From the Department of Cardiovascular Surgery and First Department of
Internal Medicine, Semmelweis University Medical School, Budapest, Hungary
(I.S., M.T.), and Departments of Pharmacology and Toxicology (P.K., H.R.) and
Physiology (P.T., M.W.), Biocenter Oulu, University of Oulu, Finland.
Correspondence to Heikki Ruskoaho, MD, PhD, Department of Pharmacology and Toxicology, University of Oulu, Kajaanintie 52 D, FIN-90220 Oulu, Finland. E-mail heikki.ruskoaho{at}oulu.fi
Background—Adrenomedullin (ADM), a
new vasorelaxing and natriuretic peptide, may function as
an endogenous regulator of cardiac function, because ADM
and its binding sites have been found in the heart. We characterize
herein the cardiac effects of ADM as well as the underlying signaling
pathways in vitro.
Methods and Results—In isolated perfused, paced rat heart
preparation, infusion of ADM at concentrations of 0.1 to 1 nmol/L for
30 minutes induced a dose-dependent, gradual increase in developed
tension, whereas proadrenomedullin N-20 (PAMP; 10 to 100 nmol/L), a
peptide derived from the same gene as ADM, had no effect. The
ADM-induced positive inotropic effect was not altered by a calcitonin
gene–related peptide (CGRP) receptor antagonist,
CGRP8–37, or H-89, a cAMP-dependent protein kinase
inhibitor. ADM also failed to stimulate
ventricular cAMP content of the perfused hearts. Ryanodine
(3 nmol/L), a sarcoplasmic reticulum Ca2+ release channel
opener, suppressed the overall ADM-induced positive inotropic effect.
Pretreatment with thapsigargin (30 nmol/L), which inhibits sarcoplasmic
reticulum Ca2+ ATPase and depletes intracellular
Ca2+ stores, attenuated the early increase in developed
tension produced by ADM. In addition, inhibition of protein kinase C by
staurosporine (10 nmol/L) and blockade of L-type
Ca2+ channels by diltiazem (1 µmol/L) significantly
decreased the sustained phase of ADM-induced increase in developed
tension. Superfusion of atrial myocytes with ADM (1 nmol/L) in isolated
left atrial preparations resulted in a marked prolongation of action
potential duration between 10 and -50 mV transmembrane voltage,
consistent with an increase in L-type Ca2+ channel
current during the plateau.
Conclusions—Our results show that ADM enhances cardiac
contractility via cAMP-independent mechanisms including
Ca2+ release from intracellular ryanodine- and
thapsigargin-sensitive Ca2+ stores, activation of protein
kinase C, and Ca2+ influx through L-type Ca2+
channels.
© 1998 American Heart Association, Inc.
Basic Science Reports
Evidence for cAMP-Independent Mechanisms Mediating the Effects of Adrenomedullin, a New Inotropic Peptide
Key Words: adrenomedullin • contractility • calcium • peptides • signal transduction
This article has been cited by other articles:
 |
|
 |
|
  I. Szokodi, R. Kerkela, A.-M. Kubin, B. Sarman, S. Pikkarainen, A. Konyi, I. G. Horvath, L. Papp, M. Toth, R. Skoumal, et al. Functionally Opposing Roles of Extracellular Signal-Regulated Kinase 1/2 and p38 Mitogen-Activated Protein Kinase in the Regulation of Cardiac Contractility Circulation, October 14, 2008; 118(16): 1651 - 1658. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Ertmer, A. Morelli, S. Rehberg, M. Lange, C. Hucklenbruch, H. Van Aken, M. Booke, and M. Westphal Exogenous adrenomedullin prevents and reverses hypodynamic circulation and pulmonary hypertension in ovine endotoxaemia Br. J. Anaesth., December 1, 2007; 99(6): 830 - 836. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Bisping, G. Tenderich, P. Barckhausen, B. Stumme, S. Bruns, D. von Lewinski, and B. Pieske Atrial myocardium is the predominant inotropic target of adrenomedullin in the human heart Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H3001 - H3007. