Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.12 (PKG)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Dipyridamole enhances interleukin-1beta-stimulated nitric oxide production by cultured rat vascular smooth muscle cells. 890 84

We and others have previously demonstrated that nitric oxide (NO)-induced inhibition of platelet shape change is important in regulating platelet adhesion and aggregation, and therapeutic intervention of this pathway is clinically relevant for secondary prevention of stroke with dipyridamole. In the present study, we investigated whether dipyridamole affected the shape change of aspirinated platelets. Platelet shape change was inhibited using both authentic NO and sodium nitroprusside, as monitored by light scattering and mean platelet volume measurements. Dipyridamole synergized with NO, even at supra-therapeutic levels, to inhibit thrombin-induced shape change and further potentiated cAMP dependent protein kinase (PKA) mediated phosphorylation of vasodilator stimulated phosphoprotein (VASP) Ser157, even without altered levels of platelet cAMP. The effect of dipyridamole on NO-inhibited shape change depended on cGMP synthesis as evaluated by inhibition of soluble guanylyl cyclase. Measured increases in cGMP levels by dipyridamole and NO was assessed by mathematical modeling and found to be consistent with inhibition of phosphodiesterase 5 (PDE5). The model could explain the unexpected efficiency of dipyridamole in inhibiting PDE5 at the measured cGMP levels, by the majority of cGMP being bound to cGMP-dependent protein kinase (PKG). Still, selective activators of PKG failed to extend NO-mediated inhibition of the thrombin-induced platelet shape change, suggesting that PKG was not responsible for the inhibitory effect of NO and dipyridamole on shape change. The effects of dipyridamole were independent of the prostanoid and ADP pathways. Thus, the effect of dipyridamole on NO-mediated inhibition of platelet shape change may be an important and additional beneficial therapeutic effect of dipyridamole, which we suggest, is acting though localized amplification of the NO/cGMP/Phosphodiesterase3/cAMP/PKA-pathway. Probably, the efficiency of dipyridamole could be amplified clinically with NO donors.
 ...
PMID:Dipyridamole synergizes with nitric oxide to prolong inhibition of thrombin-induced platelet shape change. 2095 17