(Circulation. 1995;92:286-289.)
© 1995 American Heart Association, Inc.
Articles |
Elevation of Circulating and Ventricular Adrenomedullin in Human Congestive Heart Failure
From the Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, Minn.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Adrenomedullin (ADM) is a newly discovered vasodilating and natriuretic peptide that may play an important role in cardiorenal regulation. Although ADM was originally isolated from human pheochromocytoma, ADM-like immunoreactivity has also been widely detected in various tissues, including the cardiovascular system.
Methods and Results In view of reports that ADM circulates in the body and that ADM gene and ADM-like immunoreactivity are present in the heart, the present study was designed to determine the plasma concentration of ADM in healthy subjects and in patients with congestive heart failure (CHF) and to investigate the immunohistochemical presence and localization of ADM in normal and failing human hearts. Plasma ADM concentration was 13.2±2.3 pg/mL in healthy subjects (n=11) and increased to 47.3±6.7 pg/mL in patients with CHF (n=11, P<.05 versus normal). Human cardiac tissues were obtained from five patients with end-stage CHF undergoing cardiac transplantation. Five normal donor hearts that were used for cardiac transplantation served as sources for normal atrial tissues. Normal ventricular myocardium was also obtained by endomyocardial biopsy from the right ventricles of these donor hearts immediately before cardiac transplantation. Positive immunostaining was detected within the myocardia in both atria and ventricles of healthy and severely failing human transplanted hearts and was more intense in the atria than in the ventricles. Although there were no significant differences in the intensity of immunoreactivity between normal and failing atria, ADM immunoreactivity was significantly more intense in the ventricular myocytes from failing hearts compared with normal hearts.
Conclusions The present study demonstrates that plasma concentration of ADM is increased in patients with CHF and that ADM is present in the human heart. ADM immunoreactivity is markedly increased in the failing human ventricle, suggesting that ventricular ADM expression may be influenced by the circumstances associated with CHF. This supports a potential role for this newly identified vasoactive and natriuretic peptide, ADM, in the neurohumoral activation that characterizes human CHF.
Key Words: adrenomedullin • radioimmunoassay • heart failure
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Adrenomedullin (ADM) is a newly discovered potent endogenous vasodilating peptide originally isolated from extracts of human pheochromocytoma.1 More recently, ADM production and secretion have been reported in endothelial cells.2 In addition, studies have established that ADM is also a potent natriuretic and diuretic peptide.3 Since ADM has been reported to be present in the heart,4 this newly characterized peptide could function like atrial natriuretic peptide (ANP) in the control of cardiorenal homeostasis.5
Chronic congestive heart failure (CHF) is a pathophysiological state in which activated vasodilating and natriuretic factors are opposed by coactivation of local and circulating vasoconstrictive and sodium-retaining factors. Indeed, investigations have supported a role for neurohumoral activation as important to the progression of ventricular dysfunction.6 Recently, ADM has been reported to be present in normal human plasma,7 and its plasma concentration has been reported to be increased in hypertension.8 To date, the plasma concentration of ADM in patients with CHF remains undefined. Also, although ADM immunoreactivity is detectable in mammalian hearts,4 9 10 its presence and localization in the human heart in the presence and absence of CHF also remain undefined. Our hypothesis is that like ANP, ADM, which is natriuretic and vasorelaxing, is increased in the plasma of human subjects with CHF and may have an important role in pathophysiology of CHF. Therefore, the first objective of the present study was to determine the concentration of circulating ADM in humans with CHF. The second objective was to investigate by immunohistochemistry the localization of ADM in the hearts of humans with and without CHF.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Study Subjects for Circulating ADM Concentration
Eleven patients (6 men and 5 women, 66±4 years old [mean±SEM]) with severe CHF and 11 age-matched subjects without cardiac disease (4 men and 7 women, 64±3 years old) were studied. All patients with severe CHF had a complete physical and laboratory evaluation and were classified by New York Heart Association (NYHA) functional class criteria according to their cardiac symptoms after physical examination and laboratory evaluation. Among the 11 patients with CHF studied, 4 were classified as NYHA class III and 7 as NYHA class IV. The ejection fraction determined by echocardiography was 17±2%. The causes of the ventricular dysfunction in these patients with CHF included idiopathic dilated cardiomyopathy and ischemic cardiomyopathy. All patients with CHF were on treatment, which included digitalis, diuretics, and/or vasodilators. Eleven age-matched subjects without cardiac disease were free of ventricular dysfunction. Patients with renal failure were excluded from the present study. Venipuncture for measurement of plasma concentration of ADM was performed with the patient in the supine position.
