Mechanism of dipyridamole's action in inhibition of venous and arterial smooth muscle cell proliferation.
Dipyridamole is a potential pharmacological agent to prevent vascular stenosis because of its antiproliferative properties. The mechanisms by which dipyridamole inhibits the growth of vascular smooth muscle cells, especially venous smooth muscle cells, are unclear. In the present study, dipyridamole transiently but significantly increased cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) levels in human venous and arterial smooth muscle cells in a time- and dose-dependent manner. Peak concentrations of both cyclic nucleotides were achieved at 15-30 min. and correlated with inhibition of proliferation in both cell types. The antiproliferative effects of dipyridamole observed at 48 hr were similar whether drug exposure was only 15 min. or sustained for 48 hr. Specific competitive inhibitors of protein kinases A and G attenuated the antiproliferative effects of subsaturating concentrations of dipyridamole, with the effects of protein kinase inhibition being particularly pronounced in venous smooth muscle cells. Flow cytometry analysis showed that dipyridamole caused an enrichment of cells in G(0)/G(1) and a corresponding reduction of cells in S phase. These data indicate that a transient increase in cGMP and cAMP is sufficient to induce downstream kinase activation and subsequent cell cycle arrest, and that protein kinase G may be more important than protein kinase A in mediating the growth inhibitory effect of dipyridamole in venous protein kinase.
Zhuplatov
Sergey B
SB
Veterans Affairs Salt Lake City Healthcare System, Departments of Medicine, Pharmacology & Toxicology, and Biochemistry, University of Utah, Salt Lake City, Utah, USA.
Masaki
Takahisa
T
Blumenthal
Donald K
DK
Cheung
Alfred K
AK
D001011:Aorta / Q000166:cytology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004176:Dipyridamole / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006083:Graft Occlusion, Vascular / Q000517:prevention & control; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D012501:Saphenous Vein / Q000166:cytology; D013873:Thionucleotides / Q000494:pharmacology
C090860:8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate; D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D010975:Platelet Aggregation Inhibitors; D013873:Thionucleotides; C016957:adenosine-3',5'-cyclic phosphorothioate; D004176:Dipyridamole; D000242:Cyclic AMP; D007770:L-Lactate Dehydrogenase; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP