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.
Tomoda
Y
Y
National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, 565-8565, Osaka, Japan.
Kikumoto
K
K
Isumi
Y
Y
Katafuchi
T
T
Tanaka
A
A
Kangawa
K
K
Dohi
K
K
Minamino
N
N
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