(Hypertension. 1997;30:1369-1375.)
© 1997 American Heart Association, Inc.
Articles |
Cardiac Production and Secretion of Adrenomedullin Are Increased in Heart Failure
From the Research Institute (T.N, F.Y., A.M., K.K., H.M.) and Department of Medicine (T.H., T.S., S.T.), National Cardiovascular Center, Osaka 565, Japan.
Correspondence to Toshio Nishikimi, MD, Division of Hypertension, National Cardiovascular Center, 5–7-1, Fujishirodai Suita, Osaka 565, Japan. E-mail nishikim{at}jsc.ri.ncvc.go.jp
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Abstract |
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Abstract Plasma adrenomedullin (AM) levels are reportedly increased in heart failure, but whether the cardiac production and secretion of AM is increased in heart failure remains unknown. To investigate the sites of production and secretion of AM in heart failure, we measured plasma AM levels and peptide and mRNA levels of AM in various tissues in rats with heart failure. We also examined whether the heart actually secretes AM into the circulation in patients with heart failure. We measured plasma and tissue AM levels by specific radioimmunoassay and AM mRNA by Northern blot analysis in rats with heart failure produced by aortocaval fistula. We also measured plasma AM levels in the coronary sinus and aorta in patients with left ventricular dysfunction before and after rapid right ventricular pacing. The increase in plasma AM levels in heart failure rats correlated with ventricular weight. Tissue AM levels were increased in the heart and lungs but not in the kidneys or adrenals of rats with heart failure. Similarly, tissue AM mRNA levels were also increased in the heart and lungs of heart failure rats. Plasma AM levels were higher in the coronary sinus than in the aorta in patients with left ventricular dysfunction. Rapid right ventricular pacing increased plasma atrial natriuretic peptide but not AM. These results suggest that plasma AM levels are increased in heart failure in proportion to the severity of heart failure and that cardiac production and secretion of AM is increased in heart failure rats. The lung may be another site for increased production of AM in heart failure rats. Human failing heart actually secretes AM into the circulation, and the regulation of AM secretion appears to differ from that of atrial natriuretic peptide.
Key Words: adrenomedullin • heart failure • atrial natriuretic peptide • fistula, aortocaval
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Introduction |
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Adrenomedullin, originally isolated from an extract of human pheochromocytoma tissue, is a novel vasodilatory peptide with 52 amino acid residues.1 AM circulates in human blood at levels comparable to ANP,2 and it has been reported that plasma AM levels are increased in hypertension, renal failure, and heart failure in proportion to the clinical severity of the disorders.3 4 5 Recent reports demonstrate that vascular smooth muscle cells possess specific AM receptors that are functionally coupled to adenylate cyclase.6 7 Indeed, AM dilates the regional vascular bed by a cAMP-dependent mechanism.8 It has also been shown that an NO/cGMP mechanism may be involved in the regional vasculature.9 10 These findings suggest that AM may play a role in the regulation of the cardiovascular system. An early study reported that AM mRNA is highly expressed not only in the adrenal gland but also in heart, lung, and kidney.1 A recent immunohistochemical study revealed that AM immunoreactivity is higher in the failing heart than in the normal heart.5 It was reported that AM has a negative inotropic action in the perfused rat heart.11 In addition, Ikenouchi et al12 very recently reported that AM causes a negative inotropic response in isolated rabbit cardiac myocytes through the NO/cGMP pathway. These results suggest that AM may be involved in the control of cardiac function in heart failure. However, whether the production of AM in failing hearts is increased remains unknown.
The purpose of the present study was to investigate the production and secretion of AM in the failing heart. In study 1, we produced a heart failure model in rats and measured tissue AM peptide and AM mRNA levels in heart, lung, kidney, and adrenal gland. Additionally, in study 2 we measured plasma AM levels at the aorta and coronary sinus before and after rapid right ventricular pacing in heart failure patients with left ventricular dysfunction.