Quantification of Plasma ADM Concentration
Blood samples for
ADM assay were collected in chilled tubes
containing EDTA and immediately placed on ice. After
centrifugation at 2500 rpm at 4°C for 15 minutes, the
plasma was decanted and stored at -20°C until analyzed.
Plasma (1 mL) was extracted on C-18 Bond Elute cartridges and eluted
with 95% methanol containing 1% TFA. Concentrated eluates were then
assayed with a specific and sensitive radioimmunoassay for ADM (Phoenix
Pharmaceuticals). Samples and standards were incubated with
100:1 antibody raised against human ADM(1-52) at 4°C for 24
hours. 125I-labeled ADM (100 µL) was added and incubated
another 24 hours at 4°C. Free and bound fractions were then separated
by addition of a second antibody and centrifuged. Radioactivity
of the pellet was measured with a gamma counter. Minimal detectable
concentration for this assay is 0.5 pg per tube, and the half-maximal
inhibition dose of radioiodinated ligand binding by ADM
was 10 pg per tube. Recovery was 72±2%, and intra-assay and
interassay variations were 10% and 12%, respectively.
Healthy and CHF Subjects for Immunohistochemistry
Human
cardiac tissue was obtained from five patients (four men
and one woman, 47±2 years old) with end-stage CHF (NYHA class IV)
undergoing cardiac transplantation at the Mayo Clinic. Cardiac index
and ejection fraction were decreased (1.9±0.2
L · min-1 · m-2 and
12±1.2%,
respectively), and pulmonary capillary wedge pressure was
increased (28.2±3.7 mm Hg). The causes of CHF included idiopathic
dilated cardiomyopathy and ischemic
cardiomyopathy. Cardiac tissues included both atria
and ventricles from these patients. Atrial sections were taken from the
appendages and free walls of both atria, and full-thickness sections of
human ventricular myocardium were obtained from
the middle third of the free wall of both left and right ventricles
from failing hearts. Five normal donor hearts that were used for
cardiac transplantation at the Mayo Clinic served as the source for
normal atrial tissue sections. Normal ventricular
myocardium was also obtained by
endomyocardial biopsy from the right ventricles of
these donor hearts immediately before cardiac transplantation and was
processed in an identical manner.
Immunohistochemical Staining
Immunohistochemical studies were
performed by the indirect
immunoperoxidase method as described
previously.3 4 11 12
The tissues were immediately fixed with 10% buffered formalin. These
tissues were embedded in paraffin, and sections 6 µm thick were cut
and mounted on glass slides treated with silica. The slides were
incubated at 60°C and deparaffinized with graded concentrations of
xylene and ethanol. To block the activity of endogenous
peroxidase, the slides were incubated with 0.6% hydrogen peroxide in
methanol for 20 minutes at room temperature. After being washed, they
were incubated with 5% goat serum (Dako) for 10 minutes at room
temperature to reduce nonspecific background staining and were then
incubated with rabbit polyclonal anti-ADM antiserum (Peninsula) at a
dilution of 1:800 in humidified chambers for 24 hours at room
temperature. The antiserum to ADM showed no cross-reactivities with
ANP, brain natriuretic peptide (BNP), or C-type
natriuretic peptide. All the treated slides were incubated
for 30 minutes with second antibody–horseradish peroxidase conjugate
(Tago) at a dilution of 1:100. The final reaction was achieved
by incubating the sections with freshly prepared reagent containing
3-amino-9-ethylcarbazole (Sigma) dissolved in dimethylformamide and
sodium acetate. The sections were counterstained with hematoxylin,
mounted, and reviewed with an Olympus microscope. Two trained
independent observers reviewed these sections without any knowledge as
to the respective groups from which the tissues originated. Especially
in the ventricular tissues,
endomyocardial regions of the transplanted hearts
were compared with the normal ventricular tissues, because
the biopsy specimens from the donor heart were
endomyocardial tissues. The presence of ADM
immunoreactivity was assessed by microscopic examination and evaluated
to quantify the degree of staining of ADM (0, no staining of ADM; 0.5,
minimal; 1.0, mild density; 1.5, moderate density; and 2.0, maximal
density) and percentage of area of positive staining in the entire
section examined.
