Prostacyclin adenylate cyclase

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). 

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. 

Prostacyclin (PGI) activates adenyl cyclase. Increase in cAMP lowers calcium levels and... 

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. 

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

We have previously shown that NO readily synergizes in its platelet-inhibitory action with other inhibitors including prostacyclin (an agonist of adenylate cyclase) and zaprinast and isobutylmetylxanthine (inhibitors of cyclic nucleotide phosphoiesterases) (Radomski et al 1987a). 

Platelet adenylate cyclase formation in turn is stimulated by prostacyclin (from the endothelium, also called PGy and inhibited by thromboxane-A (from within platelets, also called TXA ). 

Fisher DG, Koren HS (1981) Isolation of human monocytes. Adams DO, Edelson PJ, Koren HS (eds) In Methods for studying mononuclear phagocytes. Academic, New York, 43-47 Gorman, RR, Bunting S, Miller OV (1977) Modidation of human platelet adenylate cyclase by prostacyclin (PGX). Prostaglandins 13 377-388. 

Figure 8.1 Prostanoid-dependent activation of adenylate cyclase in whole homogenates of NCB-20 cells. Results in (A) show means SEM of triplicate determinations of adenylate cyclase activity in the presence of increasing concentrations of prostacyclin ( ), PGEi (A) and 6j5-PGIi ( ). The same data are presented in (B) as Hill plots, where r is the increase in enzyme activity above basal levels at each concentration of prostanoid, and R is the maximum activation produced by each prostanoid. (Reproduced from reference 16 with permission)...

Agonist-specific desensitization of prostacyclin-stimulated adenylate cyclase activity has been demonstrated in numerous systems, including human fibroblasts, and platelets in vitro and in vivo ". We have examined the mechanism of desensitization in both human platelets and in cells of the NCB-20 cell line Important and interesting differences have emerged which provide some insights into the events that follow agonist occupation of membrane receptors. 

Blair, I.A., Hensby, C.N. and MacDermot, J. (1980). Prostacyclin-dependent activation of adenylate cyclase in a neuronal somatic cell hybrid prostanoid structure-activity relationships. Br. ]. Pharmacol, 69, 519-525... 

MacDermot, J., Barnes, P.J. and Dollery, C.T. (1981). Distribution of prostacyclin-sensitive adenylate cyclase in guinea pig lung. In Lewis, P.J. and O Grady, J. (eds.) Clinical Pharmacology of Prostacyclin, pp. 247-248. (New York Raven Press)... 

Gorman RR, Bunting S and Miller OV. Modulation of human platelet adenylate cyclase by prostacyclin (PGX). Prostaglandins 13, 377-388, 1977. 

Prostacyclin (PGI2) synthesised by endothelial cells and released predominantly towards the luminal side (Bassenge and Heusch 1990), acts via a receptor-mediated adenylate cyclase. In platelets, the increase in cAMP inhibits adhesion, aggregation and the release of pro-aggregatory and vasoconstrictor compounds such as serotonin, thromboxane A2, and ADR... 

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