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Methods |
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Study 1
Model of Heart Failure
Adult male Wistar rats weighing from 250 to 300 g were used in this study. The rats were kept at a controlled room temperature under a 12/12-h light/dark cycle and given pellet rat chow and tap water. After an acclimatization period of at least 3 days, aortocaval fistula (n=11) was produced in rats by a method previously described13 and modified in our laboratory.14 15 In brief, after the rats were anesthetized with pentobarbital sodium 30 mg/kg IP, the abdominal cavity was entered through a midline incision. The inferior vena cava and abdominal aorta were exposed and occluded with a silk ligature below the renal artery and above the aortic bifurcation. All branches were occluded in a similar fashion. The abdominal aorta was punctured with an 18-gauge disposable needle at the midpoint between the renal artery and aortic bifurcation. The needle was then advanced into the aorta, perforating the opposite wall and then penetrating the wall of the inferior vena cava. The 18-gauge needle was withdrawn into the lumen of the abdominal aorta and then carefully guided to penetrate another region of the inferior vena cava at a different angle. This procedure was done several times. After the 18-gauge needle was fully withdrawn, a drop of cyanoacrylate glue was used to seal the aortic puncture point. After 10 to 20 seconds, the silk ligature was then removed carefully. The presence of a shunt was easily confirmed by observing the mixing of blood in the inferior vena cava. Control rats (n=8) underwent an identical operation, but a fistula was not established. Approximately 20% to 30% of aortocaval fistula rats without treatment died within 1 week. As a result, nine heart failure rats were studied.
Hemodynamic Study
Approximately 4 weeks after surgery, hemodynamic
studies were performed as reported previously.14 15 16 Rats
were anesthetized by intraperitoneal
injection of pentobarbital sodium 30 mg/kg body wt and placed on
a heating pad to maintain the body temperature at 37°C to 38°C
throughout the study. A tracheostomy was performed with a polyethylene
tube (PE-240). A polyethylene catheter (PE-50) was inserted into the
thoracic aorta via the right carotid artery to measure heart rate,
systolic and diastolic blood pressures, and mean
arterial pressure. Then the catheter was advanced into the
left ventricle to measure the left ventricular
end-diastolic pressure. All pressures were measured with a
pressure transducer (model P23 ID, Gould Inc) connected to a polygraph
and recorder (7758 B System, Hewlett-Packard). After these
hemodynamic measurements were made, 3 mL of blood was
obtained from the carotid artery and was transferred to a chilled glass
tube containing 500 U/mL aprotinin and 1 mg/mL disodium EDTA for
the measurement of plasma AM levels. Blood was centrifuged
immediately at 4°C, and the plasma was frozen and stored at -80°C
until assayed. The heart was arrested in diastole by the
injection of 2 mmol KCl through the carotid artery. Immediately
after the injection, the organs (including the ventricles, atria,
lungs, left kidney, and left adrenal gland) were removed and weighed,
frozen in liquid nitrogen, and stored at -80°C until extraction for
RIA or RNA blot analysis.
RIA for Tissue AM
Each tissue for RIA was weighed, diced, and boiled in 10 vol of
1 mol/L acetic acid for 10 minutes to inactivate
intrinsic proteases. After cooling, boiled tissue was
homogenized with a Polytron mixer for several minutes. The
homogenate was centrifuged at 3000g for
30 minutes, and the supernatant was centrifuged again at
15 000g for 10 minutes. The supernatant was evaporated in a
vacuum until dry. RIA for rat AM was performed as reported
previously.17 Anti-AM antiserum (#172CI-7), which
recognizes the C-terminal region of rat AM, was used in this RIA. The
incubation buffer for RIA contained 50 mmol/L sodium
phosphate buffer (pH 7.4), 0.5% bovine serum albumin, 0.5%
Triton X-100, 80 mmol/L NaCl, 25 mmol/L
disodium EDTA, and 0.05% NaN3. The RIA incubation mixture
consisted of 100 µL AM or an unknown sample solution, 50 µL of
antiserum at a dilution of 1:140 000, and 50 µL of
125I-labeled peptide (18 000 cpm). After incubation for 40
hours, free and bound tracers were separated by the polyethyleneglycol
method. Radioactivity of the pellet was counted with a gamma counter
(ARC-1000 mol/L, Aloka), and assays were performed in
duplicate.
RIA for Plasma AM
Rat plasma samples were diluted with an equal volume of saline
and loaded onto Sep-Pak C18 cartridges (1.0 mL) that were
preequilibrated with saline. Adsorbed materials were eluted with 4.0 mL
of 60% acetonitrile in 0.1% trifluoroacetic acid. RIA for rat plasma
AM was performed as described above.
Northern Blot Analysis for Rat AM mRNA
Total RNA was extracted from each tissue (ventricle, lung, or
kidney) by the acid guanidium thiocyanate-phenol-chloroform
method.18 The total RNA pellet was dissolved in 0.1%
diethyl pyrocarbonate–treated water and stored at -80°C until use.
The RNA concentration was determined based on absorbance at 260 nm.
