Adrenomedullin as a novel antiproliferative factor of vascular smooth muscle cells.
OBJECTIVE
The present study was designed to examine whether adrenomedullin affects fetal calf serum (FCS)-stimulated proliferation in cultured rat vascular smooth muscle cells (VSMCs).


METHODS
Rat VSMCs were grown from explants of Sprague-Dawley rat aorta and were grown using the standard cell culture method. After incubation for 24 h with various concentrations of adrenomedullin in the presence of 5% FCS, trichloroacetic acid-insoluble tritiated thymidine was measured in a liquid scintillation counter. After incubation for 48 h, cell counts were performed. Cyclic adenosine 3',5'-monophosphate (AMP) levels were determined by radioimmunoassay.


RESULTS
Rat adrenomedullin exhibited concentration-dependent inhibition of the FCS-stimulated increase in thymidine incorporation between 10(-7) and 10(-9) mol/l and of cell number at 10(-7) mol/l. However, the calcitonin generelated peptide (CGRP) receptor antagonist human CGRP(8-37) abolished these antiproliferative effects of rat adrenomedullin. Inhibition by adrenomedullin of FCS-stimulated cellular proliferation was paralleled by an increase in the cellular level of cyclic AMP. 8-Bromocyclic AMP, a cyclic AMP analogue, and forskolin, an activator of adenylate cyclase, inhibited the FCS-stimulated increase in thymidine incorporation and cell number.


CONCLUSIONS
These results suggest that adrenomedullin inhibits FCS-stimulated proliferation in cultured rat VSMCs, probably through a cyclic AMP-dependent process. Taken together with the finding that adrenomedullin is synthesized in and secreted from vascular endothelial cells, adrenomedullin may play a role as an antiproliferative factor for VSMCs in a paracrine fashion.
Kano
H
H
First Department of Internal Medicine, Osaka City University Medical School, Japan.
Kohno
M
M
Yasunari
K
K
Yokokawa
K
K
Horio
T
T
Ikeda
M
M
Minami
M
M
Hanehira
T
T
Takeda
T
T
Yoshikawa
J
J
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D053607:Adrenomedullin; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000494:pharmacology*
D010446:Peptide Fragments; D010455:Peptides; D014665:Vasodilator Agents; C058636:calcitonin gene-related peptide (8-37); D053607:Adrenomedullin; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000242:Cyclic AMP; D015740:Calcitonin Gene-Related Peptide