(Circulation. 1997;95:2318-2324.)
© 1997 American Heart Association, Inc.
Articles |
Negative Inotropic Effect of Adrenomedullin in Isolated Adult Rabbit Cardiac Ventricular Myocytes
From the Second Department of Internal Medicine, University of Tokyo (H.I., Y.H.) and the Research Institute of the National Cardiovascular Center, Osaka (K.K., H.M.), Japan.
Correspondence to Hiroshi Ikenouchi, MD, The Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113 Tokyo, Japan. E-mail ikenouchi-2im{at}h.u-tokyo.ac.jp
Background Adrenomedullin (AM) is a potent vasodilator peptide. AM-induced vasodilatation is mediated by an increase of NO as well as cAMP. Both AM and binding sites for this peptide have been found in cardiac tissue, indicating the possible existence of an autocrine or paracrine system of AM in the heart.
Methods and Results Myocytes were isolated by use of retrograde coronary perfusion with physiological solution containing collagenase and hyaluronidase from adult rabbit ventricles. Contraction of cardiac myocytes was traced with a video motion detector, and [Ca2+]i was measured with indo 1 at 37°C. The ICa was measured with a whole-cell patch clamp at 23°C. AM and calcitonin gene–related peptide (CGRP), another member of the same peptide family, showed a concentration-dependent negative inotropic effect (10-7 mol/L AM: contraction amplitude, 64±7% of control; [Ca2+]i, 52±5% of control; n=10; 10-6 mol/L CGRP: contraction amplitude, 64±25%; [Ca2+]i, 70±3%; n=5; mean±SD). ICa was decreased to 60±39% by superfusion with AM after the cessation of NG-monomethyl-L-arginine (L-NMMA), an NO synthase inhibitor. Pretreatment with L-NMMA (10 µmol/L) abolished the negative inotropic effect of AM, whereas switching from AM+L-NMMA to AM+L-arginine (1 mmol/L) restored it. Superfusion with 8-bromo-cGMP also showed a negative inotropic effect. AM significantly increased the intracellular content of cGMP, a second messenger of NO, but not that of cAMP. AM (10 nmol/L) blunted the effect of 1 µmol/L forskolin.
Conclusions AM has a negative inotropic effect and decreased both [Ca2+]i and ICa, with these effects being at least partly mediated via the L-arginine–NO pathway in adult rabbit ventricular myocytes.
Key Words: adrenomedullin • myocytes • contractility • calcium • nitric oxide
This article has been cited by other articles:
 |
|
 |
|
  X.-H. Zhang, G.-R. Li, and J.-P. Bourreau The effect of adrenomedullin on the L-type calcium current in myocytes from septic shock rats: signaling pathway Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2888 - H2893. [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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 Y. Zhao, D. Bell, L. R. Smith, L. Zhao, A. B. Devine, E. M. McHenry, D. P. Nicholls, and B. J. McDermott Differential Expression of Components of the Cardiomyocyte Adrenomedullin/Intermedin Receptor System following Blood Pressure Reduction in Nitric Oxide-Deficient Hypertension J. Pharmacol. Exp. Ther., March 1, 2006; 316(3): 1269 - 1281. [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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
H. Iwasaki, M. Shichiri, F. Marumo, and Y. Hirata Adrenomedullin Stimulates Proline-Rich Tyrosine Kinase 2 in Vascular Smooth Muscle Cells Endocrinology, February 1, 2001; 142(2): 564 - 572. [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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
T. Tsuruda, J. Kato, K. Kitamura, K. Kuwasako, T. Imamura, Y. Koiwaya, T. Tsuji, K. Kangawa, and T. Eto Adrenomedullin: A Possible Autocrine or Paracrine Inhibitor of Hypertrophy of Cardiomyocytes Hypertension, January 1, 1998; 31(1): 505 - 510. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|