Platelet cyclic AMP

C. Aspirin inhibits platelet cyclooxygenase. Abciximab, a monoclonal antibody, binds to and inhibits the platelet glycoprotein Ilb/IIIa receptor. Dipyridamole inhibits platelet cyclic AMP phosphodiesterase and raises cyclic AMP levels. Eptifibatide binds to the glycoprotein Ilb/IIIa complex. 

Graber SE, Hawiger I Evidence that changes in platelet cyclic AMP levels regulate thcfibrinogcnreoeptcr... 

Muggli R, Tsdiopp TB, Mittelholzer E, Baumgartner HR 7-Bromo-l,5-dihydro-3,6-dimethyl-imidazo[2,l-b]quin olin-2(3H)- one(Ro 15-2041), apotent antithrombotic agent that sdectivdy inhibits platelet cyclic AMP-fdiospho esterase. J Pharmacol Exp Ther 1985 235 212-219. 

Resink, T. J., Burgisser, E. and Buhler, F. R. Enhanced platelet cyclic AMP reqxmse to prostaglandin... 

Mazeaud, M. M., Le Quan Sang, K.-H. and Devynck, M-A. Platelet cyclic AMP in essential hypertensive and normotensive offspring. J. Hyperten. 7 (Suppl. 6), S148-S149,1989. 

AlheidU, Reidiwehr I, Forstermann U (1989) Human endothelial cells inhibit platdet aggregation by sqtarately stimulating platelet cyclic AMP and cyclic GMP. Eur J Pharmacol 164 103-110. 

Inhibitors or activators of platelet aggregation act directly or indirectly by altering the rate of formation or degradation of platelet cyclic AMP. Local concentrations of these substances determine whether the platelet adhesion/aggregation process will occur. 

Finally, it has even been found that two prostaglandins belonging to the same type (but differing in degree of unsaturation) may exert opposite actions PGE, causes an increase in platelet cyclic AMP whereas PGEj lowers the cAMP levels. 

Prostacyclin. Prostacyclin inhibits platelet aggregation and the release reaction. This involves binding to a specific membrane receptor, and a subsequent increase in cyclic AMP. In this respect prostacychn is 10 times more potent than PGD2 and 30 times more potent than PCEj. An increase in platelet cyclic AMP has been reported to inhibit arachidonic acid release from phospholipids, to inhibit cyclooxygenase and to have a direct inhibitory action on the contractile mechanism of the release reaction (Granstrom et al. 1982). 

P2Y receptors are activated by adenine and uridine nucleotides. Most of the known P2Y receptors have been detected in the nervous system [21]. The majority of P2Y receptors inhibit neuronal N-type Ca2+ channels and M-type K+ channels. P2Y1 receptors are found exclusively on platelets, on their precursor megakaryocyte cells and on certain other cultured hematopoietic cells, such as K562 leukemia cells. They can be distinguished from other P2 receptors in that ADP is the most potent natural agonist and ATP is a competitive antagonist. ADP acts via a G protein to inhibit cyclic AMP accumulation, mobilize intracellular Ca2+ and stimulate granule secretion. ADP... 

CYP450 system Anagrelide enhanced the inhibition of platelet aggregation by aspirin and is an inhibitor of cyclic AMP PDE III (may exaggerate the properties of milrinone, enoximone, amrinone, olprinone, and cilostazol). 

Epoprostenol is the natural occurring prostacyclin which is formed in vascular endothelial cells. It increases cyclic AMP in the thrombocyte and is a strong platelet aggregation inhibitor. It is used to prevent thrombotic complications during hemodialysis when heparin is contraindicated. As its duration of action is no longer than 30 minutes it has to be given as an intravenous infusion. 

Ebstein R, Belmaker R, Grunhaus L, et al Lithium inhibition of adrenaline-stimulated adenylate cyclase in humans. Nature 259 411-413, 1976 Ebstein RP, Hermoni M, Belmaker RH The effect of lithium on noradrenahne-in-duced cyclic AMP accumulation in rat brain inhibition after chronic treatment and absence of supersensitivity. J Pharmacol Exp Ther 213 161-167, 1980 Ebstein RP, Lerer B, Shlaufman M, et al The effect of repeated electroconvulsive shock treatment and chronic lithium feeding on the release of norepinephrine from rat cortical vesicular preparations. Cell Mol Neurobiol 3 191-201, 1983 Ebstein RP, Moscovich D, Zeevi S, et al Effect of lithium in vitro and after chronic treatment on human platelet adenylate cyclase activity prosreceptor modification or second messenger signal amplification. Psychiatry Res 21 221-228, 1987 Eccleston D, Cole AJ Calcium-channel blockade and depressive illness. Br J Psychiatry 156 889-891, 1990... 