Total RNA (30 µg per lane) was denatured with formaldehyde and
formamide and electrophoresed on a 1% agarose gel containing
formaldehyde. The 28S and 18S ribosomal RNAs were stained with ethidium
bromide in the gels to confirm the integrity of loaded RNA. RNA in the
gel was then transferred to a nylon membrane (Zeta-Probe blotting
membrane, Bio-Rad Laboratories) and cross-linked by ultraviolet
irradiation. The membrane was prehybridized at 42°C for 3 hours in a
solution containing 1% SDS, 5x SSPE (0.75 mol/L NaCl, 60
mmol/L NaH2PO4, 5 mmol/L
EDTA; pH 7.4), 50% formamide, 5x Denhardt's solution (0.1%
polyvinylpyrrolidone, 0.1% Ficoll, 0.1% bovine serum
albumin), and 250 µg/mL salmon sperm DNA; it was then
hybridized with a 32P-labeled cDNA probe in the same
solution at 42°C for 18 to 20 hours. The cDNA probe used as a probe
was an EcoRI/Nae I restriction fragment of rat AM
cDNA corresponding to nucleotides -153 to 436 that was
radiolabeled by random priming with [
-32P] dCTP
(Amersham). After hybridization, the membrane was washed with 0.5x SSC
(75 mmol/L NaCl, 7.5 mmol/L sodium citrate)
containing 0.1% SDS at 40°C for 30 minutes and then submitted to
autoradiography. Band intensity was estimated by a
radioimage analyzer (BAS 2000, Fuji). To normalize the rat AM
signal to the loaded amounts and transfer efficiencies, the same
membrane was rehybridized with a ß-actin cDNA probe. Rehybridization
was carried out after probes were stripped by a boiling in 0.1% SDS
for 20 minutes.
Study 2
Patients
Informed consent was obtained from each patient, and the
protocol was approved by the ethics committee of our institution.
Eighteen patients with heart failure (NYHA class II, n=14; NYHA class
III, n=4) were studied. Patient characteristics are presented
in Table 3
. The cause of the ventricular dysfunction in
these patients included cardiomyopathy (n=15) and
other metabolic heart diseases (n=3). All patients with
heart failure were undergoing treatment, which included digitalis,
diuretics, and/or vasodilators. M-mode
echocardiography was performed within 1 week of
cardiac catheterization with a Toshiba Sonolayer
SSH-160A echocardiograph (Toshiba) and transducers with an
oscillator frequency of 2.5 or 3.75 MHz as reported
previously.19 20 Left ventricular internal
dimensions were made at both end-diastole and end-systole
in accordance with the recommendations of the American Society of
Echocardiography.21 Percent fractional
shortening was calculated with standard formulas.
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Protocol
When patients underwent left and right cardiac
catheterization, the following study was performed.
After routine cardiac catheterization was finished and
hemodynamics were stabilized, a 5F multi-purpose
catheter was placed in the coronary sinus under fluoroscopic
guidance, and the position of the catheter tip in the coronary
sinus was confirmed by the injection of a small dose of contrast
medium. Right ventricular pacing was performed (140/min)
for 15 minutes. Before and immediately after pacing, 5 mL of blood was
taken from each of the coronary sinuses and aortas and was
transferred to chilled glass tubes containing 500 U/mL aprotinin and 1
mg/mL disodium EDTA for the measurement of AM and ANP. Plasma AM
levels were measured by specific RIA after extraction of plasma with
Sep-Pak C18 as previously reported.2 22 Plasma ANP was
measured by immunoradiometric assay with a Shiono RIA ANP assay kit
(Shionogi Co, Ltd).23
Statistical Analysis
All results are presented as mean±SD. Unpaired or
paired Student's t test was performed to determine the
presence of significant differences between the two groups, if
appropriate. A value of P<.05 was considered significant.
Correlation coefficients were calculated using linear regression
analysis.
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Results |
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Study 1
Organ Weight and Hemodynamics in Sham-Operated Rats and Rats With Heart Failure
The body weight and weights of the ventricles, atria, lungs,
kidney, and adrenal glands in sham-operated and heart failure groups
are presented in Table 1.
Ventricular, atrial, and lung weights were greater in the
heart failure groups than in the sham-operated groups. No significant
differences in kidney and adrenal gland weights existed between the two
groups. Hemodynamics of the sham-operated and heart
failure groups are shown in Table 2.
Heart failure rats had a higher left ventricular
end-diastolic pressure and pulse pressure than the sham
rats. There were no differences in heart rate between the two groups;
however, the mean arterial pressures were lower in the
heart failure group than in the sham-operated group.
