Adenylate cyclase platelets

Forskolin (5-[acetyloxy]-3-ethenyldodecahydro-6,10,10b-trihydroxy-3,4a,7,7,10a-penta-methyl-[3R- 3a-4aP, SP, 6P, 6aa,10a, lOaP, 10ba -lFf-naphtho[2,l-b]pyran-l-one) [66575-29-9] M 410.5, m 229-232°, 228-233°. Recrystd from CfiH6-pet ether. It is antihypertensive, positive ionotropic, platelet aggregation inhibitory and adenylate cyclase activating properties [Chem AbstrS9 1978 244150, de Souza et al. Med Res Rev 3 201 1983]. 

Prostacyclin and its analogues also function by increasing the level of platelet cAMP, presumably by activation of the enzyme adenyl cyclase. A chemically stable analogue of prostacyclin called Iloprost has been effective in preventing consumption of platelets (71). 

Henry DY, Gueritte-Voegelein F, Insel PA, Ferry N, Bouguet J, Potier P, Hanoune J. Isolation and characterization of 9-hydroxy- 10-trans,12-cis-octadecadienoic acid, a novel regulator of platelet adenylate cyclase from Glechoma hederacea L. Labiatae. Eur J Biochem 1987 170 389-394. 

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. 

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... 

Newman ME, Drummer D, Lerer B Single and combined effects of desimipramine and lithium on serotonergic receptor number and second messenger function in rat brain. J Pharmacol Exp Ther 252 826-831, 1990 Newman ME, Lerer B, Lichtenberg P, et al Platelet adenylate cyclase activity in depression and after clomipramine and lithium treatment. Psychopharmacology 109 231-234, 1992... 

Stimulation of the platelets by prostacyclin (prostaglandin I2 see Chapter 22) leads to a 10- to 40- fold increase in cAMP concentration and a 4- to 5-fold increase in the rate of lsO incorporation.178 A quite different soluble adenylate cyclase is present in spermatozoa. It is stimulated directly by bicarbonate ions. It may be a bicarbonate sensor in sperm cells and in some other bicarbonate-responsive tissues as well as in cyanobacteria.178a,178b... 

A) Inhibition of platelet phosphodiesterases (PDEs) [91]. Quercetin and myricetin potentiated the anti-aggregatory action of prostacyclin (PGI2), a potent stimulator of platelet adenylate cyclase synthesised by the vascular endothelium, on ADP-induced platelet aggregation in washed human platelets, and the elevation of platelet cyclic adenosine monophosphate (cAMP) elicited by PGI2 [89,92,93]. These effects are probably due to an inhibition of PDEs. As suggested by Ferrell and co-workers [92], this inhibition arises from the similarity between the pyranone ring of flavonoids and the pyrimidine ring of adenine. 

Specific binding of PGE2 to a variety of cells correlates with an activation of adenylate cyclase and the accumulation of cAMP. In human adipocytes, PGE2 causes a 15-fold increase in the concentration of cAMP. In platelets, PGI2 rather than PGE2 appears to mediate the increase in cAMP. 

The enzymes responsible for the platelet metabolism are distributed in different platelet structures, For example, the plasma membrane contains adenylate cyclase in contrast, phospholipase (PL) A2, diglycerol lipase, cyclooxygenase... 

There are three important ADP receptors on the platelet surface (16). The P2X, inotrophic receptor is responsible for rapid influx of calcium into the cytosol. The P2Y, receptor mediates mobilization of calcium through activation of PLC and shape change. The P2Y,2 receptor is coupled to adenyl cyclase inhibition mediated by a G-protein with subsequent decrease in the cAMP The decrease in cAMP stimulates dephosphorylation of VASP that is closely correlated with the GPIIb/llla activation. 

Gachet C, Cazenave JR Ohlmann R et al. The thienopyridine ticlopidine selectively prevents the inhibitory effects of ADP but not of adrenaline on cAMP levels raised by stimulation of the adenylate cyclase of human platelets by PGEI. Biochem Pharmacol 1990 40 2683-2687. 

Mills DC, Puri R, Hu CJ, etal. Clopidogrel inhibits the binding of ADP analogues to the receptor mediating inhibition of platelet adenylate cyclase. Arterioscler Thromb 1992 12 430-436. 

Adenosine, in addition to serving as a substrate for the generation of cAMP plays a physiologic role as a platelet inhibitor and a vasodilator and may attenuate neutrophil-mediated damage to endothelial cells, Adenosine diphosphate (ADP)— a potent platelet agonist—is converted to adenosine, which is taken up rapidly by cells, especially erythrocytes and endothelial cells, A small proportion is metabolized to the aforementioned cyclic nucleotides. The remainder is broken down to inosine and subsequently to xanthine. Dipyridamole inhibits the active transport of adenosine into cells, but does not interfere with the passive diffusion. Since the platelet inhibitory effects of adenosine proceed via stimulation of adenylate cyclase, these effects can also be amplified by dipyridamole, In circulating blood, the largest amount of adenosine is found in red blood cells, This may, in part, help explain why dipyridamole is much more effective in whole blood than in plasma. 

Anand-Srivastava MB. 1993. Rat platelets from spontaneously hypertensive rats exhibit decreased expression of inhibitory guanine nucleotide regulatory protein relationship with adenylate cyclase activity. Circ Res 173 1032-1039. 

Livingstone, C., A.R. McLellan, M.A. McGregor, A. Wilson, J.M. Connell, M. Small, G. Milligan, K.R. Paterson, and M.D. Houslay. 1991. Altered G-protein expression and adenylate cyclase activity in platelets of non-insulin-dependent diabetic (NIDDM) male subjects. Biochim. Biophys. Acta 1096 127-133. 

Hydroxy alkenals affect adenylate cyclase activity and phospholipase C activities reduce cell growth and promote cell differentiation inhibit platelet aggregation block macrophage action block thiol group... 

Alkenals, such as 4-hydroxynonenal (Esterbauer, 1985) which is very biologically active, inhibiting platelet aggregation, activating adenyl cyclase activity (Esterbauer, 1985) and is a substrate for glutathione transferases and... 

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

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