiac ß1-adrenergic receptor density was decreased while its dissociation constant (Kd) was not altered in the viable tissue of the left ventricle of the CHF rat, which is consistent with ß-adrenergic receptor downregulation. Cardiac norepinephrine content decreased in the CHF rats. Rats were treated orally with ACE inhibitors, 3 mg/kg trandolapril or 10 mg/kg enalapril once daily, or 5 mg/kg captopril twice daily from the 2nd to the 12th weeks after the operation. Treatment with ACE inhibitors attenuated the reduction in cardiac output and stroke volume indices and improved the inotropic response to dobutamine and isoprenaline and reversed partially the cardiac norepinephrine content in the CHF rat. ACE inhibitor treatment also attenuated the reduction in ß1-adrenergic receptor density in the viable tissue of the left ventricle of the CHF rat.
Conclusions The results suggest that ACE inhibitor treatment attenuates the blunting of cardiac responses to ß-adrenergic agonists in the CHF rat and that one of the mechanisms underlying this effect is prevention of cardiac ß1-adrenergic receptor downregulation.
Key Words: angiotensin • receptors, adrenergic, beta • heart failure
|
Introduction |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Cardiac response to ß-adrenergic stimulants has been shown to be decreased in both experimental animals and humans with CHF.1 2 3 4 5 6 7 8 9 The decrease in the response has been demonstrated to be accompanied by functional impairment of the heart.2 4 5 Furthermore, several reports have shown a selective decrease in the density of ß-adrenergic receptors in failing human hearts and a significant reduction in cardiac contractile force in response to ß-adrenoceptor agonists.2 3 5 Thus, one of the mechanisms responsible for the decreased response of failing human hearts to ß-adrenoceptor agonist is considered to be the downregulation of ß-adrenergic receptors.10 11 12 13 14 15
Long-term treatment with ACE inhibitors has been demonstrated to improve cardiac performance and survival in humans and animals with CHF.16 17 18 19 Several mechanisms have been considered to play a role in this effect, such as decreases in preload and afterload,20 21 a restoration of reduced baroreflex sensitivity,22 23 and an inhibition of tissue renin-angiotensin system activation.24 25 26 Altered interaction between renin-angiotensin system and sympathetic nerve system is another possible mechanism. Several reports have shown that angiotensin II enhances sympathetic nerve activity by potentiating the release of NE27 28 29 30 and by inhibiting the reuptake of NE in sympathetic nerve terminal.31 32 Angiotensin II also facilitates the release of catecholamines from the adrenal medulla.33 34 Thus, an increase in local NE concentration in response to angiotensin II may result in a downregulation of cardiac ß-adrenergic receptors and a reduction in contractile response to ß-adrenoceptor agonists in the failing heart. The possibility exists, therefore, that the beneficial effect of ACE inhibition in CHF is, in part, due to prevention of the desensitization of cardiac ß-adrenergic receptor/adenylate cyclase pathway.
There is, however, little information concerning the effect of ACE inhibitors on cardiac responsiveness to ß-adrenergic stimulation in CHF animals. The present study was designed to examine the effect of long-term treatment with a variety of ACE inhibitors, captopril, a typical ACE inhibitor with sulfhydryl moiety in its chemical structure, enalapril, a potent ACE inhibitor prodrug, and trandolapril, a novel, long-acting ACE inhibitor prodrug,35 on cardiac responsiveness to ß-adrenergic stimulation in rats with CHF after myocardial infarction. It is one of the purposes of the present study to compare therapeutic potency of trandolapril with that of captopril and enalapril in terms of improvement of cardiac function and ß-adrenergic receptor system in the CHF animals.
|
Methods |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Male Wistar rats (SLC, Shizuoka, Japan) weighing 200 to 260 g were used in the present study. Before and during experiments, they were fed standard rat chow and tap water ad libitum, housed in polyethylene cages, and maintained in a 12-hour light and 12-hour dark cycle according to the Guidelines of Experimental Animal Care issued by the Prime Minister's Office of Japan.
Coronary Artery Ligation
Myocardial infarction was induced in
150 rats by occluding the
left coronary artery according to the method described
previously.36 37 Animals were anesthetized with
ether. The skin was incised along the left sternal border and the
fourth rib was cut proximal to the sternum. The pericardial sac was
perforated, and the heart was exteriorized through the intracostal
space. The left coronary artery was ligated approximately 2 mm
from its origin with a suture of 5-0 silk. The heart was repositioned
in the chest. During the operation, the rats were maintained with
positive-pressure ventilation. The mortality of the operated
animals was approximately 42% within 1 week. Sixty-five
sham-operated animals were treated similarly except that the suture
was not tied around the coronary artery.
Hemodynamic and biochemical assessments were performed
12 weeks after operation. In a previous study, it was found that
cardiac output and stroke volume indices were not altered after 4 weeks
but were significantly decreased 8 and 12 weeks after the
operation.36 Thus, we consider that a chronic phase of
heart failure is established by the 12th week after the operation.
Treatment With ACE Inhibitors
Rats were treated with an oral
administration of either 5 mg/kg
of captopril twice daily or 10 mg/kg of enalapril or 3 mg/kg of
trandolapril once daily, from the 2nd to 12th week after the operation.
Trandolapril was suspended in 0.25% sodium carboxymethyl cellulose,
and enalapril and captopril were dissolved in distilled water. The drug
solutions with a volume of 0.3 mL were injected into the stomach
through a probe.