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Plasma and Tissue AM Levels in Sham and Heart Failure Rats
Plasma levels of AM are shown in Fig 1. The mean plasma AM level in
sham-operated rats was 3.3 pmol/L. The mean plasma AM level in
the heart failure group was significantly greater than in the
sham-operated group. Plasma AM levels were significantly correlated
with left ventricular weight in the heart failure group
(Fig 2). Tissue AM levels are shown in
Fig 3. The heart failure group had higher
tissue AM levels in the ventricle and lungs compared with the
sham-operated group. Tissue AM levels in atria tended to be lower in
the heart failure group than in the sham-operated group; however, the
differences did not reach statistical significance. No differences in
tissue AM levels in the kidney or adrenal gland existed between the two
groups.
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Expression of Rat AM mRNA in Various Tissues
The expression of rat AM mRNA in the ventricle, lung, and kidney
of both heart failure rats and sham-operated rats was studied by
Northern blot analysis. Fig 4
shows a representative result of RNA blot
analysis from these tissues. The bands hybridizing to the rat
AM cDNA probe were found at the position of approximately 1.6 Kb. A
quantitative analysis of these blots corrected for the level of
ß-actin mRNA as an internal standard is shown in Fig 5. The expression of AM mRNA in the
ventricle was higher in heart failure rats (1.7 fold) than in
sham-operated rats. The AM mRNA levels of the lung in rats with heart
failure were also significantly increased (1.8 fold). In the kidney,
however, AM gene expression did not differ between heart failure and
sham-operated rats.
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Study 2
Plasma AM and ANP levels before and after pacing are shown in Fig 6. Plasma ANP levels before pacing were
significantly higher in the coronary sinus than in the aortas
in 18 patients with heart failure. Fifteen minutes of pacing
significantly increased plasma ANP levels in both the aorta and
coronary sinus. Plasma AM levels before pacing were slightly
but significantly higher in the coronary sinus than in the
aorta. However, 15 minutes of pacing did not increase the plasma AM
levels in the aorta or coronary sinus.
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Discussion |
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In the present study, we demonstrated that plasma AM levels are increased in heart failure rats compared with the sham-operated rats and that plasma AM levels were significantly correlated with ventricular weight. Furthermore, the heart and lung of rats with heart failure had higher tissue AM peptide and AM mRNA levels than those of sham-operated rats; however, no differences in tissue AM levels in the kidney, atria, or adrenal gland existed between the two groups. Plasma AM levels were slightly but significantly higher in the coronary sinus than in the aorta in patients with left ventricular dysfunction; however, rapid right ventricular pacing did not increase plasma AM levels either in the coronary sinus or aorta. These results suggest that plasma AM levels are increased in heart failure in proportion to the heart failure severity and that tissue AM peptide levels and AM mRNA levels are increased in the heart and lungs in heart failure in an organ-specific manner. The human failing heart actually secretes AM into the circulation, and the regulation of AM secretion appears to be different from that of ANP.
AM is a recently discovered hypotensive peptide that was isolated from human pheochromocytoma tissue by monitoring cAMP activity in rat platelets and consists of 52 amino acids.1 Many physiological actions of AM have been reported. Previous reports have shown that AM not only reduces the blood pressure but also increases renal blood flow and the excretion of sodium and water.24 25 AM also has been shown to reduce pulmonary artery pressure and increase pulmonary blood flow by decreasing pulmonary vascular resistance.26 27 Immunoreactive AM has been detected in human plasma in levels comparable to those of ANP.1 These results suggest that AM may be involved in the pathophysiology of heart failure. Indeed, increased plasma concentrations of AM have been reported in patients with heart failure in proportion to the clinical severity of heart failure.4 5 28 In the present study, we demonstrated that plasma AM levels were increased in rats with heart failure produced by an aortocaval fistula. This model has typical characteristics of heart failure such as altered hemodynamics, a neuroendocrine disorder, and lower survival rate.14 15 29 30 31 32 Plasma AM levels significantly correlated with ventricular weight as an index of severity of heart failure, supporting the idea that plasma AM levels are increased in heart failure in proportion to the heart failure severity.