To examine the immunohistochemical specificity of the reaction between antiserum and tissue, absorption tests were performed. The anti-ADM antiserum was preincubated with 10-6 mol/L of human ADM(1-52) (Phoenix Pharmaceuticals) overnight. After centrifugation at 4500 rpm for 10 minutes, the supernatant was used instead of primary antiserum. The specificity was further confirmed by substitution of nonimmune rabbit serum (Dako) or PBS for primary antiserum.
Statistical Analysis
Values are expressed as mean±SEM.
Statistical comparisons
between each group were performed by ANOVA for repeated measures
followed by Fisher's least-significant-difference test of repeated
measures when appropriate, and statistical comparisons between groups
were made by factorial ANOVA followed by Fisher's
least-significant-difference test of repeated measures. Statistical
significance was accepted for P<.05.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Circulating ADM Concentration
Plasma ADM concentration was 13.2±2.3 pg/mL in healthy age-matched subjects (n=11). Plasma ADM concentration increased to 47.3±6.7 pg/mL in patients with severe CHF (n=11, P<.05 versus healthy group) (see Fig 1
).
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Immunohistochemistry
Immunohistochemistry for ADM
demonstrated unequivocal evidence of
ADM positivity within the atrial and ventricular myocytes
from both healthy and severely failing hearts. ADM immunoreactivity was
observed within the cytoplasm of myocytes and was distributed widely in
the peripheral cytoplasm. There were some indications that
ADM immunoreactivity was located in the perinuclear region. ADM
immunohistochemical scores and percentage distribution (percent
positive staining area) are reported in the Table. ADM
immunoreactivity was more intense in the atria than in the ventricles
from both healthy hearts and severely failing hearts. Although ADM
immunoreactivity in the atria was at similar intensities in both
healthy hearts and severely failing hearts, it was significantly more
intense in the ventricular myocytes from severely failing
hearts compared with normal hearts. There was no evidence of
immunoperoxidase activity in the endocardium, epicardium, pericardium,
or connective tissues. Fig 2 illustrates
representative immunohistochemical staining for ADM in
the atrial and ventricular myocardia from a healthy and a
severely failing human heart. The sections treated with preabsorbed
antiserum, nonimmune rabbit serum, or PBS instead of primary antibody
as a negative control failed to show immunoperoxidase activity within
the myocardia.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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ADM is a newly discovered amino acid peptide that has potent vasodilating1 and natriuretic effects.3 Previous reports have demonstrated that circulating ADM is increased in patients with essential hypertension.8 The present study documents for the first time that the plasma concentrations of circulating ADM are increased in patients with CHF compared with those in healthy subjects. We also report for the first time the presence and distribution of ADM immunoreactivity in human atrial and ventricular myocardium and its elevation in failing human ventricular myocardium.
The mechanism of circulating ADM elevation in patients with CHF is unknown. At present, the synthesis, secretion, and metabolism of ADM are not fully understood. There may be an increase in the production and secretion of ADM and/or a decrease in degradation of ADM in patients with CHF. Although the major source of circulating ADM is unclear, previous investigators measured plasma concentration of ADM from various sites in humans without ventricular dysfunction and found that there was no step-up of ADM in the coronary sinus, suggesting that the heart is not the main source of circulating ADM.13 This may be in contrast to ANP, which is produced and secreted by the heart and whose concentration in plasma is increased in patients with CHF secondary to enhanced myocardial production.14 Similarly, Yasue et al15 reported that the secretion of BNP from the ventricle is increased in proportion to the severity of the ventricular dysfunction. Although there is no evidence that the major source of circulating ADM is the heart, the observation in the present study of increased ventricular ADM immunoreactivity suggests that the failing ventricular myocardium may be characterized by increased production and secretion of ADM, like ANP and BNP. Further studies are necessary to address this issue.
Plasma ADM concentrations were significantly higher in patients with severe CHF than in the healthy subjects without ventricular dysfunction. Since we chose an age-matched group for control subjects, the elevation of plasma ADM in patients with CHF is not considered to be an age effect but rather is secondary to the neurohumoral activation that characterizes human CHF.
Recently, ADM was reported to be present within the myocardium in both atria and ventricles of normal dogs.4 To date, no reports have described the immunohistochemical presence and distribution of ADM in the human heart, although ADM mRNA and ADM immunoreactivity by radioimmunoassay have been reported in normal human hearts.9 16 The present study demonstrates for the first time by immunohistochemistry that ADM is present in the human heart. Although the immunohistochemical localization of ADM within the heart is consistent with local cardiovascular production, another explanation is that the immunoreactivity may represent binding of endogenous ADM of extracardiovascular origin to the cardiovascular sites of action.
