Department of Cardiology , Welsh Heart Research Institute , University of Wales College of Medicine , Heath Park , Cardiff .
Br J Pharmacol 114 : 1652-6 ( 1995)
Abstract
.
We studied the effect of two structurally-related , selective inhibitors of protein kinase C , Ro 31-8220 and Ro 31-7549 , on the reinitiation of proliferation in quiescent first passage rabbit aortic smooth muscle cells in response to ( a ) the direct activator of protein kinase C , phorbol dibutyrate ( PDBu ) , ( b ) platelet-derived growth factor ( PDGF ) , ( c ) a combination of PDGF and 5-hydroxytryptamine ( 5-HT ) or ( d ) serum .
2 . Ro 31-8220 and Ro 31-7549 concentration-dependently inhibited proliferation in response to each mitogen .
The inhibitory potency ( IC50 ) of Ro 31-8220 and Ro 31-7549 , respectively , was similar against proliferation induced by PDBu ( 0.55 and 1.1 microM ) , PDGF ( 0.6 and 0.9 microM ) , PDGF and 5-HT ( 0.68 and 1.1 microM ) , although slightly less against serum ( 1.7 and 5 microM ) .
The effects of the protein kinase C inhibitors on proliferation could not be ascribed to cytotoxicity .
Neither Ro 31-8220 nor Ro 31-7549 ( 0.3-3 microM ) inhibited PDGF receptor tyrosine phosphorylation .
3 . The results show that Ro 31-8220 and Ro -7549 are potent inhibitors of smooth muscle cell proliferation in response to a direct activator of protein kinase C , the defined growth factors , PDGF and 5-HT , and the complex mixture of mitogens in serum .
Protein kinase C activation thus appears to be an important growth transducing mechanism for each of these agents .