The source of increased plasma AM levels in heart failure remains unknown. An early study reported that AM mRNA was highly expressed in the adrenal gland, heart, kidney, and lung,1 suggesting that these organs may produce and secrete AM into the circulation. Therefore, in the present study, we measured tissue AM levels in the adrenal gland, heart, kidney, and lung in rats with heart failure and sham-operated rats to investigate the possibility of greater AM production in these organs in heart failure. No significant difference in tissue AM levels in the kidney, atria, or adrenal glands was found, whereas a significant increase of tissue AM levels in the heart and lung in rats with heart failure compared with sham-operated rats was demonstrated. This suggests that tissue AM levels are increased in an organ-specific manner in heart failure. This increase of AM levels in the heart seems to be consistent with previous findings that AM immunoreactivity is greater in failing than that in normal hearts.5 However, immunohistochemical studies cannot determine whether the heart actually produces more AM in heart failure because the heart has been reported to have many AM binding sites.33 The present study demonstrated that AM mRNA expression in the heart and lung was greater in rats with heart failure than in sham-operated rats. These results suggest that the heart and lung synthesize more AM in rats with heart failure than in sham-operated rats and that the heart and lungs may contribute in part to the increased plasma AM levels in heart failure.
In the present study, we also investigated whether the human failing heart can actually secrete AM into the circulation and whether rapid ventricular pacing stimulates the release of AM from the heart. We showed that plasma AM levels were slightly but significantly higher in the coronary sinus than in the aorta of patients with left ventricular dysfunction, suggesting that the human failing heart actually secretes AM into the circulation. This finding is consistent with previous reports.28 In this study, we extended our investigation into the effect of right ventricular pacing on plasma AM levels and demonstrated that right ventricular pacing for 15 minutes did not increase plasma AM levels in the coronary sinus or aorta, although pacing significantly increased plasma ANP levels. We recently reported that exercise or acute volume infusion increased plasma ANP levels but not plasma AM levels in patients with heart failure or hypertension.34 35 36 On the other hand, we previously reported that plasma AM levels significantly decreased in patients with heart failure after treatment for a mean duration of 14 days.4 Taken together with the present results, these findings indicate that the regulation of AM secretion is different from that of ANP. The slow regulation of plasma AM levels may be partly due to its mechanism of secretion. Many hormones, including ANP, are stored in large amounts in secretory granules and are secreted via a regulated pathway. Therefore, ANP responds rapidly after pacing. In contrast, AM production is regulated at the levels of gene expression and AM is secreted via a constitutive pathway without intermediate storage in secretory granules.18 37 Thus, a relatively chronic stimulus may be required to induce AM gene expression and secretion of AM.
In the present study, we showed that AM peptide and mRNA levels in the heart are increased in heart failure. Owji et al33 reported that there are many AM binding sites in the heart. AM has been reported to have a negative inotropic action in the perfused heart in rats.11 The considerable overlap between expression of AM peptide or mRNA and expression of AM receptors suggests that AM may act in an autocrine and/or paracrine manner in the heart and directly influence cardiac function. In fact, Ikenouchi et al12 have recently reported that AM decreased both contractility and calcium ions in the myocyte in a dose-dependent manner in isolated rabbit cardiac myocytes through the NO/cGMP pathway. Furthermore, Ikeda et al38 reported that the heart is a target organ of AM and that AM augments NO synthesis in the heart through a cAMP pathway under cytokine-stimulations. These findings suggest that increased AM in the heart may lead to a reduction in cardiac contractility through a NO/cGMP pathway, which has been shown to suppress myocardial contractility by decreasing cytoplasmic Ca2+ concentration. Whether this increased production of AM in the heart during heart failure is beneficial remains to be determined in future studies. Chronic activation of angiotensin II and endothelin in the heart, which have positive inotropic actions through an increase of cytoplasmic Ca2+ concentrations in the myocyte, has been shown to correlate with a poor prognosis in heart failure.39 40 41 Thus, it is possible that increased AM in the heart may act as a protective mechanism against the development of left ventricular dysfunction.
We also showed that AM peptide and mRNA levels in the lungs are
increased in heart failure compared with those in sham-operated rats.
Previous investigators reported an abundance of AM-specific binding
sites in the lungs.33 It has been reported that vascular
smooth muscle cells contain AM specific receptors that are functionally
coupled to adenylate cyclase.6 7 AM has been to
shown to reduce pulmonary artery pressure by decreasing
pulmonary vascular resistance.26 27 These findings
suggest that specific AM binding sites in the pulmonary artery
are present and that AM may be involved in the defense mechanism
against further elevation of secondary pulmonary hypertension
due to heart failure. The pulmonary vasodilatory mechanism of
AM remains unknown at the present time. Nossaman et
al42 reported that the pulmonary vasodilatory
activity of AM was 
10-fold more potent in the cat than in the rat,
whereas pulmonary vasodilatory responses to calcitonin
gene–related peptide were very similar in both species, suggesting
that potency of vasodilatory effects of AM are different in the
species. In addition, a recent study of Nossaman et al43
has shown that NO mediates pulmonary vasodilation of AM in the
rat but not in the cat. Thus, significant species differences exist in
regard to the mechanism of action of AM. Further studies, including
cloning of the AM receptor, are necessary to understand the cellular
mechanism of the vasodilatory action of AM.