In the present study, we show that ADM immunoreactivity is significantly more intense in the ventricular myocytes from severely failing hearts than in those from normal hearts. As discussed above, the production of ADM, especially in the ventricles, may be increased in patients with CHF. The fact that ADM is increased in the ventricles suggests that ventricular ADM expression may be influenced by the circumstances associated with CHF. It is also known that ventricular production of the natriuretic peptides ANP and BNP secondary to ventricular dilatation and myocyte hypertrophy is markedly augmented in patients with CHF.12 15 Like the natriuretic peptides, ventricular expression of ADM may be enhanced in patients with CHF, and ventricular ADM may contribute, at least in part, to the rise in the plasma concentrations of ADM in patients with CHF. The demonstration that ADM mediates its biological actions via generation of cAMP17 may relate to CHF. It is tempting to speculate that the activation of ADM in CHF could be a compensatory response to enhance myocardial contractility via cAMP. To date, no direct action of ADM on myocardial contractility has been reported. In addition, like the natriuretic peptide in evolving CHF, ADM may also play a compensatory role in the kidney to maintain sodium balance during the early stage of ventricular dysfunction in the maintenance of optimal intravascular volume and cardiac filling pressures despite ventricular dysfunction.18 Furthermore, on the basis of its known cardiorenal actions, one could also speculate on a role for exogenous ADM as a therapeutic agent to improve left ventricular function by reducing both preload and afterload in patients with CHF.
In the present study, normal ventricular myocardium was obtained by endomyocardial biopsy from the right ventricles of donor hearts immediately before cardiac transplantation. In contrast, whole ventricular tissues of the transplanted hearts were used for the immunohistochemistry. Since the biopsy specimens were endomyocardial tissues, we compared these biopsy specimens with the endomyocardial region of the transplanted ventricles. However, the difference in immunoreactivity may be related to the different methods used to obtain tissue rather than a true pathophysiological difference. The difference in obtaining ventricular tissues between normal and failing heart is therefore a limitation of the present study.
In summary, the present study demonstrates that circulating ADM is increased in patients with CHF, that ADM is present in the human heart, and that its immunoreactivity is markedly increased in the failing human ventricle, suggesting that ventricular ADM expression may be influenced by the circumstances associated with CHF. This supports a potential role for this newly identified vasoactive and natriuretic peptide in the neurohumoral activation that characterizes human CHF.
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Acknowledgments |
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This work was supported by National Heart, Lung, and Blood Institute grants HL-36634 and HL-03174-01, the American Heart Association, Minnesota Affiliate (MN-94-GB-20), and the Mayo Foundation. We acknowledge the technical assistance of Denise M. Heublein and Sharon M. Sandberg and the collaboration of Dr Christopher G.A. MacGregor.
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Footnotes |
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Reprint requests to Michihisa Jougasaki, MD, PhD, Cardiorenal Research Laboratory, Mayo Clinic and Foundation, 915 Guggenheim, 200 First St, SW, Rochester, MN 55905. E-mail jburnett@mayo.edu.
Received April 4, 1995; revision received May 11, 1995; accepted June 4, 1995.