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Dong, M. M. Taylor, W. K. Samson, and J. Ren Intermedin (adrenomedullin-2) enhances cardiac contractile function via a protein kinase C- and protein kinase A-dependent pathway in murine ventricular myocytes J Appl Physiol, September 1, 2006; 101(3): 778 - 784. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mittra and J.-P. Bourreau Gs and Gi coupling of adrenomedullin in adult rat ventricular myocytes Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1842 - H1847. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Charles, M. T. Rademaker, and A. M. Richards Hemodynamic, Hormonal, and Renal Actions of Adrenomedullin-2 in Normal Conscious Sheep Endocrinology, April 1, 2006; 147(4): 1871 - 1877. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C J Charles, D L Jardine, M G Nicholls, and A M Richards Adrenomedullin increases cardiac sympathetic nerve activity in normal conscious sheep J. Endocrinol., November 1, 2005; 187(2): 275 - 281. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Xu and T. L. Krukoff Adrenomedullin Stimulates Nitric Oxide Release from SK-N-SH Human Neuroblastoma Cells by Modulating Intracellular Calcium Mobilization Endocrinology, May 1, 2005; 146(5): 2295 - 2305. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Nishikimi, K. Tadokoro, K. Akimoto, Y. Mori, Y. Ishikawa, K. Ishimura, T. Horio, K. Kangawa, and H. Matsuoka Response of adrenomedullin system to cytokine in cardiac fibroblasts-role of adrenomedullin as an antifibrotic factor Cardiovasc Res, April 1, 2005; 66(1): 104 - 113. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Pemberton, H. Tokola, Z. Bagi, A. Koller, J. Pontinen, A. Ola, O. Vuolteenaho, I. Szokodi, and H. Ruskoaho Ghrelin induces vasoconstriction in the rat coronary vasculature without altering cardiac peptide secretion Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1522 - H1529. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Luodonpaa, H. Leskinen, M. Ilves, O. Vuolteenaho, and H. Ruskoaho Adrenomedullin modulates hemodynamic and cardiac effects of angiotensin II in conscious rats Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2004; 286(6): R1085 - R1092. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mittra, J.-M. Hyvelin, Q. Shan, F. Tang, and J.-P. Bourreau Role of cyclooxygenase in ventricular effects of adrenomedullin: is adrenomedullin a double-edged sword in sepsis? Am J Physiol Heart Circ Physiol, March 1, 2004; 286(3): H1034 - H1042. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. T. Dorner, G. Garhofer, K.-H. Huemer, E. Golestani, C. Zawinka, L. Schmetterer, and M. Wolzt Effects of Adrenomedullin on Ocular Hemodynamic Parameters in the Choroid and the Ophthalmic Artery Invest. Ophthalmol. Vis. Sci., September 1, 2003; 44(9): 3947 - 3951. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Piuhola, M. Makinen, I. Szokodi, and H. Ruskoaho Dual role of endothelin-1 via ETA and ETB receptors in regulation of cardiac contractile function in mice Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H112 - H118. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Feelisch Nitroxyl gets to the heart of the matter PNAS, April 29, 2003; 100(9): 4978 - 4980. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Piuhola, I. Szokodi, P. Kinnunen, M. Ilves, R. deChatel, O. Vuolteenaho, and H. Ruskoaho Endothelin-1 Contributes to the Frank-Starling Response in Hypertrophic Rat Hearts Hypertension, January 1, 2003; 41(1): 93 - 98. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Szokodi, P. Tavi, G. Foldes, S. Voutilainen-Myllyla, M. Ilves, H. Tokola, S. Pikkarainen, J. Piuhola, J. Rysa, M. Toth, et al. Apelin, the Novel Endogenous Ligand of the Orphan Receptor APJ, Regulates Cardiac Contractility Circ. Res., September 6, 2002; 91(5): 434 - 440. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Tsuruda and J. C. Burnett Jr Adrenomedullin: An Autocrine/Paracrine Factor for Cardiorenal Protection Circ. Res., April 5, 2002; 90(6): 625 - 627. [Full Text] [PDF]