Measurements of Hemodynamic Parameters
in Open Chest Rats
Hemodynamic parameters of CHF and
sham-operated animals with or without ACE inhibitor
treatment were determined according to the method described
previously.36 Twelve weeks after the operation, the animal
was anesthetized with a gas mixture of nitrous
oxide–oxygen (3:1) containing 0.5% to 2.5% halothane. The
animals were heated by an electronic panel heater to maintain their
body temperature at 36.5°C during the experiments. Under
positive-pressure ventilation, a right thoracotomy was performed
and an electromagnetic flowmeter with a diameter of 2 to 2.5 mm (model
MFV-3100, Nihonkohden) was placed around the ascending aorta for
measurement of aortic flow as described previously.36 MAP
was measured via a cannula inserted into the left femoral artery by
means of a pressure transducer (model DX-360, Nihonkohden). Heart rate
measurement was triggered from changes in systemic blood pressure
(model AT-601G, Nihonkohden). After a 10-minute equilibration period,
the parameters were recorded on a thermal pen
recorder for 10 minutes (model RTA-1200, Nihonkohden). Cardiac
output and stroke volume indices were calculated by dividing aortic
flow by body weight and cardiac output index by heart rate,
respectively. SVR was calculated by dividing mean arterial
pressure by cardiac output index.38 In a preliminary
study, we performed blood gas analysis of the experimental
animals by means of a blood gas analyzer (model 288 Blood Gas
System, Ciba-Corning). The pH, Po2, and
PCO2 of the animals 5 minutes after the onset
of the experiment were 7.41±0.02, 90.0±11.5, and 36.5±1.2
mm Hg and
after 45 minutes, 7.36±0.03, 100.8±3.2, and 30.5±3.5
mm Hg (n=6),
respectively. These results indicate that the present experiment
was carried out under stable conditions.
Effects of Long-term Treatment With ACE Inhibitors
on the Response of Hemodynamic Parameters
to ß-Adrenergic Receptor Agonists in Open Chest Rats
After
measurement of baseline values of
hemodynamic parameters, the effects of
ß-adrenoceptor agonists on these parameters were
examined. Dobutamine (2, 4, and 8 µg/kg), a relatively
selective ß1-adrenoceptor agonist, or isoprenaline (0.01
µg/kg), a nonselective ß-adrenoceptor agonist, was administered
intravenously through a cannula inserted into the right
femoral vein. All drugs were dissolved in 0.9% NaCl to yield a
concentration of 1 mg/mL and diluted to the desired concentrations with
0.9% NaCl. All drug solutions were freshly prepared. The injection
volume of each drug was less than 0.2 mL per rat. The effects of these
agents on aortic flow, MAP, heart rate, and time course of changes in
these parameters were recorded. The peak values of
these parameters were examined.
Measurements of Tissue Weight and Infarct Size
After
measurement of the aortic flow, the animals were killed by
intravenous administration of 1 mL of 30 mmol/L KCl. The
heart was isolated and cut into eight slices of 1-mm width. The slices
were stained with 0.0125% nitro blue tetrazolium chloride (NBT). The
infarct and remaining left ventricular areas were
determined by the method of Pfeffer et al.16
Preparation of the Samples for Receptor Binding Assay
The
specific binding of [3H]CGP-12177 to cardiac
ß-adrenergic receptors, ß1- plus
ß2-receptors of the sham-operated rats and the CHF
rats with or without ACE inhibitor treatment was measured
according to the method of Gopalarishnan et al,10 with a
minor modification. Animals were killed by decapitation. Hearts were
quickly isolated and rinsed in ice-cold 50 mmol/L
tris(hydroxymethyl)aminomethane (Tris)-HCl buffer (pH 7.2).
After the atria and connective tissue were removed, the ventricles were
separated into three sections, scar tissue, the remaining left
ventricle including interventricular septum, and right
ventricle. After weighing, the remaining left ventricle was
homogenized in 10 vol/g wet wt of Tris-HCl buffer, pH 7.2,
with a Polytron homogenizer (model PT-10, Kinematica)
with two cycles of 15 seconds at the maximal speed. The
homogenates were filtered through four layers of gauze, and
the filtrate was used for the radioligand receptor binding
assay. Several reports have shown a significant loss in the densities
of total binding sites (
70% to 80%) when radioligand
binding assays were performed using microsomal membranes prepared by
differential centrifugation
methods.10 39 40 Therefore, to examine
the loss of density
of total binding site and the potential artifact that might arise
during preparation of membranes by a differential
centrifugation method, we carried out the binding study
using both homogenate and microsomal membrane preparations.
Microsomal membrane fractions were prepared by centrifuging the
homogenate at 1100g for 20 minutes, followed by
centrifugation of the supernatant at
45 000g for 45 minutes. The final pellet was resuspended
and used for the binding assay.
To obtain the total binding capacity, the homogenates (250 to 350 µg protein) of the remaining left ventricles were incubated at 25°C for 60 minutes in 0.5 mL of the Tris-HCl buffer containing 5x10-11 to 1x10-9 mol/L of [3H]CGP-12177, filtered through a glass fiber filter (model GC-50, Advantec), and washed twice with a 2-mL volume of ice-cold buffer. After drying the filter parer, its radioactivity was counted by liquid scintillation spectrometry (LSC-1000, Aloka) with an efficiency of 55% to 65%. The nonspecific binding capacity was determined in the presence of 10-6 mol/L propranolol. The specific binding activity of [3H]CGP-12177 to cardiac homogenates was estimated by subtracting the nonspecific binding activity from the total binding activity.
Subpopulation of ß-adrenergic receptor was measured according to the method of Satoh et al,41 with a minor modification: The binding activity was determined in a 0.5-mL incubation buffer (Tris-HCl, pH 7.2) containing 0.75 nmol/L [3H]CGP-12177 in the presence of various concentrations of antagonists in the same manner as above. In the present study, betaxolol and ICI-118551 were used as a selective ß1-adrenergic receptor antagonist and a selective ß2-adrenergic receptor antagonist, respectively.
Kinetic analysis was carried out on an NEC PC-9801 computer system that can perform iterative nonlinear regression according to the method of Satoh et al,41 based on the theory of Munson and Rodbard.42 Dissociation constant (Kd) and maximum binding capacity (Bmax) of specific [3H]CGP-12177 binding were determined by Scatchard analysis.43 In the displacement study, parameters (IC50 values at ß1- and ß2-adrenergic receptors, and %ß1- and %ß2-adrenergic receptors) for competitions of betaxolol and ICI-118551 with specific [3H]CGP-12177 binding at two sites were estimated by nonlinear regression analysis of data that were fitted to a two-site binding model. Values for inhibition constants (Ki) of betaxolol and ICI-118551 to [3H]CGP-12177 specific binding at ß1- and ß2-adrenergic receptors, respectively, were estimated using the equation of Cheng and Prusoff.44 In the present study, we used only trandolapril to examine the effects of ACE inhibitor on the subpopulation of ß-adrenoceptors of the CHF rat heart homogenate since the agent was most effective in improving hemodynamic variables of the CHF rat among these ACE inhibitors. Protein concentrations of the samples were determined by the method of Lowry et al45 using bovine serum albumin as standard.