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References |
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K Tambara, M Fujita, N Nagaya, S Miyamoto, A Iwakura, K Doi, G Sakaguchi, K Nishimura, K Kangawa, and M Komeda Increased pericardial fluid concentrations of the mature form of adrenomedullin in patients with cardiac remodelling Heart, March 1, 2002; 87(3): 242 - 246. [Abstract] [Full Text] [PDF]
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 A. Cataliotti, G. Boerrigter, H. H. Chen, M. Jougasaki, L. C. Costello, T. Tsuruda, S.-C. Lee, L. S. Malatino, and J. C. Burnett Jr Differential Actions of Vasopeptidase Inhibition Versus Angiotensin-Converting Enzyme Inhibition on Diuretic Therapy in Experimental Congestive Heart Failure Circulation, February 5, 2002; 105(5): 639 - 644. [Abstract] [Full Text] [PDF]
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T. Saito, K. Maehara, K. Tamagawa, Y. Oikawa, T. Niitsuma, S.-I. Saitoh, and Y. Maruyama Alterations of endothelium-dependent and -independent regulation of coronary blood flow during heart failure Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H80 - H86. [Abstract] [Full Text] [PDF]
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B. Geny, R. Richard, B. Mettauer, J. Lonsdorfer, and F. Piquard Cardiac natriuretic peptides during exercise and training after heart transplantation Cardiovasc Res, August 15, 2001; 51(3): 521 - 528. [Full Text] [PDF]
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C-M Yu, B M Y Cheung, R Leung, Q Wang, W-H Lai, and C-P Lau Increase in plasma adrenomedullin in patients with heart failure characterised by diastolic dysfunction Heart, August 1, 2001; 86(2): 155 - 160. [Abstract] [Full Text] [PDF]
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D. J Autelitano, R. Ridings, and F. Tang Adrenomedullin is a regulated modulator of neonatal cardiomyocyte hypertrophy in vitro Cardiovasc Res, August 1, 2001; 51(2): 255 - 264. [Abstract] [Full Text] [PDF]
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A. M. Richards, R. Doughty, M. G. Nicholls, S. MacMahon, N. Sharpe, J. Murphy, E. A. Espiner, C. Frampton, T. G. Yandle, and for the Australia-New Zealand Heart Failure Group Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: Prognostic utility and prediction of benefit from carvedilol in chronic ischemic left ventricular dysfunction J. Am. Coll. Cardiol., June 1, 2001; 37(7): 1781 - 1787. [Abstract] [Full Text] [PDF]
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M. Jougasaki and J. C Burnett Jr. Continuing insights into the heart as an endocrine organ: adrenomedullin and cardiac fibroblasts Cardiovasc Res, March 1, 2001; 49(4): 695 - 696. [Full Text] [PDF]
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Y. Tomoda, K. Kikumoto, Y. Isumi, T. Katafuchi, A. Tanaka, K. Kangawa, K. Dohi, and N. Minamino Cardiac fibroblasts are major production and target cells of adrenomedullin in the heart in vitro Cardiovasc Res, March 1, 2001; 49(4): 721 - 730. [Abstract] [Full Text] [PDF]
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H. Romppanen, J. Puhakka, G. Foldes, I. Szokodi, O. Vuolteenaho, H. Tokola, M. Toth, and H. Ruskoaho Endothelin-1-Independent and Angiotensin II-Independent Induction of Adrenomedullin Gene Expression Hypertension, January 1, 2001; 37(1): 84 - 90. [Abstract] [Full Text] [PDF]
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K. Terata, H. Miura, Y. Liu, F. Loberiza, and D. D. Gutterman Human coronary arteriolar dilation to adrenomedullin: role of nitric oxide and K+ channels Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2620 - H2626. [Abstract] [Full Text] [PDF]
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R. W. Troughton, L. K. Lewis, T. G. Yandle, A. M. Richards, and M. G. Nicholls Hemodynamic, Hormone, and Urinary Effects of Adrenomedullin Infusion in Essential Hypertension Hypertension, October 1, 2000; 36(4): 588 - 593. [Abstract] [Full Text] [PDF]
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J. G. Lainchbury, D. M. Meyer, M. Jougasaki, J. C. Burnett Jr., and M. M. Redfield Effects of adrenomedullin on load and myocardial performance in normal and heart-failure dogs Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H1000 - H1006. [Abstract] [Full Text] [PDF]