In conclusion, this study provides evidence that plasma AM levels are increased in volume-overloaded rats with heart failure in proportion to ventricular weight. In particular, tissue AM peptide and AM mRNA levels are increased in the heart and lung of rats with heart failure compared with sham-operated rats. In the human failing heart, plasma AM levels are slightly but significantly higher in the coronary sinus than in the aorta. However, rapid right ventricular pacing did not change these AM levels. These results suggest that plasma AM levels are increased in heart failure in proportion to heart failure severity and that the heart and lung may partly contribute to this increase. The human failing heart actually can secrete AM into the circulation. This regulation of secretion appears to be slow. Further research should determine the exact role of increased plasma AM levels and increased AM production in the heart and lung of patients with heart failure.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by Special Coordination Funds for Promoting Science and Technology (Encouragement System of COE) from the Science and Technology Agency of Japan, the Ministry of Health and Welfare, and the Human Science Foundation of Japan. We wish to thank Yoko Saito for her technical assistance.
Received April 14, 1997; first decision May 23, 1997; accepted June 25, 1997.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, Eto T. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun. 1993;192:553–560.[Medline] [Order article via Infotrieve]
- Kitamura K, Ichiki Y, Tanaka M, Kawamoto M, Emura J, Sakakibara S, Kangawa K, Matsuo H, Eto T. Immunoreactive adrenomedullin in human plasma. FEBS Lett. 1994;341:288–290.[Medline] [Order article via Infotrieve]
- Ishimitsu T, Nishikimi T, Saito Y, Kitamura K, Eto T, Kangawa K, Matsuo H, Omae T, Matsuoka H. Plasma levels of adrenomedullin, a hypotensive peptide, in patients with hypertension and renal failure. J Clin Invest. 1994;94:2158–2161.
- Nishikimi T, Saito Y, Kitamura K, Ishimitsu T, Eto T, Kangawa K, Matsuo H, Omae T, Matsuoka H. Increased plasma levels of adrenomedullin in patients with heart failure. J Am Coll Cardiol. 1995;26:1424–1431.[Abstract]
-
Jougasaki M, Wei C, McKinley LJ, Burnett JC. Elevation
of circulating and ventricular adrenomedullin in human
congestive heart failure. Circulation. 1995;92:286–289.
[Abstract/Free Full Text] - Eguchi S, Hirata Y, Kano H, Sato K, Watanabe Y, Watanabe X, Nakajima K, Sakakibara S, Marumo F. Specific receptors for adrenomedullin in cultured rat vascular smooth muscle cells. FEBS Lett. 1994;340:226–230.[Medline] [Order article via Infotrieve]
- Ishizaka Y, Ishizaka Y, Tanaka M, Kitamura K, Kangawa K, Minamino N, Matsuo H, Eto T. Adrenomedullin stimulates cyclic AMP formation in rat vascular smooth muscle cells. Biochem Biophys Res Commun. 1994;200:642–646.[Medline] [Order article via Infotrieve]
-
Champion HC, Santiago JA, Murphy WA, Coy DH, Kadowitz
PJ. Adrenomedullin- (22–52) antagonizes vasodilator responses to CGRP
but not adrenomedullin in the cat. Am J Physiol. 1997;272:R234–R242.
[Abstract/Free Full Text] - Feng CJ, Kang B, Kaya AD, Kadowitz PJ, Nossaman BD. L-NAME modulates responses to adrenomedullin in the hindquarters vascular bed of the rat. Life Sci. 1994;55:433–438.
-
Majid DS, Kadowitz OPJ, Coy DH, Navar LG. Renal
responses to intra-arterial administration of
adrenomedullin in dogs. Am J Physiol. 1996;270:F200–F205.
[Abstract/Free Full Text] - Perret M, Broussard H, LeGros T, Burns A, Chang J-K, Summer W, Hyman A, Lippton H. The effect of adrenomedullin on the isolated heart. Life Sci. 1993;53:377–379.[Medline] [Order article via Infotrieve]
-
Ikenouchi Y, Kangawa K, Matsuo H, Hirata Y. Negative
inotropic effect of adrenomedullin in isolated adult rabbit cardiac
ventricular myocytes. Circulation. 1997;95:2318–1324.
