Carvedilol, a multiple-action neurohumoral antagonist, inhibits mitogen-activated protein kinase and cell cycle progression in vascular smooth muscle cells.
Recent findings that the multiple-action neurohumoral antagonist carvedilol inhibits the mitogenic effects of a broad variety of mitogens and produces marked protection against neointima formation after balloon angioplasty injury prompted further study into the molecular and biochemical mechanism of action. In the present study, the effects of carvedilol on mitogen-activated protein (MAP) kinase activity and cell cycle progression were evaluated. Carvedilol produced significant concentration-dependent inhibition of mitogen-induced MAP kinase activity in rat smooth muscle cells. Furthermore, when MAP kinase was purified from mitogen-stimulated cells by FPLC Mono Q chromatography, carvedilol produced direct enzyme inhibition. In the cell-free assay, carvedilol (10 microM) produced 50% inhibition of MAP kinase activity. Cell flow cytometry studies revealed that quiescent rat aortic smooth muscle cells showed 96% of the cell population in the G0/G1 phase of the cell cycle. The addition of serum (10%) increased the number of cells in S and G2/M phases 20% to 40%, respectively. Carvedilol (10 microM) significantly decreased (30-50%) the number of cells in S and G2/M phase. In addition, carvedilol significantly inhibited (>70%) serum-induced stimulation of the S phase-specific marker thymidine kinase. These data suggest that the antimitogenic actions of carvedilol on vascular smooth muscle may be in part due to the inhibition of MAP kinase activity and regulation of cell cycle progression.
Sung
C P
CP
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939, USA.
Arleth
A J
AJ
Eichman
C
C
Truneh
A
A
Ohlstein
E H
EH
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013937:Thymidine Kinase / Q000378:metabolism
D002227:Carbazoles; D004791:Enzyme Inhibitors; D010982:Platelet-Derived Growth Factor; D011412:Propanolamines; D000077261:Carvedilol; D013937:Thymidine Kinase; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D013755:Tetradecanoylphorbol Acetate