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 F. Piquard, A. Charloux, B. Mettauer, E. Epailly, E. Lonsdorfer, S. Popescu, J. Lonsdorfer, and B. Geny Exercise-Induced Increase in Circulating Adrenomedullin Is Related to Mean Blood Pressure in Heart Transplant Recipients J. Clin. Endocrinol. Metab., August 1, 2000; 85(8): 2828 - 2831. [Abstract] [Full Text]
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P. Kinnunen, I. Szokodi, M. G. Nicholls, and H. Ruskoaho Impact of NO on ET-1- and AM-induced inotropic responses: potentiation by combined administration Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2000; 279(2): R569 - R575. [Abstract] [Full Text] [PDF]
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M. Sata, M. Kakoki, D. Nagata, H. Nishimatsu, E. Suzuki, T. Aoyagi, S. Sugiura, H. Kojima, T. Nagano, K. Kangawa, et al. Adrenomedullin and Nitric Oxide Inhibit Human Endothelial Cell Apoptosis via a Cyclic GMP-Independent Mechanism Hypertension, July 1, 2000; 36(1): 83 - 88. [Abstract] [Full Text] [PDF]
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 F Pousset, F Masson, O Chavirovskaia, R Isnard, A Carayon, J.L Golmard, P Lechat, D Thomas, and M Komajda Plasma adrenomedullin, a new independent predictor of prognosis in patients with chronic heart failure Eur. Heart J., June 2, 2000; 21(12): 1009 - 1014. [Abstract] [PDF]
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 J. P. Hinson, S. Kapas, and D. M. Smith Adrenomedullin, a Multifunctional Regulatory Peptide Endocr. Rev., April 1, 2000; 21(2): 138 - 167. [Abstract] [Full Text]
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N. Nagaya, T. Nishikimi, F. Yoshihara, T. Horio, A. Morimoto, and K. Kangawa Cardiac adrenomedullin gene expression and peptide accumulation after acute myocardial infarction in rats Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2000; 278(4): R1019 - R1026. [Abstract] [Full Text] [PDF]
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 T. Stefanec Endothelial Apoptosis: Could It Have a Role in the Pathogenesis and Treatment of Disease? Chest, March 1, 2000; 117(3): 841 - 854. [Abstract] [Full Text] [PDF]
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N. Nagaya, T. Satoh, T. Nishikimi, M. Uematsu, S. Furuichi, F. Sakamaki, H. Oya, S. Kyotani, N. Nakanishi, Y. Goto, et al. Hemodynamic, Renal, and Hormonal Effects of Adrenomedullin Infusion in Patients With Congestive Heart Failure Circulation, February 8, 2000; 101(5): 498 - 503. [Abstract] [Full Text] [PDF]
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F. Yoshihara, T. Nishikimi, T. Horio, C. Yutani, N. Nagaya, H. Matsuo, T. Ohe, and K. Kangawa Ventricular adrenomedullin concentration is a sensitive biochemical marker for volume and pressure overload in rats Am J Physiol Heart Circ Physiol, February 1, 2000; 278(2): H633 - H642. [Abstract] [Full Text] [PDF]
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E. Oie, L. E. Vinge, A. Yndestad, C. Sandberg, H. K. Grogaard, and H. Attramadal Induction of a Myocardial Adrenomedullin Signaling System During Ischemic Heart Failure in Rats Circulation, February 1, 2000; 101(4): 415 - 422. [Abstract] [Full Text] [PDF]
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M. Jougasaki, I. Tachibana, A. Luchner, H. Leskinen, M. M. Redfield, and J. C. Burnett Jr Augmented Cardiac Cardiotrophin-1 in Experimental Congestive Heart Failure Circulation, January 4, 2000; 101(1): 14 - 17. [Abstract] [Full Text] [PDF]
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 M. R. Lauria, C. A. Standley, Y. Sorokin, F. D. Yelian, and D. B. Cotton Adrenomedullin Levels in Normal and Preeclamptic Pregnancy at Term Reproductive Sciences, November 1, 1999; 6(6): 318 - 321. [Abstract] [PDF]
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N Nagaya, T Nishikimi, M Uematsu, Y Yoshitomi, Y Miyao, S Miyazaki, Y Goto, S Kojima, M Kuramochi, H Matsuo, et al. Plasma adrenomedullin as an indicator of prognosis after acute myocardial infarction Heart, May 1, 1999; 81(5): 483 - 487. [Abstract] [Full Text]
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A. Morimoto, T. Nishikimi, F. Yoshihara, T. Horio, N. Nagaya, H. Matsuo, K. Dohi, and K. Kangawa Ventricular Adrenomedullin Levels Correlate With the Extent of Cardiac Hypertrophy in Rats Hypertension, May 1, 1999; 33(5): 1146 - 1152. [Abstract] [Full Text] [PDF]