[Abstract/Free Full Text] -
Garcia R, Diebold S. Simple, rapid and effective method
of producing aortocaval shunts in the rat. Cardiovasc Res. 1990;24:430–432.
[Abstract/Free Full Text] - Nishikimi T, Saito Y, Kawano Y, Matsuoka H. Effect of long-term treatment with selective vasopressin V1 and V2 receptor antagonist on the development of heart failure in rats. J Cardiovasc Pharmacol. 1996;27:275–282.[Medline] [Order article via Infotrieve]
- Nishikimi T, Tani T, Ohmura T, Yamagishi H, Yanagi S, Yoshiyama M, Toda I, Teragaki M, Akioka K, Takeuchi K, Takeda T. Angiotensin II type-1 receptor antagonist as well as angiotensin converting enzyme inhibitor attenuates the development of heart failure in aortocaval fistula rats. Jpn Circ J. 1995;59:754–761.[Medline] [Order article via Infotrieve]
-
Nishikimi T, Miura K, Minamino N, Takeuchi K, Takeda T.
Role of endogenous atrial natriuretic peptide
on systemic and renal hemodynamics in heart failure
rats. Am J Physiol. 1994;267:H182–H186.
[Abstract/Free Full Text] - Sakata J, Shimokubo T, Kitamura K, Nishizono M, Ichiki Y, Kangawa K, Matsuo H, Eto T. Distribution and characterization of immunoreactive rat adrenomedullin in tissue and plasma. FEBS Lett. 1994;352:105–108.[Medline] [Order article via Infotrieve]
-
Sugo S, Minamino N, Shoji H, Kangawa K, Kitamura K, Eto
T, Matsuo H. Production and secretion of adrenomedullin from
vascular smooth muscle cells:augmented production by tumor
necrosis factor . Biochem Biophys Res Commun. 1994;203:719–726.[Medline]
[Order article via Infotrieve]
-
Yoshitomi Y, Nishikimi T, Abe H, Yoshihara F, Suzuki T,
Ashizawa A, Nagata S, Kuramochi M, Matsuoka H, Omae T. Comparison of
changes in cardiac structure after treatment in secondary hypertension.
Hypertension. 1996;27:319–323.
[Abstract/Free Full Text] - Yoshihara F, Nishikimi T, Abe H, Yoshitomi Y, Suzuki T, Ashizawa A, Nagata S, Kuramochi M, Matsuoka H, Omae T. Left ventricular structural and functional characteristics in renovascular hypertension, primary aldosteronism and essential hypertension. Am J Hypertens. 1996;9:523–528.[Medline] [Order article via Infotrieve]
-
Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations
regarding quantitation in M-mode echocardiography:
results of a survey of echocardiographic measurements.
Circulation. 1978;58:1072–1083.
[Abstract/Free Full Text] -
Nishikimi T, Kitamura K, Saito Y, Shimada K, Ishimitsu
T, Takamiya M, Kangawa K, Matsuo H, Eto T, Omae, Matsuoka H. Clinical
studies on the sites and production of circulating
adrenomedullin in human subjects. Hypertension.. 1994;24:600–604.
[Abstract/Free Full Text] -
Nishikimi T, Yoshihara F, Morimoto A, Ishikawa K,
Ishimitsu T, Saito Y, Kangawa K, Matsuo H, Omae T, Matsuoka H.
Relationship between left ventricular geometry and
natriuretic peptides levels in essential hypertension.
Hypertension. 1996;28:22–30.
[Abstract/Free Full Text] - Ebara T, Miura K, Okumura M, Matsuura T, Kim S, Yukimura T, Iwao H. Effect of adrenomedullin on renal hemodynamics and function in dogs. Eur J Pharmacol. 1994;263:69–73.[Medline] [Order article via Infotrieve]
-
Jougasaki M, Wei CM, Aarhus AA, Heublein DM, Sandberg
SM, Burnett JC Jr. Renal localization and actions of adrenomedullin: a
natriuretic peptide. Am J Physiol. 1995;268:F657–F663.
[Abstract/Free Full Text] -
Lippton H, Chang JK, Hao Q, Summer W, Hyman A.
Adrenomedullin dilates the pulmonary vascular bed in vivo.
J Appl Physiol. 1994;76:2154–2156.
[Abstract/Free Full Text] - Heaton J, Lin B, Chang JK, Steinberg S, Hyman A, Lippton H. Pulmonary vasodilation to adrenomedullin: a novel peptide in humans. Am J Physiol. 1995;1995:268:H2211–H2215.