Determination of Cardiac NE
In the present study, we used
only trandolapril to examine
the effects of ACE inhibitor on the NE contents of the
remaining left ventricle in CHF rat for the same reason as above. The
rats were anesthetized with 50 mg/kg IP sodium pentobarbital.
The animals were ventilated with 2.75 to 3.0 mL/cycle of air at 60
cycles/min. After thoracotomy, the myocardium was rapidly
frozen by pouring liquid nitrogen into a column surrounding the
myocardium (column freezing method) as described
previously36 37 and then isolated. The isolated
frozen
myocardium was separated under liquid nitrogen cooling into
three portions: scar tissue, the remaining left ventricle and
interseptum, and right ventricle. The frozen tissue of the remaining
left ventricle was homogenized in 0.2 mol/L
HClO4 and 0.01% EDTA-Na2 with a Polytron
homogenizer (model PT-10, Kinematica). The
homogenate was centrifuged at 10 000g
for 15 minutes at 4°C. The supernatant solution was passed through
alumina acidified with diluted HCl. The eluate was filtered through a
membrane filter (0.45 µm) and the aliquot was applied to a
high-performance liquid chromatograph (HPLC) with
an electrical detector (model ECD-100, Eicom, Kyoto). The HPLC-ECD
system was composed of a reverse-phase column (MA-5 ODS, 150x4.6
mm inside diameter, Eicom). The mobile phase contained 0.1 mol/L citric
acid/0.1 mol/L sodium acetate, 5 mg/L EDTA-Na2, 230
mg/L sodium octane sulfonate, and 5% methanol, pH 3.5, in deionized
and distilled water.
Materials
[3H]CGP-12177 (specific
activity, 1.96 TBq/mmol)
was obtained from Amersham. Dobutamine hydrochloride was
purchased from Shionogi Co Ltd, l-isoprenaline hydrochloride and
captopril from Sigma Chemical Co, and ICI-118551 from Cambridge
Research Biochemicals Ltd. Betaxolol hydrochloride was kindly given by
Mitsubishi Chemical Co. Enalapril maleate and trandolapril were donated
by Nippon Russel Co Ltd.
Statistical Analysis
Data are expressed as mean±SEM.
Statistical significance was
estimated by unpaired Student's t test for comparison of
values between sham-operated and CHF rats and between CHF rats with
and without trandolapril treatment, or ANOVA, followed by Dunnett's
multiple comparison for comparison of values with and without ACE
inhibitor treatment.
|
Results |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Tissue Weight and Infarct Size
Effects of long-term treatment with ACE inhibitors on the tissue weight of CHF rats are shown in Table 1
.
There were no significant differences in the body and left
ventricular weights between the sham-operated and CHF
rats. The right ventricular and lung weights in the CHF rat
were higher than those of the sham-operated rat. The ratios of
right ventricular weight/body weight and lung weight/body
weight in the CHF rat were higher than those of the sham-operated
rat. Treatment with ACE inhibitors decreased the body
weight, left ventricular weight, right ventricular weight,
and lung weight of the CHF rat, but left ventricular
weight/body weight ratio was not altered. The left ventricle and lung
weights of the sham-operated rat were decreased by treatment with
enalapril and trandolapril. The left ventricular
weight/body weight ratio of the sham-operated rat was decreased by
treatment with captopril and enalapril, and the lung weight/body weight
ratio by treatment with enalapril. The infarct areas of the CHF rat are
shown in Table 2. The infarct size of the CHF rat was
about 40% of the left ventricle and this level was not altered by ACE
inhibitor treatment.
|
|
Effects of ß-Adrenoceptor Agonist on
Hemodynamic Parameters
Typical responses of hemodynamic
parameters to dobutamine (2 µg/kg IV), a
ß1-adrenoceptor agonist, in the sham-operated rat and
the CHF rat with or without long-term trandolapril treatment are
shown in Fig 1. The effects of long-term treatment
with several ACE inhibitors on the response of
hemodynamic parameters to the
ß-adrenoceptor agonists in open chest CHF rats are shown in Figs 2 through
6.
|
|
|
|
|
|
Significant decreases in baseline values of cardiac output and stroke volume indices and a significant increase in SVR were observed in the CHF rat compared with those of the sham-operated rat. There were no significant differences in baseline values of MAP and heart rate between the sham-operated and the CHF rats. The ACE inhibitor treatment significantly attenuated the reduction in baseline values of cardiac output and stroke volume indices and the increase in SVR in the CHF rat. Treatment with trandolapril decreased in baseline values of MAP in the CHF rats. There were no significant differences in baseline values of heart rate between untreated and treated CHF rats. Treatment with ACE inhibitors resulted in no significant differences in any parameter of baseline values of the sham-operated rat.
Dobutamine dose-dependently increased
the cardiac
output and stroke volume indices in the sham-operated rat (Figs
2
and 3). The positive inotropic effect of
isoprenaline
was also observed in the sham-operated rat. The responsiveness of
cardiac output and stroke volume indices to the ß-adrenoceptor
agonists was reduced in the CHF rat. Long-term treatment with ACE
inhibitors improved the response of cardiac output and
stroke volume indices to ß-adrenoceptor agonists in the CHF rat.
ß-Adrenoceptor agonist–induced changes in cardiac output and
stroke volume were unaltered in sham-operated groups by ACE
inhibitor treatment. The response of heart rate to
dobutamine was decreased in the CHF rat compared with that
of the sham-operated rat (Fig 4).
Dobutamine did not alter heart rate in the CHF rat
regardless of whether they were or were not treated with ACE
inhibitors. The response of heart rate to the
ß-adrenoceptor agonists was also reduced in the
sham-operated rat after long-term treatment with trandolapril.