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B. Geny, G. Brandenberger, J. Lonsdorfer, N. Chakfe, P. Haberey, and F. Piquard Circulating adrenomedullin is increased after heart transplantation Cardiovasc Res, March 1, 1999; 41(3): 731 - 736. [Abstract] [Full Text] [PDF]
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N. Nagaya, T. Nishikimi, T. Horio, F. Yoshihara, A. Kanazawa, H. Matsuo, and K. Kangawa Cardiovascular and renal effects of adrenomedullin in rats with heart failure Am J Physiol Regulatory Integrative Comp Physiol, January 1, 1999; 276(1): R213 - R218. [Abstract] [Full Text] [PDF]
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T. Horio, T. Nishikimi, F. Yoshihara, N. Nagaya, H. Matsuo, S. Takishita, and K. Kangawa Production and Secretion of Adrenomedullin in Cultured Rat Cardiac Myocytes and Nonmyocytes: Stimulation by Interleukin-1{beta} and Tumor Necrosis Factor-{alpha} Endocrinology, November 1, 1998; 139(11): 4576 - 4580. [Abstract] [Full Text] [PDF]
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M. Jougasaki, J. A. Schirger, R. D. Simari, and J. C. Burnett Jr Autocrine Role for the Endothelin-B Receptor in the Secretion of Adrenomedullin Hypertension, November 1, 1998; 32(5): 917 - 922. [Abstract] [Full Text] [PDF]
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 H. Komai, Y. Naito, K. Fujiwara, Y. Noguchi, and Y. Nishimura Plasma adrenomedullin level after cardiopulmonary bypass Perfusion, September 1, 1998; 13(5): 334 - 337. [Abstract] [PDF]
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 O. Lisy, M. Jougasaki, J. A. Schirger, H. H. Chen, P. T. Barclay, and J. C. Burnett Jr. Neutral endopeptidase inhibition potentiates the natriuretic actions of adrenomedullin Am J Physiol Renal Physiol, September 1, 1998; 275(3): F410 - F414. [Abstract] [Full Text] [PDF]
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V. A. Cameron and A. M. Fleming Novel Sites of Adrenomedullin Gene Expression in Mouse and Rat Tissues Endocrinology, May 1, 1998; 139(5): 2253 - 2264. [Abstract] [Full Text] [PDF]
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M. Saita, A. Shimokawa, T. Kunitake, K. Kato, T. Hanamori, K. Kitamura, T. Eto, and H. Kannan Central actions of adrenomedullin on cardiovascular parameters and sympathetic outflow in conscious rats Am J Physiol Regulatory Integrative Comp Physiol, April 1, 1998; 274(4): R979 - R984. [Abstract] [Full Text] [PDF]
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I. Szokodi, P. Kinnunen, P. Tavi, M. Weckstrom, M. Toth, and H. Ruskoaho Evidence for cAMP-Independent Mechanisms Mediating the Effects of Adrenomedullin, a New Inotropic Peptide Circulation, March 24, 1998; 97(11): 1062 - 1070. [Abstract] [Full Text] [PDF]
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 L. K. Lewis, M. W. Smith, T. G. Yandle, A. M. Richards, and M. G. Nicholls Adrenomedullin(1–52) measured in human plasma by radioimmunoassay: plasma concentration, adsorption, and storage Clin. Chem., March 1, 1998; 44(3): 571 - 577. [Abstract] [Full Text] [PDF]
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 N.K. Schiller, H. C. Champion, S.Y. Hugghins, A.M. Timothy, W.A. Murphy, D.H. Coy, J.R. Peter, P. J. Kadowitz, and D.B. McNamara Adrenomedullin Does Not Inhibit Human Platelet Aggregation Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 1998; 3(3): 223 - 228. [Abstract] [PDF]
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Y. Miyao, T. Nishikimi, Y. Goto, S. Miyazaki, S. Daikoku, I. Morii, T. Matsumoto, S. Takishita, A. Miyata, H. Matsuo, et al. Increased plasma adrenomedullin levels in patients with acute myocardial infarction in proportion to the clinical severity Heart, January 1, 1998; 79(1): 39 - 44. [Abstract] [Full Text] [PDF]
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T. Nishikimi, T. Horio, T. Sasaki, F. Yoshihara, S. Takishita, A. Miyata, H. Matsuo, and K. Kangawa Cardiac Production and Secretion of Adrenomedullin Are Increased in Heart Failure Hypertension, December 1, 1997; 30(6): 1369 - 1375. [Abstract] [Full Text]
