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National Cardiovascular Center Research Institute (Y.I., H.S., S.S., T.T., K.K., H.M., N.M.), Fujishirodai, Suita, Osaka 565, Japan; and Faculty of Pharmaceutical Sciences (Y.I., M.Y.), Setsunan University, Hirakata, Osaka 573–01, Japan
Address all correspondence and requests for reprints to: Naoto Minamino, Ph.D., National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565, Japan. E-mail: minamino{at}ri.ncvc.go.jp
Adrenomedullin (AM) is a potent vasorelaxant peptide recently
identified in extracts of pheochromocytoma. We have found that AM is
actively secreted from endothelial cell (EC) and vascular smooth muscle
cell (VSMC). To elucidate the function of AM secreted from EC, the
effects of 43 substances on secretion of AM from cultured rat EC were
examined in this study. We first confirmed that synthesized AM was not
stored but constitutively secreted from EC, indicating that the amount
secreted could be used as an index of AM synthesis in EC. EC secreted
AM at a rate 5.8 times higher than VSMC, and AM gene transcription in
EC significantly contributed to the total aortic AM messenger RNA.
Tumor necrosis factor, interleukin-1, and lipopolysaccharide augmented
AM secretion from EC, showing cooperative effects, which suggests that
AM secreted from EC participates in the induction of hypotension in
septic shock. Transforming growth factor ß1 and FCS
suppressed AM secretion but stimulated endothelin-1 (ET-1) secretion.
Thrombin potently stimulated AM secretion from EC but suppressed it
from VSMC. Thyroid hormone and phorbol ester increased AM and ET-1
secretion but to a lesser extent. Interferon-
inhibited AM secretion
from EC, whereas oxidized LDL stimulated it. Regulation of AM
production in EC is found to be similar to that of VSMC with several
exceptions, but AM and ET-1 production in EC are deduced to be
controlled independently and by different mechanisms. AM stimulates
cAMP production in EC, though receptors expressed on cultured rat EC
are not specific to AM but to calcitonin gene-related peptide. Based on
these findings, AM production in EC is thought to be regulated by a
variety of substances coming from blood and neighboring cells, and the
secreted AM is deduced to dilate blood vessels as an
endothelium-derived relaxing factor competing with ET-1.
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T. H. Elsasser, J. L. Sartin, A. Martínez, S. Kahl, L. Montuenga, R. Pío, R. Fayer, M. J. Miller, and F. Cuttitta Underlying Disease Stress Augments Plasma and Tissue Adrenomedullin (AM) Responses to Endotoxin: Colocalized Increases in AM and Inducible Nitric Oxide Synthase within Pancreatic Islets Endocrinology, November 1, 1999; 140(11): 5402 - 5411. [Abstract] [Full Text]
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 S. Inoue, Y. Hayashi, Y. Ohnishi, K. Kikumoto, N. Minamino, K. Kangawa, H. Matsuo, H. Furuya, and M. Kuro Cerebral Production of Adrenomedullin After Hypothermic Cardiopulmonary Bypass in Adult Cardiac Surgical Patients Anesth. Analg., May 1, 1999; 88(5): 1030 - 1035. [Abstract] [Full Text] [PDF]
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 A. Kubo, N. Minamino, Y. Isumi, T. Katafuchi, K. Kangawa, K. Dohi, and H. Matsuo Production of Adrenomedullin in Macrophage Cell Line and Peritoneal Macrophage J. Biol. Chem., July 3, 1998; 273(27): 16730 - 16738. [Abstract] [Full Text] [PDF]
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Y. Isumi, N. Minamino, T. Katafuchi, M. Yoshioka, T. Tsuji, K. Kangawa, and H. Matsuo Adrenomedullin Production in Fibroblasts: Its Possible Function as a Growth Regulator of Swiss 3T3 Cells Endocrinology, May 1, 1998; 139(5): 2552 - 2563. [Abstract] [Full Text] [PDF]
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