Dipyridamole enhances interleukin-1beta-stimulated nitric oxide production by cultured rat vascular smooth muscle cells.
We examined whether dipyridamole affected interleukin-1beta-stimulated nitric oxide (NO) production by cultured rat vascular smooth muscle cells. Interleukin-1beta stimulated the production of nitrite and nitrate, stable metabolites of NO, in a dose- and time-dependent manner in vascular smooth muscle cells. Dipyridamole (1-100 mu M) enhanced interleukin-1beta-induced nitrite production in a dose- and time-dependent manner. The mRNA expression of inducible NO synthase was up-regulated by dipyridamole (0.3-10 mu M) treatment in a dose-dependent manner. Both 8-bromo-guanosine 3',5'-cyclic monophosphate (8-bromo-cGMP) and dibutyryl adenosine 3',5'-cyclic monophosphate (db-cAMP) enhanced the nitrite production in the presence of interleukin-1beta. Dipyridamole up-regulated the effect of both 8-bromo-cGMP and db-cAMP on the interleukin-1beta-induced nitrite production. Dipyridamole increased the intracellular cAMP content in the presence of interleukin-1beta (10 ng/ml), but did not affect the intracellular cGMP content. 8R*,9S*,11S*-(-)-9-hydroxy-9-n-hexyloxy-8-methyl-2,3,9,10- tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo-(a,g)-cy cloocta ++-(c,d,e)-trinden-1-one (KT 5720), a selective inhibitor of cAMP-dependent protein kinase, abolished the enhancement of interleukin-1beta-induced nitrite production by dipyridamole, whereas 8R*,9S*,11S*-(-)-9-methoxy-carbamyl-8-methyl-2,3,9,10-tetrahydro-8,11-ep oxy-1H,8H,11H-2,7b,11a-trizadibenzo-(a,g)-cyclo-octa-(c,d,e)-tr inden-1-one (KT 5823), an inhibitor of cGMP-dependent protein kinase, did not attenuate the enhancement. Furthermore, Rolipram and 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro-20-1724), cAMP-specific phosphodiesterase type IV inhibitors, augmented the interleukin-1beta-induced nitrite production. We concluded that dipyridamole enhanced the interleukin-1beta-induced NO production via an increase in intracellular cAMP content in cultured rat vascular smooth muscle cells.
Iimura
O
O
Department of Nephrology, Jichi Medical School, Minamikawachi, Japan.
Kusano
E
E
Amemiya
M
M
Muto
S
S
Ikeda
U
U
Shimada
K
K
Asano
Y
Y
D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000032:analysis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D006152:Cyclic GMP / Q000032:analysis; D004176:Dipyridamole / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D007375:Interleukin-1; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D009569:Nitric Oxide; D004176:Dipyridamole; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D006152:Cyclic GMP