Dipyridamole (Persantine) is a vasodilator that, in combination with warfarin, inhibits embolization from prosthetic heart valves and, in combination with aspirin, reduces thrombosis in patients with thrombotic diseases. Dipyridamole by itself has little or no benefit in fact, in trials where a regimen of dipyridamole plus aspirin was compared with aspirin alone, dipyridamole provided no additional beneficial effect. Dipyridamole interferes with platelet function by increasing the cellular concentration of adenosine 3, 5 -monophosphate (cyclic AMP). This effect is mediated by inhibition of cyclic nucleotide phosphodiesterase and by blockade of uptake of adenosine, which acts at A2 receptors for adenosine to stimulate platelet adenylyl cyclase. The only current recommended use of dipyridamole is for primary prophylaxis of thromboemboli in patients with prosthetic heart valves the drug is given in combination with warfarin. 

Some, but not all, of the pharmacological effects of eicosanoids are mediated through alterations in the concentration of cyclic adenosine monophosphate (cyclic AMP). For example, prostaglandins Ej and E2 inhibit platelet aggregation by increasing the cyclic AMP concentration. Conversely,... 

A molecule such as cyclic AMP, cyclic GMP or phosphatidylinositol that regulates intracellular processes in response to an extracellular signal. Uncontrolled or paroxysmal brain activity that is usually expressed through the motor system. Antidepressants such as fluoxetine and fluvoxamine that show specificity in inhibiting the uptake of 5-hydroxytryptamine into platelets or brain tissue in vitro and in vivo. 

Dopamine can thus be added to the list of hormones and neurotransmitters which can stimulate or inhibit cyclic AMP formation, depending upon their tissue of action. Thus, while dopamine stimulates cyclic AMP formation in parathyroid cells, superior cervical ganglia, retina and striatal tissue (27, 58-61), it inhibits the accumulation of the cyclic nucleotide in cells of the intermediate and anterior lobes of the pituitary gland. Opposite effects on the cyclic AMP system are also found with LHRH which stimulates and inhibits cyclic AMP levels in the anterior pituitary gland (62) and ovary (63), respectively. Similarly, alpha-adrenergic agents show opposite effects on cyclic AMP formation in brain (64) and platelets (65). PGE, stimulates cyclic AMP formation in the anterior pituitary gland (62) while it inhibits the same parameter in fat cells (66). 

Dipyridamole exerts its antiplatelet action by several mechanisms [7]. One of these is through the inhibition of phosphodiesterase enzyme in platelets, resulting in an increase in intraplatelet cyclic AMP and the consequent potentiation of the platelet inhibiting actions of prostacyclin. Another is the direct stimulation of the release of this eicosanoid by vascular endothelium, and the third is the inhibition of cellular uptake and metabolism of adenosine (thereby increasing its concentration at the platelet vascular interface). 

Prostacyclin (PGI2). Released by endothelium. Activates platelet Gs proteiu-liuked receptors, which in turn activate adenyl cyclase increased levels of cyclic AMP inhibit platelet... 

Hoshijima, M., Kiknchi, A., Kawata, M., Ohmori, T., Hashimoto, E., Yamamnra, H., and Takai, Y. (1988). Phosphorylation by cyclic AMP-dependent protein kinase of a hnman platelet Mr 22,000 GTP-binding protein (smg p21) having the same pntative effector domain as the ras gene products. Biochem Biophys Res Commun 157 851-860. 

Ho HJ, Cho JY, Rhee MH, Park HJ. Cordycepin (3 -deoxya-denosine) inhibits human platelet aggregation in a cyclic AMP-and cyclic GMP-dependent manner. Eur. J. Pharmacol. 2007 558 43-51. 

Johnson GJ, Rao GHR, Leis LA, White JG. Effects of agents which alter cyclic AMP on arachidonate-induced platelet aggregation in dog. Blood 1980 SS 722 729... 

Ichinohe T, Takayama H, Ezumi Y, Yanagi S, Yamamura H, Okuma M Cyclic AMP-insoisitive activation of c-Src and Syk protein4yrosine kinases through platelet membrane glycoprotein VI. J Biol Chem 270 28029-28036,1995... 

Hirafiiji M, Nezu A, Shinoda H, Minami M Involvement of platdet cydic GMP but not cyclic AMP suppression in leukocyte-dependent platelet adhesion to endothdiad cdls induced by datdd-activating factor in vitro. Brit J Pharmacol 1996 117 299-304... 

Wardell MR, Reynolds CC, Bemdt MC, Wallace RW, Fox JE. Platelet glycoprotein Ibb is [hosphorylated on serine 166 by cyclic AMP-dependent protein kinase. JBiol Chem 1989 264 15656-61. 

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