MAP was increased in untreated sham-operated rats by
dobutamine injection (Fig 5). However,
dobutamine reduced the MAP of sham-operated rats with
long-term ACE inhibitor treatment. The response of MAP
to dobutamine was attenuated in the CHF rat compared with
that of the sham-operated rat. In the CHF rat with long-term
trandolapril treatment, dobutamine reduced the MAP compared
with that of the untreated group. Isoprenaline also reduced the MAP in
the CHF rat with long-term trandolapril treatment. There were no
differences in SVR response to ß-adrenoceptor agonists between
the sham-operated and the CHF rats (Fig 6).
Treatment with either trandolapril or enalapril enhanced the reduction
in SVR in response to dobutamine in both sham-operated
and CHF rats.
Radioligand Binding Activity
Fig 7 shows
typical binding activities using
[3H]CGP-12177 in heart homogenates of
sham-operated and CHF rats with or without trandolapril treatment.
A single population of [3H]CGP-12177 binding site was
detected in the viable left ventricular
homogenates of both sham-operated and CHF rats within
the ligand concentration range studied. Specific
[3H]CGP-12177 binding activity to ventricular
homogenates ranging from 50% to 70% of total binding
activity was unaltered between the sham-operated and the CHF rats.
The maximum density of [3H]CGP-12177 binding site in the
viable left ventricular homogenates of the CHF
rat was reduced regardless of whether it was expressed in terms of wet
weight or protein content. There was no change in the equilibrium
dissociation constant (Kd) in the viable left
ventricular homogenates of the CHF rat compared
with that of the sham-operated rat (Table 3).
|
|
We also observed a decrease (P<.05) in the density of maximum [3H]CGP-12177 binding site of microsomal membranes isolated from the left ventricle of CHF rats (34.22±0.96 fmol/mg protein, n=4) compared with that of sham-operated rats (42.13±2.24 fmol/mg protein, n=4), without a significant change in the Kd (sham-operated: 0.215±0.047 nmol/L, n=4; CHF: 0.180±0.020 nmol/L, n=4).
Long-term treatment with
ACE inhibitors prevented the
decrease in maximum density of the binding site for
[3H]CGP-12177 in the remaining left
ventricular homogenates of CHF rats when
expressed in terms of protein content or wet weight (Table 3).
Subpopulations of ß1- and ß2-adrenergic
receptors in the remaining left ventricular
homogenates of CHF rats treated or untreated with
trandolapril are shown in Table 4. When betaxolol was
used for the binding study, we found the distribution of about 70% of
ß1- and 30% of ß2-adrenergic receptors in
the left ventricular homogenates of
sham-operated rats. When ICI-118551 was used, 27% of
ß2- and 72% of ß1-adrenergic receptors
were detected in sham-operated rats. This implicated that
distribution of ß1- and ß2-adrenergic
receptors on cardiac muscles is approximately 70% of ß1-
and 30% of ß2-adrenergic receptors. The ratio of
ß1-:ß2-adrenergic receptors changed in CHF
rats (ß1:ß2=52:48), and the subpopulation
of ß1-adrenergic receptor density was decreased in the
remaining left ventricular homogenates of the
CHF rats compared with that of sham-operated rats despite no
changes in ß2-adrenergic receptor density.
Long-term treatment with trandolapril attenuated the changes in the
ratio of ß1-:ß2-adrenergic receptors and
the decrease in ß1 subpopulation density in the remaining
left ventricular homogenates of CHF rats. There
were no significant changes in Ki between
the sham-operated rats and the CHF rats with and without
trandolapril treatment.
|
Cardiac NE Contents
Table 4 shows cardiac NE
contents in CHF rats with and
without trandolapril treatment. A decrease in the left
ventricular NE content was observed in CHF rats compared
with that of sham-operated rats. Long-term treatment with
trandolapril prevented the decrease in the remaining left
ventricular NE content of the CHF rats.
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
In the present study, we have shown that coronary artery ligation of the rat induced a 40% left ventricular muscle infarction, decreased cardiac output and stroke volume indices, and increased SVR 12 weeks after the operation, which demonstrated the development of CHF with low cardiac output. Significant improvement of cardiac output and stroke volume indices and significant attenuation of the increase in SVR were observed in rats with CHF after long-term treatment with ACE inhibitors. The pathophysiological alterations in hemodynamic variables in the CHF model and the effects of ACE inhibitors on the alterations are essentially in agreement with the observations of other investigators, who used captopril as an ACE inhibitor and examined cardiac function in in vivo animals16 20 or isolated papillary muscles.9
The increases in cardiac output and stroke volume by a nonselective ß-adrenoceptor agonist, isoprenaline, and a relatively selective ß1-adrenoceptor agonist, dobutamine,46 were markedly attenuated in CHF rats in vivo. Treatment with ACE inhibitors restored the response of cardiac output and stroke volume to ß-adrenoceptor agonists in rats with CHF. Our findings are new in terms of altered responsiveness of the heart to ß-adrenoceptor agonists in vivo and the effects of different ACE inhibitors on the parameters.
To examine the effects of cardiotonic agents on cardiac function, we measured cardiac output in the anesthetized open chest rat in the present study. Since approximately 40% of the left ventricle was infarcted in the CHF rat, only the remaining viable myocardium could respond to cardiotonic agents. Thus, the decreased cardiac responsiveness to cardiotonic agents might be due to the loss of myocardial mass in CHF rats. The left ventricular weight and left ventricular weight/body weight ratio of CHF rats, however, were not altered compared with those of sham-operated rats despite the presence of a 40% loss of myocardial mass. This may result from compensatory hypertrophy of the remaining myocardium. Furthermore, the infarct size was not altered in CHF rats by ACE inhibitor treatment. Therefore, the decreased ß-adrenergic responsiveness may be due to desensitization of the remaining myocardium, and the recovery of the ß-adrenergic responsiveness after ACE inhibitor treatment may be due to resensitization.