|
|
|
|
|
|
A. T. Baumer, C. Schumann, B. Cremers, G. Itter, W. Linz, F. Jockenhovel, and M. Bohm Gene expression of adrenomedullin in failing myocardium: comparison to atrial natriuretic peptide J Appl Physiol, March 1, 2002; 92(3): 1058 - 1063. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
C. J. Charles, M. G. Nicholls, M. T. Rademaker, and A. M. Richards Comparative actions of adrenomedullin and nitroprusside: interactions with ANG II and norepinephrine Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2001; 281(6): R1887 - R1894. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Piuhola, A. Hammes, K. Schuh, L. Neyses, O. Vuolteenaho, and H. Ruskoaho Overexpression of sarcolemmal calcium pump attenuates induction of cardiac gene expression in response to ET-1 Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2001; 281(3): R699 - R705. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Kinnunen, J. Piuhola, H. Ruskoaho, and I. Szokodi AM reverses pressor response to ET-1 independently of NO in rat coronary circulation Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1178 - H1183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
D. O. McGregor, R. W. Troughton, C. Frampton, K. L. Lynn, T. Yandle, A. M. Richards, and M. G. Nicholls Hypotensive and Natriuretic Actions of Adrenomedullin in Subjects With Chronic Renal Impairment Hypertension, May 1, 2001; 37(5): 1279 - 1284. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Eklund, J. Piuhola, J. Komulainen, R. Sormunen, C. Ongvarrasopone, R. Fässler, A. Muona, M. Ilves, H. Ruskoaho, T. E. S. Takala, et al. Lack of type XV collagen causes a skeletal myopathy and cardiovascular defects in mice PNAS, January 23, 2001; (2001) 31444798. [Abstract] [Full Text]
|
|
|
|
|
|
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]
|
|
|
|
|
|
N Nagaya, T Nishikimi, M Uematsu, T Satoh, H Oya, S Kyotani, F Sakamaki, K Ueno, N Nakanishi, K Miyatake, et al. Haemodynamic and hormonal effects of adrenomedullin in patients with pulmonary hypertension Heart, December 1, 2000; 84(6): 653 - 658. [Abstract] [Full Text]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 J. G. Lainchbury, R. W. Troughton, L. K. Lewis, T. G. Yandle, A. M. Richards, and M. G. Nicholls Hemodynamic, Hormonal, and Renal Effects of Short-Term Adrenomedullin Infusion in Healthy Volunteers J. Clin. Endocrinol. Metab., March 1, 2000; 85(3): 1016 - 1020. [Abstract] [Full Text]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
A. Rossler, Z. Laszlo, B. Haditsch, and H. G. Hinghofer-Szalkay Orthostatic Stimuli Rapidly Change Plasma Adrenomedullin in Humans Hypertension, November 1, 1999; 34(5): 1147 - 1151. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Taskinen, M. Toth, O. Vuolteenaho, J. Magga, and H. Ruskoaho Inhibition of Atrial Wall Stretch-Induced Cardiac Hormone Secretion by Lavendustin A, a Potent Tyrosine Kinase Inhibitor Endocrinology, September 1, 1999; 140(9): 4198 - 4207. [Abstract] [Full Text]
|
|
|
|
|
|
T. Tsuruda, J. Kato, K. Kitamura, M. Kawamoto, K. Kuwasako, T. Imamura, Y. Koiwaya, T. Tsuji, K. Kangawa, and T. Eto An autocrine or a paracrine role of adrenomedullin in modulating cardiac fibroblast growth Cardiovasc Res, September 1, 1999; 43(4): 958 - 967. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
L. Eklund, J. Piuhola, J. Komulainen, R. Sormunen, C. Ongvarrasopone, R. Fassler, A. Muona, M. Ilves, H. Ruskoaho, T. E. S. Takala, et al. Lack of type XV collagen causes a skeletal myopathy and cardiovascular defects in mice PNAS, January 30, 2001; 98(3): 1194 - 1199. [Abstract] [Full Text] [PDF]
|
|