Effect of cilostazol, a cAMP phosphodiesterase inhibitor, on nitric oxide production by vascular smooth muscle cells.
We investigated the effects of cilostazol, a cAMP phosphodiesterase inhibitor, on nitric oxide (NO) synthesis in cultured rat vascular smooth muscle cells. Incubation of the cultures with interleukin-1 beta (10 ng/ml) for 24 h caused a significant increase in the accumulation of nitrite, a stable metabolite of NO. Although cilostazol itself showed no effect on nitrite accumulation, it stimulated interleukin-1 beta-induced nitrite accumulation in a concentration-dependent manner (10(-8)-10(-5) M). This effect of cilostazol was completely abolished in the presence of NG-monomethyl-L-arginine, actinomycin D or dexamethasone. The cilostazol-induced nitrite production was accompanied by increased inducible NO synthase protein expression. In the presence of dibutyryl-cAMP, interleukin-1 beta-induced nitrite accumulation was further increased, but the stimulatory effect of cilostazol on nitrite accumulation was blunted. The effect of cilostazol was also abolished in the presence of Rp-8-bromoadenosine-3',5-cyclic monophosphorothioate, a competitive inhibitor of protein kinase A. Addition of cilostazol to the cultures significantly increased intracellular cAMP levels of vascular smooth muscle cells. These results indicate that cilostazol increases NO synthesis in interleukin-1 beta-stimulated smooth muscle cells, at least partially through a cAMP-dependent pathway.
Ikeda
U
U
Department of Cardiology, Jichi Medical School, Tochigi, Japan. uikeda@jichi.ac.jp
Ikeda
M
M
Kano
S
S
Kanbe
T
T
Shimada
K
K
D000818:Animals; D002478:Cells, Cultured; D000077407:Cilostazol; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000494:pharmacology*
D010726:Phosphodiesterase Inhibitors; D013777:Tetrazoles; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D000077407:Cilostazol