We observed that ß-adrenergic receptor density, measured by [3H]CGP-12177 binding, was reduced in homogenates of failing hearts, which is consistent with the reports of other investigators.10 11 12 13 14 15 Furthermore, the present study has shown that the subpopulation of cardiac ß-adrenergic receptors of the sham-operated rats consists of approximately 70% of ß1- and 30% of ß2-adrenergic receptors. Similar values for the subpopulation of ß1- and ß2-adrenergic receptors have been demonstrated in normal rats47 and humans.15 48 Our data show that ß1-adrenergic receptor was downregulated, whereas any change in ß2-adrenergic receptor density was not detected. Long-term treatment with trandolapril prevented the decrease in ß1-adrenergic receptor density of the remaining left ventricle without a significant change in the Kd in the CHF rat. Thus, the preservation of ß-adrenoceptor response after ACE inhibitor treatment may be due to prevention of ß1-adrenergic receptor downregulation or enhancement of upregulation in the remaining left ventricle in rats with CHF.
The mechanisms underlying changes in number of ß1-adrenergic receptor have not been extensively addressed in the present study. It is generally accepted that the sympathetic nervous system and renin-angiotensin system are closely interrelated.9 49 Angiotensin II facilitates sympathetic nerve activity by potentiating the NE release27 28 29 30 and by inhibiting the reuptake of NE in sympathetic nerve terminal31 32 as described in the introduction of this article. This may be followed by an increase in circulating NE levels. Actually, several reports have shown the increase in plasma NE levels in animals and humans with CHF.50 51 52 Chronic exposure of cardiac membranes to high levels of NE in response to angiotensin II may result in a downregulation of cardiac ß1-adrenergic receptors and a reduction in contractile response to ß-adrenoceptor agonists in the failing heart. Thus, ACE inhibitor treatment may affect cardiac ß1-adrenergic receptor density and cardiac NE content by attenuating the stimulatory effect of angiotensin II on the sympathetic nerve activity. The findings of a significant decrease in cardiac NE content in the CHF rats, a partial reversal of the NE content by treatment with trandolapril, and an almost complete prevention of ß-adrenergic receptor downregulation in the myocardium by the ACE inhibitor treatment in the present study are in agreement with this hypothesis.
It is likely that the decreased cardiovascular response to ß-adrenoceptor agonists observed in the present study can be attributed to the reduction in cardiac ß1-adrenergic receptor density. No change in cardiac ß-adrenergic receptor density was found, however, in the same model 2 to 3 weeks after coronary artery ligation.8 53 54 These differences may be due to period of the examination of ß-adrenoceptor density. This is supported by the findings that the reduction in ß-adrenergic receptor density of the remaining left ventricle was observed in rats 8 and 9 weeks or 5 months after coronary artery ligation.10 55 56 Thus, the downregulation of ß-adrenergic receptors in the remaining left ventricle after myocardial infarction may occur at a late stage of CHF.
The decrease in cardiac ß-adrenergic receptor density was relatively small compared with that in cardiac response to ß-adrenoceptor agonists. Thus, other mechanisms may also be involved in the recovery of responsiveness to ß-adrenergic stimulation after ACE inhibitor treatment. Ungerer et al1 reported that in the failing heart, the function of the remaining receptors was impaired due to phosphorylation by ß-adrenergic receptor kinase. In addition to biochemical changes at the receptor site, inhibitory guanine nucleotide-binding regulatory protein (Gi protein) has been reported to be increased in failing human hearts.4 57 58 Increased function of the Gi protein–mediated inhibitory pathway may compromise the ability of the failing heart to generate sufficient amount of c-AMP. Long-term treatment with ACE inhibitors may attenuate these alterations in the failing heart.
The ß-adrenoceptor agonist–induced decreases in MAP and SVR in CHF and sham-operated rats were enhanced by ACE inhibitor treatment. Stead and Bloor59 showed that captopril potentiated the hypotensive effect of sodium nitroprusside and decreased dose requirement of the sodium nitroprusside in halothane-anesthetized rabbits. They postulated that this phenomenon was due to inhibition of both sympathetic nervous system and renin-angiotensin system by ACE inhibitor treatment. The decreases in MAP and SVR by ß-adrenoceptor agonists in the present study may also be attributed to this mechanism.
In the present study, we used 10 mg/kg captopril, 10 mg/kg enalapril, and 3 mg/kg trandolapril. The efficacy of the three ACE inhibitors at doses used was similar in terms of the recovery of responsiveness to ß-adrenoceptor agonist and prevention of downregulation of ß-adrenergic receptors in the failing hearts. Improved cardiac function and survival have been reported in CHF rats after administration of 10 mg/kg captopril for 12 weeks61 and the administration of 10 mg/kg enalapril for 1 week prolonged the time to development of severe heart failure in dogs induced by rapid ventricular pacing.61 Trandolapril is a novel ACE inhibitor that has been reported to be 2.3- to 10-fold more potent than enalapril.35 62 63 64 The CHF therapy in the present study showed the similar efficacy of these ACE inhibitors in the responsiveness of the heart to ß-adrenoceptor agonists and the cardiac ß-adrenergic receptor downregulation in the CHF rats. The differences in the efficacy of these ACE inhibitors at doses used were only seen in the effects on MAP and SVR in the CHF animals. Trandolapril treatment was the most effective in reducing these variables. This suggests that the effects of the ACE inhibitors on vascular resistance are unlikely related to, or indirectly involved in, the prevention of downregulation of the heart in the CHF animals.
In summary, we demonstrated in the present study that long-term treatment with several ACE inhibitors attenuates the blunting of cardiac responses to ß-adrenergic agonists in the CHF rat under in vivo conditions and that one of the mechanisms underlying this effect is the restoration of the number of cardiac ß1-adrenergic receptors. The effects may be, in part, due to prevention and/or improvement of downregulated ß1-adrenergic receptor in the remaining left ventricle. Since other investigators8 53 54 did not observe the development of ß-adrenergic receptor downregulation 2 to 3 weeks after coronary artery ligation, a time to initiate the ACE inhibitor therapy, improvement of downregulated ß1-adrenergic receptor is unlikely to be a mechanism for the benefit of ACE inhibitor therapy. The prevention of ß1-adrenergic receptor downregulation, in addition to the inhibition of renin-angiotensin system, may play an important role in the effect of ACE inhibitors on the failing heart.
|
Selected Abbreviations and Acronyms |
|---|
|
Received September 7, 1994; revision received May 24, 1995; accepted June 12, 1995.
|
References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Ungerer M, Böhm M, Elce JS, Erdmann E, Lohse MJ. Altered expression of ß-adrenergic receptor kinase and ß1-adrenergic receptors in the failing human heart. Circulation. 1993;87:454-463.
