Platelet activation phosphodiesterases

Fig. 9.1 Nitric oxide mediated inhibition of platelet activation. Abbreviations used NO, nitric oxide EDRF, endothelium-derived relaxing factor GC, guanylyl cyclase PDE, phosphodiesterase cGMP-PK, GMP-dependent protein kinase Raplb, small GTPase Raplb ...

PGR analog/mimetic (epoprostenol, FR181157) Sildenafil Inhibits platelet aggregation Inhibits type-5 phosphodiesterase and reduces platelet activation... 

Inhibition of phosphodiesterase, causing elevation of intracellular platelet cyclicAMP and a consequent reduction in calcium inhibitions this platelet activation and granule releases... 

Seiler S,Gflleq>ieE,AnicddA( Brassard CL, MeanwdlNA, Fleming JS hnidazDquinoline derivatives Potent inhibitors of platelet cAMP phosphodiesterase which devate cAMP levels and activate protdn kinase in platdets. Thromb Res 1991 62 31-42. 

Recently, in 1997, Ghisalberti [14] published a review on the cardiovascular activity of naturally occurring lignans, including the effects on cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE), Ca2+ channel movement, hypertension, and as platelet activating factor (PAF) and endothelin antagonists. Antioxidant and vasorelaxant effects were also covered. The most relevant finding on this subject from 1996 until 1999 are dealt with below. 

Several newer approaches to antiplatelet drug development have been recently discovered (122). These include inhibitions of the vWf/GPIb interaction, the platelet/collagen interaction, and the thrombin-induced platelet activation. Other approaches to platelet inhibition include the use of serotonin antagonists (because serotonin induces platelet aggregation), nitric oxide-donating antiplatelet agents, phosphodiesterase inhibitors, and inducers of adenyl cyclase. 

Fleming, J.S., Gillespie, E Hayes, D.C., and Stanton, H.C. (1992) Inhibitors of blood platelet cAMP phosphodiesterase. 2. Structure-activity relationships associated with imidazo[4,5-b]quinolin-2-ones substituted with functionalized side chains. Journal of Medicinal Chemistry, 35, 2672-2687. 

The intra-platelet levels of cAMP can be stabilized by prostacyclin or its analogues (e.g., iloprost) or by dipyridamole. The former activates adenyl cyclase via a G-protein-coupled receptor the latter inhibits a phosphodiesterase that breaks down cAMP. 

Mechanism of Action A blood modifier and platelet aggregation inhibitor that inhibits the activity of adenosine deaminase and phosphodiesterase, enzymes causing accumulation of adenosine and cyclic adenosine monophosphate. Therapeutic Effect Inhibits platelet aggregation may cause coronary vasodilation. 

Dipyridamole is a vasodilator that inhibits platelet function by inhibiting adenosine uptake and cGMP phosphodiesterase activity. Dipyridamole by itself has little or no beneficial effect. Therefore, therapeutic use of this agent is primarily in combination with aspirin to prevent cerebrovascular ischemia. It may also be used in combination with warfarin for primary prophylaxis of thromboemboli in patients with prosthetic heart valves. A combination of dipyridamole complexed with 25 mg of aspirin is now available for secondary prophylaxis of cerebrovascular disease. 

Lam SC-T Guccione MA, Packham MA, et al. Effect of cAMP phosphodiesterase inhibitors on ADP-induced shape change, cAMP and nucleoside diphosphokine activity of rabbit platelets. Thromb Haemost 1982 47 90-95. 

As previously mentioned, for SMC proliferation after coronary angioplasty, cell activation and cell-to-cell interaction of platelets and leukocytes mediated by adhesion molecules are considered to be important. Coronary stenting produces the release of an adhesion molecule, P-selectin, from d-granule of activated platelets. P-selectin-mediated platelet-leukocyte interaction has a crucial role in the development of stent restenosis. Cilostazol is an antiplatelet, antithrombotic, phosphodiesterase III inhibitor that by inhibiting P-selectin release has inhibitory effects on SMC migration. In addition, cilostazol may directly act to inhibit intimal hyperplasia. 

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