Cardiac fibroblasts are major production and target cells of adrenomedullin in the heart in vitro.
OBJECTIVE
Adrenomedullin (AM) is a potent vasodilator peptide. Plasma AM concentration is increased in patients with various heart diseases, and both myocytes (MCs) and non-myocytes (NMCs) secrete AM and express its receptors. These facts suggest that cardiac cells possess an autocrine/paracrine capability mediated by AM.


METHODS
MCs and NMCs were prepared from cardiac ventricles of neonatal rats. AM and endothelin-1 concentrations were measured by radioimmunoassays, and interleukin-6 level by a specific bioassay. Total nitrite/nitrate contents were measured with a fluorescence assay kit.


RESULTS
A basal secretion rate of AM from NMCs was 2.8-fold higher than that from MCs. Interleukin-1beta, tumor necrosis factor-alpha and lipopolysaccharide stimulated AM secretion from NMCs but not from MCs. AM stimulated interleukin-6 production in the presence of these cytokines or lipopolysaccharide, which was more prominent in NMCs. In the presence of interleukin-1beta, AM augmented nitric oxide synthesis 2.7-fold in NMCs, but slightly in MCs. NMCs secreted endothelin-1 at a rate nine times higher than MCs, and AM inhibited endothelin-1 secretion from NMCs.


CONCLUSIONS
This in vitro study suggests that AM in the heart is mainly produced in NMCs and exerts its effects through NMCs, especially under inflammatory conditions.
National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, 565-8565, Osaka, Japan.
Y
Y
Tomoda
K
K
Kikumoto
Y
Y
Isumi
T
T
Katafuchi
A
A
Tanaka
K
K
Kangawa
K
K
Dohi
N
N
Minamino
D053607:Adrenomedullin; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology*; D019332:Endothelin-1 / Q000032:analysis / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000032:analysis / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000032:analysis / Q000096:biosynthesis; D010455:Peptides / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013268:Stimulation, Chemical; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D019332:Endothelin-1; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D053607:Adrenomedullin; D009569:Nitric Oxide; D000242:Cyclic AMP; D015740:Calcitonin Gene-Related Peptide