2. Bristow MR, Ginsburg R, Minobe W, Cubicciotti RS, Sageman WS, Lurie K, Billingham ME, Harrison DC, Stinson EB. Decreased catecholamine sensitivity and ß-adrenergic-receptor density in failing human hearts. N Engl J Med. 1982;307:205-211. [Abstract]
3.
Bristow MR, Ginsburg R, Umans V, Fowler M, Minobe W,
Rasmussen R, Zera P, Menlove R, Shah P, Jamieson S, Stinson EB.
ß1- and ß2-Adrenergic-receptor
subpopulations in nonfailing and failing human ventricular
myocardium: coupling of both receptor subtypes to muscle
contraction and selective ß1-receptor downregulation in
heart failure. Circ Res. 1986;59:297-309.
4.
Bristow MR, Anderson FL, Port JD, Skerl L, Hershberger
RE, Larrabee P, O'Connell JB, Renlund DG, Volkman K, Murray J, Feldmam
AM. Differences in ß-adrenergic neuroeffector mechanisms
in ischemic versus idiopathic dilated
cardiomyopathy.
Circulation. 1991;84:1024-1039.
5.
Fowler MB, Laser JA, Hopkins GL, Minobe W, Bristow MR.
Assessment of the ß-adrenergic receptor pathway in the
intact failing human heart: progressive receptor downregulation and
subsensitivity to agonist response.
Circulation. 1986;74:1290-1302.
6. Fan T-HM, Liang C-S, Kawashima S, Banerjee SP. Alterations in cardiac ß-adrenoceptor responsiveness and adenylate cyclase system by congestive heart failure in dogs. Eur J Pharmacol. 1987;140:123-132.[Medline] [Order article via Infotrieve]
7.
Levett JM, Marinelli CC, Lund DD, Pardini BJ, Nader S,
Scott BD, Augelli NV, Kerber RE, Schmid PG Jr. Effects of
ß-blockade on neurohumoral responses and neurochemical markers in
pacing-induced heart failure. Am J Physiol. 1994;266:H468-H475.
8.
Cherng W-J, Liang C-S, Hood WB Jr. Effects of
metoprolol on left ventricular function in rats with
myocardial infarction. Am J Physiol. 1994;266:H787-H794.
9.
Litwin SE, Morgan JP. Captopril enhances
intracellular calcium handling and ß-adrenergic responsiveness of
myocardium from rats with postinfarction failure.
Circ Res. 1992;71:797-807.
10.
Gopalakrishnan M, Triggle DJ, Rutledge A, Kwon YW,
Bauer JA, Fung H-L. Regulation of K+ and
Ca2+ channels in experimental cardiac
failure. Am J Physiol. 1991;261:H1979-H1987.
11. Liang C-S, Fan T-HM, Sullebarger JT, Sakamoto S. Decreased adrenergic neuronal uptake activity in experimental right heart failure: a chamber-specific contributor to beta-adrenoceptor downregulation. J Clin Invest. 1989;84:1267-1275.
12. Denniss AR, Colucci WS, Allen PD, Marsh JD. Distribution and function of human ventricular beta adrenergic receptors in congestive heart failure. J Mol Cell Cardiol. 1989;21:651-660. [Medline] [Order article via Infotrieve]
13. Gengo PJ, Sabbah HN, Steffen RP, Sharpe JK, Kono T, Stein PD, Goldstein S. Myocardial beta adrenoceptor and voltage sensitive calcium channel changes in a canine model of chronic heart failure. J Mol Cell Cardiol. 1992;24:1361-1369. [Medline] [Order article via Infotrieve]
14. Kozlovskis PL, Smets MJD, Duncan RC, Bailey BK, Bassett AL, Myerburg RJ. Regional beta-adrenergic receptors and adenylate cyclase activity after healing of myocardial infarction in cats. J Mol Cell Cardiol. 1990;22:311-322. [Medline] [Order article via Infotrieve]
15.
Beau SL, Tolley TK, Saffitz JE.
Heterogeneous transmural distribution of
ß-adrenergic receptor subtypes in failing human hearts.
Circulation. 1993;88:2501-2509.
16.
Pfeffer JM, Pfeffer MA, Braunwald E. Influence
of chronic captopril therapy on the infarcted left ventricle of the
rat. Circ Res. 1985;57:84-95.
17. Pfeffer JM, Pfeffer MA, Braunwald E. Hemodynamic benefits and prolonged survival with long-term captopril therapy in rats with myocardial infarction and heart failure. Circulation. 1987;75(suppl I):I-149-I-155.
18. The SOLVD investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293-302. [Abstract]
19. The SOLVD investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992;327:685-691. [Abstract]
20.
Raya TH, Gay RG, Aguirre M, Goldman S.
Importance of venodilatation in prevention of left
ventricular dilatation after chronic large myocardial
infarction in rats: a comparison of captopril and
hydralazine. Circ Res. 1989;64:330-337.
21. Emmert SE, Stabilito II, Sweet CS. Acute and subacute hemodynamic effects of enalaprilat, milrinone and combination therapy in rats with chronic left ventricular dysfunction. Clin Exp Hypertens (A). 1987;9(2-3):297-306.
22.
Deck CC, Raya TE, Gaballa MA, Goldman S.
Baroreflex control of heart rate in rats with heart failure
after myocardial infarction: effects of captopril. J
Pharmacol Exp Ther. 1992;263:1424-1431.
23.
Packer M. Neurohormonal interactions and
adaptations in congestive heart failure.
Circulation. 1988;77:721-730.
24.
Hirsh AT, Talsness CE, Schunkert H, Paul M, Dzau VJ.
Tissue-specific activation of cardiac
angiotensin converting enzyme in experimental heart
failure. Circ Res. 1991;69:475-482.
