Department of Pharmacology , Chang Gung Medical College , Kwei-San , Tao-Yuan , Taiwan .
Br J Pharmacol 114 : 1227-35 ( 1995)
Abstract
.
The effects of A02011-1 , a pyrazole derivative , on the proliferation of rat vascular smooth muscle cells ( VSMCs ) were examined .
2 . A02011-1 ( 1-100 microM ) concentration-dependently inhibited [ 3H]-thymidine incorporation into DNA in rat VSMCs that were synchronized by 48 h serum depletion and then re-stimulated by addition of foetal calf serum ( FCS , % ) , platelet-derived growth factor ( PDGF , 10 ng ml-1 ) , -hydroxytryptamine ( 10 microM ) or ADP ( 10 microM ) .
The inhibitory effect of A02011-1 was fully reversible .
However , FCS-induced [ 3H]-thymidine incorporation into rat endothelial cells was unaffected by A02011-1 .
3 . The concentration of A02011-1 necessary for inhibition of the FCS-induced proliferation was similar to that necessary for adenosine 3':5'-cyclic monophosphate ( cyclic AMP ) formation .
Adenylyl cyclase activity was increased in A02011-1-treated VSMCs , whereas cyclic AMP-specific phosphodiesterase activity was unchanged .
4 . A02011-1 was equipotent with forskolin but was more potent than 8-bromo-cyclic AMP against FCS ( 10%)-induced proliferation .
5 . The antiproliferative action of A02011-1 was mimicked by 8-bromo-cyclic AMP , a membrane-permeable cyclic AMP analogue and was antagonized by 2',5'-dideoxyadenosine , an adenylyl cyclase inhibitor and by Rp-cyclic AMPS , a competitive inhibitor of cyclic AMP-dependent protein kinase ( PKA ) type I and II .
-Isobutyl-1-methylxanthine ( IBMX ) caused significant potentiation of the antiproliferative activity of A02011-1 .
However , Rp-8-bromo-cyclic GMPS and staurosporine did not affect the antiproliferative activity of A02011-1.(ABSTRACT TRUNCATED AT 250 WORDS )