- Jougasaki M, Rodeheffer RJ, Redfield MM, Yamamoto K, Wei C, McKinley LJ, Burnett JC. Cardiac secretion of adrenomedullin in human heart failure. J Clin Invest. 1996;97:2370–2376.[Medline] [Order article via Infotrieve]
-
Nishikimi T, Frohlich ED. Glomerular
hemodynamics in aortocaval fistula rats: role of renin-
angiotensin system. Am J Physiol. 1993;264:R681–R686.
[Abstract/Free Full Text] -
Garcia R, Lachance D, Thibault G. Atrial
natriuretic factor release and natriuresis in rats with
high-output heart failure. Am J Physiol. 1990;259:H1374–H1379.
[Abstract/Free Full Text] -
Flaim SF, Minteer WJ, Nellis SH, Clark DP. Chronic
arteriovenous shunt: evaluation of a model for heart failure in rats.
Am J Physiol. 1979;236:H698–H704.
[Abstract/Free Full Text] -
Pieruzzi F, Abssi ZA, Keiser HR. Expression of
renin-angiotensin system components in the heart, kidneys,
and lungs of rats with experimental heart failure.
Circulation. 1995;92:3105–3112.
[Abstract/Free Full Text] - Owji AA, Smith DM, Coppock HA, Morgan DGA, Bhogal R, Ghatei MA, Bloom SR. An abundant and specific binding site for the novel vasodilator adrenomedullin in the rat. Endocrinology. 1995;136:2127–2134.[Abstract]
- Ishimitsu T, Nishikimi T, Matsuoka H, Kangawa K, Kitamura K, Minami J, Matsuo H, Eto T. Behaviors of adrenomedullin during acute and chronic salt loading in normotensive and hypertensive subjects. Clin Sci. 1996;91:293–298.[Medline] [Order article via Infotrieve]
- Morimoto A, Nishikimi T, Takaki H, Okano Y, Kangawa K, Matsuo H, Kitamura K, Eto T, Takishita S, Matsuoka H. Effect of exercise on plasma adrenomedullin and brain natriuretic peptide levels in patients with old myocardial infarction and normal subjects. Clin Exp Pharmacol Physiol. 1997;24:315–320.[Medline] [Order article via Infotrieve]
- Nishikimi T, Morimoto A, Ishikawa K, Saito Y, Kangawa K, Matsuo H, Kitamura K, Takishita S, Matsuoka H. Different secretion patterns of adrenomedullin, brain natriuretic peptide, and atrial natriuretic peptide during exercise in hypertensive and normotensive subjects. Clin Exp Hypertens. 1997;19:503–518.
- Sugo S, Minamino N, Kangawa K, Miyamoto K, Kitamura K, Sakata J, Eto T, Matsuo H. Endothelial cells actively synthesize and secrete adrenomedullin. Biochem Biophys Res Commun. 1994;201:1160–1166.[Medline] [Order article via Infotrieve]
-
Ikeda U, Kanbe T, Kawahara Y, Yokoyama M, Shimada K.
Adrenomedullin augments inducible nitric oxide synthase expression in
cytokine-stimulated cardiac myocytes. Circulation. 1996;94:2560–2565.
[Abstract/Free Full Text] -
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.
[Abstract/Free Full Text] - Pfeffer MA, Braunwald E, Moye L, Basta L, Brown EJ, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, Klein M, Lamas GA, Packer M, Rouleau J, Rutherford J, Wertheimer JH, Hawkins CM. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the survival and ventricular enlargement trial. N Engl J Med. 1992;327:669–677.[Abstract]
- Sakai S, Miyauchi T, Kobayashi M, Yamaguchi I, Goto K, Sugishita Y. Inhibition of myocardial endothelin pathway improves long-term survival in heart failure. Nature. 1996;384:353–355.[Medline] [Order article via Infotrieve]
- Nossaman BD, Feng CJ, Cheng DY, Dewitt BJ, Coy DH, Murphy WA, Kadowitz PJ. Comparative effects of adrenomedullin, an adrenomedullin analog, and CGRP in the pulmonary vascular bed of the cat and rat. Life Sci. 1995;56:63–66.[Medline] [Order article via Infotrieve]
-
Nossaman BD, Feng CJ, Kaye AD, Dewitt BJ, Coy DH,
Murphy WA, Kadowitz PJ. Pulmonary vasodilator responses to
adrenomedullin are reduced by NOS inhibitors in rats but
not in cats. Am J Physiol. 1996;270:L782–L789.
[Abstract/Free Full Text]
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