25. Fabris B, Jackson B, Kohzuki M, Perich R, Johnston CI. Increased cardiac angiotensin-converting enzyme in rats with chronic heart failure. Clin Exp Pharmacol Physiol. 1990;17:309-314. [Medline] [Order article via Infotrieve]
26. Yamagishi H, Kim S, Nishikimi T, Takeuchi K, Takeda T. Contribution of cardiac renin-angiotensin system to ventricular remodeling in myocardial-infarcted rats. J Mol Cell Cardiol. 1993;25:1369-1380. [Medline] [Order article via Infotrieve]
27. Hatton R, Clough DP. Captopril interferes with neurogenic vasoconstriction in the pithed rat by angiotensin-dependent mechanisms. J Cardiovasc Pharmacol. 1982;4:116-123. [Medline] [Order article via Infotrieve]
28.
Isaacson JS, Reid IA. Importance of
endogenous angiotensin II in the
cardiovascular responses to sympathetic stimulation in
conscious rabbits. Circ Res. 1990;66:662-671.
29.
Rump LC, Schwertfeger E, Schaible U, Fraedrich G,
Schollmeyer P. ß2-Adrenergic receptor and
angiotensin II receptor modulation of sympathetic
neurotransmission in human atria. Circ
Res. 1994;74:434-440.
30. Clemson B, Gaul L, Gubin SS, Campsey, DM, McConville J, Nussberger J, Zelis R. Prejunctional angiotensin II receptors. J Clin Invest. 1994;93:684-691.
31. Hughes J, Roth RH. Evidence that angiotensin enhances transmitter release during sympathetic nerve stimualtion. Br J Pharmacol. 1971;41:239-255. [Medline] [Order article via Infotrieve]
32. Kiran BK, Khairallah PA. Angiotensin and norepinephrine efflux. Eur J Pharmacol. 1969;6:102-108. [Medline] [Order article via Infotrieve]
33. Feuerstein G, Boonyaviroj P, Gutman Y. Renin-angiotensin mediation of adrenal catecholamine secretion induced by haemorrhage. Eur J Pharmacol. 1977;44:131-142. [Medline] [Order article via Infotrieve]
34. Feuerstein G, Boonyaviroj P, Gutman Y, Khosla MC, Bumpus FM. Adrenal catecholamine response to haemorrhage abolished by an angiotensin antagonist. Eur J Pharmacol. 1977;41:85-86. [Medline] [Order article via Infotrieve]
35. Duc LNC, Brunner HR. Trandolapril in hypertension: overview of a new angiotensin-converting enzyme inhibitor. Am J Cardiol. 1992;70:27D-34D. [Medline] [Order article via Infotrieve]
36. Sanbe A, Tanonaka K, Hanaoka Y, Katoh T, Takeo S. Regional energy metabolism of failing hearts following myocardial infarction. J Mol Cell Cardiol. 1993;25:995-1013. [Medline] [Order article via Infotrieve]
37.
Sanbe A, Tanonaka K, Niwano Y, Takeo S.
Improvement of cardiac function and energy
metabolism of rats with chronic heart failure by
long-term coenzyme Q10 treatment. J
Pharmacol Exp Ther. 1994;269:51-56.
38.
Hirata Y, Matsuoka H, Suzuki E, Hayakawa H, Sugimoto T,
Matsuda Y, Morishita Y, Kangawa K, Minamino N, Matsuo H, Sugimoto T.
Role of endogenous atrial natriuretic peptide in
DOCA-salt hypertensive rats: effects of a novel nonpeptide
antagonist for atrial natriuretic peptide
receptor. Circulation. 1993;87:554-561.
39. Bambrick LL, Howlett SE, Feng Z-P, Gordon T. Radioligand binding to muscle homogenates to quantify receptor and ion channel numbers. J Pharmacol Methods. 1988;20:313-321. [Medline] [Order article via Infotrieve]
40.
Wolff AA, Hines DK, Karliner JS. Refined
membrane preparations mask ischemic fall in myocardial
ß-receptor density. Am J Physiol. 1989;257:H1032-H1036.
41. Satoh E, Narimatsu A, Hosohata Y, Tsuchihashi H, Nagatomo T. The affinity of betaxolol, a ß1-adrenoceptor-selective blocking agent, for ß-adrenoceptor in the bovine trachea and heart. Br J Pharmacol. 1993;108:484-489. [Medline] [Order article via Infotrieve]
42. Munson PJ, Rodbard D. Ligand: a versatile computerized approach for the characterization of ligand binding systems. Anal Biochem. 1980;107:220-239.[Medline] [Order article via Infotrieve]
43. Scatchard G. The attraction of proteins for small molecules and ions. Ann N Y Acad Sci. 1949;51:660-672.
44. Cheng YC, Prusoff WH. Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 percent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol. 1973;22:3099-3108. [Medline] [Order article via Infotrieve]
45.
Lowry OH, Rosebrough HJ, Farr AL, Randall RJ.
Protein measurement with the Folin phenol reagent.
J Biol Chem. 1951;193:265-275.
46. Maccarrone C, Malta E, Raper C. ß-Adrenoceptor selectivity of dobutamine: in vivo and in vitro studies. J Cardiovasc Pharmacol. 1984;6:132-141. [Medline] [Order article via Infotrieve]
47. Tsutihashi H, Yokoyama H, Nagatomo T. Binding characteristics of 3H-CGP12177 to ß-adrenoceptors in rat myocardial membranes. Jpn J Pharmacol. 1989;49:11-19. [Medline] [Order article via Infotrieve]
48. Bristow MR, Hershberger RE, Port JD, Minobe W, Rasmussen R. ß1-and ß2-Adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing human ventricular myocardium. Mol Pharmacol. 1989;35:295-303. [Abstract]
49.
Gilbert EM, Sandoval A, Larrabee P, Renlund DG,
O'Connell JB, Bristow MR. Lisinopril lowers cardiac
adrenergic drive and increases ß-receptor density in the failing
human heart. Circulation. 1993;88:472-480.
50.
Meredith IT, Eisenhofer G, Lambert GW, Dewar EM,
Jennings GL, Esler MD. Cardiac sympathetic nervous activity in
congestive heart failure: evidence for increased neuronal
norepinephrine release and preserved neuronal
uptake. Circulation. 1993;88:136-145.