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T. Nishikimi, S. Nagata, T. Sasaki, S. Tomimoto, H. Matsuoka, S. Takishita, K. Kitamura, A. Miyata, H. Matsuo, and K. Kangawa Plasma concentrations of adrenomedullin correlate with the extent of pulmonary hypertension in patients with mitral stenosis Heart, October 1, 1997; 78(4): 390 - 395. [Abstract] [Full Text] [PDF]
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M. Jougasaki, T. L. Stevens, D. D. Borgeson, A. Luchner, M. M. Redfield, and J. C. Burnett Jr. Adrenomedullin in experimental congestive heart failure: cardiorenal activation Am J Physiol Regulatory Integrative Comp Physiol, October 1, 1997; 273(4): R1392 - R1399. [Abstract] [Full Text] [PDF]
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M. T. Rademaker, C. J. Charles, L. K. Lewis, T. G. Yandle, G. J. S. Cooper, D. H. Coy, A. M. Richards, and M. G. Nicholls Beneficial Hemodynamic and Renal Effects of Adrenomedullin in an Ovine Model of Heart Failure Circulation, September 16, 1997; 96(6): 1983 - 1990. [Abstract] [Full Text]
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T. Kurashina, A. R. Patel, J. P. Granger, and K. A. Kirchner Pressure Natriuresis After Adrenomedullin in Anesthetized Spontaneously Hypertensive Rats Hypertension, September 1, 1997; 30(3): 660 - 663. [Abstract] [Full Text]
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T. Sumimoto, T. Nishikimi, M. Mukai, K. Matsuzaki, E. Murakami, S. Takishita, A. Miyata, H. Matsuo, and K. Kangawa Plasma Adrenomedullin Concentrations and Cardiac and Arterial Hypertrophy in Hypertension Hypertension, September 1, 1997; 30(3): 741 - 745. [Abstract] [Full Text]
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H. Ikenouchi, K. Kangawa, H. Matsuo, and Y. Hirata Negative Inotropic Effect of Adrenomedullin in Isolated Adult Rabbit Cardiac Ventricular Myocytes Circulation, May 6, 1997; 95(9): 2318 - 2324. [Abstract] [Full Text]
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P. G. Andreis, G. Neri, T. Prayer-Galetti, G. P. Rossi, G. Gottardo, L. K. Malendowicz, and G. G. Nussdorfer Effects of Adrenomedullin on the Human Adrenal Glands: An in Vitro Study J. Clin. Endocrinol. Metab., April 1, 1997; 82(4): 1167 - 1170. [Abstract] [Full Text] [PDF]
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M. Nakamura, H. Yoshida, S. Makita, N. Arakawa, H. Niinuma, and K. Hiramori Potent and Long-Lasting Vasodilatory Effects of Adrenomedullin in Humans: Comparisons Between Normal Subjects and Patients With Chronic Heart Failure Circulation, March 4, 1997; 95(5): 1214 - 1221. [Abstract] [Full Text]
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 M. G. Lang, R. Paterno, F. M. Faraci, D. D. Heistad, and J. R. Kirsch Mechanisms of Adrenomedullin-Induced Dilatation of Cerebral Arterioles Stroke, January 1, 1997; 28(1): 181 - 185. [Abstract] [Full Text]
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H. C. Champion, R. C. Fry, W. A. Murphy, D. H. Coy, and P. J. Kadowitz Catecholamine Release Mediates Pressor Effects of Adrenomedullin-(15-22) in the Rat Hypertension, December 1, 1996; 28(6): 1041 - 1046. [Abstract] [Full Text]
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U. Ikeda, T. Kanbe, Y. Kawahara, M. Yokoyama, and K. Shimada Adrenomedullin Augments Inducible Nitric Oxide Synthase Expression in Cytokine-Stimulated Cardiac Myocytes Circulation, November 15, 1996; 94(10): 2560 - 2565. [Abstract] [Full Text]
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T. Shimosawa and T. Fujita Hypotensive Effect of a Newly Identified Peptide, Proadrenomedullin N-Terminal 20 Peptide Hypertension, September 1, 1996; 28(3): 325 - 329. [Abstract] [Full Text]
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U. Ikeda, T. Kanbe, and K. Shimada Adrenomedullin Increases Inducible Nitric Oxide Synthase in Rat Vascular Smooth Muscle Cells Stimulated With Interleukin-1 Hypertension, June 1, 1996; 27(6): 1240 - 1244. [Abstract] [Full Text]
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H. Nishimatsu, Y. Hirata, T. Shindo, H. Kurihara, M. Kakoki, D. Nagata, H. Hayakawa, H. Satonaka, M. Sata, A. Tojo, et al. Role of Endogenous Adrenomedullin in the Regulation of Vascular Tone and Ischemic Renal Injury: Studies on Transgenic/Knockout Mice of Adrenomedullin Gene Circ. Res., April 5, 2002; 90(6): 657 - 663. [Abstract] [Full Text] [PDF]
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