51. Francis GS, Goldsmith SG, Cohn JN. Relationship of exercise capacity to resting left ventricular performance and basal plasma norepinephrine levels in patients with congestive heart failure. Am Heart J. 1982;104:725-731. [Medline] [Order article via Infotrieve]
52.
Hodsman GP, Kohzuki M, Howes LG, Sumithran E, Tunoda K,
Johnston CI. Neurohumoral responses to chronic myocardial
infarction in rats. Circulation. 1988;78:376-381.
53. Clozel J-P, Holck M, Osterrieder W, Burkard W, Prada MD. Effects of chronic myocardial infarction on responsiveness to isoprenaline and the state of myocardial beta adrenoceptors in rats. Cardiovasc Res. 1987;21:688-695. [Medline] [Order article via Infotrieve]
54. Yamamoto J, Ohyanagi M, Morita M, Iwasaki T. ß-Adrenoceptor-G protein-adenylate cyclase complex in rat hearts with ischemic heart failure produced by coronary artery ligation. J Mol Cell Cardiol. 1994;26:617-626. [Medline] [Order article via Infotrieve]
55.
Warner AL, Bellah KL, Raya TE, Roeske WR, Goldsmith S.
Effects of ß-adrenergic blockade on papillary muscle
function and the ß-adrenergic receptor system in noninfarcted
myocardium in compensated ischemic left
ventricular dysfunction.
Circulation. 1992;86:1584-1595.
56. Meggs LG, Huang H, Li P, Capasso JM, Anversa P. Chronic nonocclusive coronary artery constriction in rats. J Clin Invest. 1991;88:1940-1946.
57.
Böhm M, Gierschik P, Jakobs K-H, Pieske B,
Schnabel P, Ungerer M, Erdmann E. Increase of Gia in
human hearts with dilated but not ischemic
cardiomyopathy.
Circulation. 1990;82:1249-1265.
58.
Eschenhagen T, Mende U, Nose M, Schmitz W, Scholz H,
Haverich A, Hirt S, Dõing V, Kalmár P, Hõppner W,
Seitz H-J. Increased messenger RNA level of the
inhibitory G protein 
subunit Gia-2 in human
end-stage heart failure. Circ Res. 1992;70:688-696.
59. Stead SW, Bloor BC. The effects of captopril on the renin-angiotensin system and the sympathetic nervous system during sodium nitroprusside-induced hypotension in the halothane-anesthetized rabbit. J Cardiovasc Pharmacol. 1990;15:465-471. [Medline] [Order article via Infotrieve]
60.
Bech OM, Sorensen JD, Jensen MK, Diamant B, Steiness E.
Effects of long-term coenzyme Q10 and captopril treatment on
survival and functional capacity in rats with experimentally induced
heart infarction. J Pharmacol Exp Ther. 1990;255:346-350.
61. Moe GW, Montgomery C, Howard RJ, Grima EA, Armstrong PW. Left ventricular myocardial blood flow, metabolism, and effects of treatment with enalapril: further insights into the mechanisms of canine experimental pacing-induced heart failure. J Lab Clin Med. 1993;121:294-301. [Medline] [Order article via Infotrieve]
62. Fornes P, Richer C, Pussard E, Heudes D, Domergue V, Giudicelli J-F. Beneficial effects of trandolapril on experimentally induced congestive heart failure in rats. Am J Cardiol. 1992;70:43D-51D. [Medline] [Order article via Infotrieve]
63. Luca ND, Rosiello G, Lamenza F, Ricciardlli B, Marchegiano R, Volpe M, Marelli C, Trimarco B. Reversal of cardiac and large artery structural abnormalities induced by long-term antihypertensive treatment with trandolapril. Am J Cardiol. 1992;70:52D-59D. [Medline] [Order article via Infotrieve]
64. Freslon J-L, Pourageaud F, Lecaque D, Secchi J. Effects of trandolapril on vascular morphology and function during the established phase of systemic hypertension in the spontaneously hypertensive rat. Am J Cardiol. 1992;70:35D-42D.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  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]
|
|
|
|
 |
|
 T. Makino, Y. Hattori, N. Matsuda, H. Onozuka, I. Sakuma, and A. Kitabatake Effects of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Type 1 Receptor Blockade on beta -Adrenoceptor Signaling in Heart Failure Produced by Myocardial Infarction in Rabbits: Reversal of Altered Expression of beta -Adrenoceptor Kinase and Gialpha J. Pharmacol. Exp. Ther., January 1, 2003; 304(1): 370 - 379. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Yoshida, K. Tanonaka, Y. Miyamoto, T. Abe, M. Takahashi, M. B Anand-Srivastava, and S. Takeo Characterization of cardiac myocyte and tissue {beta}-adrenergic signal transduction in rats with heart failure Cardiovasc Res, April 1, 2001; 50(1): 34 - 45. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Witte, K. Hu, J. Swiatek, C. Mussig, G. Ertl, and B. Lemmer Experimental heart failure in rats: effects on cardiovascular circadian rhythms and on myocardial {beta}-adrenergic signaling Cardiovasc Res, August 1, 2000; 47(2): 350 - 358. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Igawa, T. Nozawa, N. Yoshida, N. Fujii, M. Inoue, S. Tazawa, H. Asanoi, and H. Inoue Heterogeneous cardiac sympathetic innervation in heart failure after myocardial infarction of rats Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1134 - H1141. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Yonemochi, S. Yasunaga, Y. Teshima, T. Iwao, K. Akiyoshi, M. Nakagawa, T. Saikawa, and M. Ito Mechanism of ß-Adrenergic Receptor Upregulation Induced by ACE Inhibition in Cultured Neonatal Rat Cardiac Myocytes : Roles of Bradykinin and Protein Kinase C Circulation, June 9, 1998; 97(22): 2268 - 2273. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bohm, O. Zolk, M. Flesch, F. Schiffer, P. Schnabel, J.-P. Stasch, and A. Knorr Effects of Angiotensin II Type 1 Receptor Blockade and Angiotensin-Converting Enzyme Inhibition on Cardiac ß-Adrenergic Signal Transduction Hypertension, March 1, 1998; 31(3): 747 - 754. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||