Prostacyclin platelet aggregation inhibition

Prostacyclin (PGI2) has remarkable antihypertensive and platelet aggregation inhibiting properties. This important compound has been synthesized from the 5,6-djdehydro-PGF2a derivative as outlined in Scheme 8 10b). The unique 2-alkylidenetetrahydrofuran structure is constructed with excellent stereoselectivity (Z E > 33 1) by cyclization of the ace-... 

Prostacyclin I2 (PGI2) inhibits platelet aggregation and relaxes coronary arteries Like PGE2 and TXA2 it is formed from arachidomc acid via PGH2... 

Methylpyrazole has been investigated as a possible treatment for alcoholism. The stmcture—activity relationship (SAR) associated with a series of pyrazoles has been examined ia a 1992 study (51). These compounds were designed as nonprostanoid prostacyclin mimetics to inhibit human platelet aggregation. In this study, 3,4,5-triphenylpyrazole was linked to a number of alkanoic acids, esters, and amides. From the many compounds synthesized, triphenyl-IJT-pyrazole-l-nonanoic acid (80) was found to be the most efficacious candidate (IC g = 0.4 //M). 

A thrombotic tendency is present in diabetes due to an imbalance between prostacyclin and thromboxane. Lipid peroxides and newly generated free radicals are thought to inhibit the vasodilator and anti-platelet effects of endothelial-derived prostacyclin, but stimulate platelet cyclooxygenase activity, thereby promoting the production of thromboxane A2. This leads to vasoconstriction and platelet aggregation - the concept of peroxide vascular tone (Halliwell and Gutteridge, 1989). 

The advent of COX-2-selective inhibitors has led to unexpected results. By selectively inhibiting the COX-2 isoform, COX-2-selective NSAIDs increase the risk of cardiovascular events in certain patientsP COX-2 is responsible for the production of prostacyclin, a vasodilatory and antiplatelet substance. On the other hand, COX-1 controls the production of thromboxane A2, a vasoconstrictor and platelet aggregator. Selective inhibition of COX-2 results in decreased prostacyclin levels in the face of stable thromboxane A2 levels. An imbalance in the thromboxane A2 prostacyclin ratio ensues, which creates an environment that favors thrombosis. 

Another metabolite of arachidonic acid is prostacyclin (PGI2). As with TxA2, PGI2 is produced continuously. Synthesized by vascular smooth muscle and endothelial cells, with the endothelium as the predominant source, PGI2 mediates effects that are opposite to those of TxA2. Prostacyclin causes vasodilation and inhibits platelet aggregation and, as a result, makes an important contribution to the antithrombogenic nature of the vascular wall. 

Aspirin is maximally effective as an antithrombotic agent at the comparatively low dose of 81 to 325 mg per day. (The antipyretic dose of aspirin in adults is 325 to 650 mg every 4 h.) Higher doses of aspirin are actually contraindicated in patients prone to thromboembolism. At higher doses, aspirin also reduces synthesis of prostacyclin, another arachidonic acid metabolite. Prostacyclin normally inhibits platelet aggregation. The prophylactic administration of low-dose aspirin has been shown to increase survival following myocardial infarction, decrease incidence of stroke, and assist in maintenance of patency of coronary bypass grafts. 

BAY 41-2272 is a novel non-NO-based soluble GC activator. It produced a marked inhibition of platelet aggregation in washed platelets and PRP, however, with much lower potency in PRP. Both NO and prostacyclin exhibited synergistic activity with BAY 41-2272 to inhibit platelet aggregation. In vivo, BAY 41-2272 significantly reduced blood pressure in rats, but it had only a small effect on FeCl3-induced thrombosis [107]. 

Besides cholesterol efflux from arterial wall and its role in RCT, additional properties of HDL have been proposed for its protective anti-atherogenic activities. HDL protects vascular function by a number of potential alternative mechanisms, including inhibition of LDL oxidation [8,9], platelet aggregation and coagulation [10], and endothelial monocyte adhesion [11], as well as promotion of endothelial nitric oxide synthase (eNOS) [12], and prostacyclin synthesis [13-15]. The proposed alternate protective mechanisms for HDL are attractive but many of them lack validation under in vivo conditions. 

Figure 11.31 Effects of endothelial cells, via prostacyclins, and platelets, via thromboxanes, on aggregation of platelets. Aggregation of platelets plays an important role in thrombosis. The drug inhibited COX-2 and hence prostacyclin formation. However, both COX-1 and COX-2 are present in platelets so COX-1 continues to produce thromboxane.

Low doses of aspirin inhibit platelet aggregation and may be more effective than higher doses. Larger doses inhibit cyclooxygenase in arterial walls, interfering with prostacyclin production, a potent vasodilator and inhibitor of platelet aggregation. 

Far out the most important agent in this group is aspirin, a cyclooxygenase inhibitor which is discussed in more detail in Chapter 26. Its unique properties as a platelet aggregation inhibitor are brought forward by the fact that while platelet cyclooxygenase is irreversibly inhibited at low doses of aspirin the synthesis in endothelium of prostacyclin, a platelet aggregation inhibitor itself, recovers more quickly. 

All NSAIDs except aspirin inhibit cyclooxygenase reversibly. Inhibition by aspirin, caused by the covalent acetylation of the enzyme, is irreversible. In platelets most NSAIDs block thromboxane synthesis more than that of prostacyclin and the overall effect is therefore inhibition of platelet aggregation. This effect is already noticeable at low doses. Because of the irreversible nature of the enzyme inhibition by aspirin and the fact that in platelets the novo enzyme synthesis is not possible the aggregation inhibitory effects of aspirin last several days. 

TXA ) from platelets promote and prostacyclin (PGI ) from vessel wall inhibit platelet aggregation. 

E May also inhibit formation of prostacyclin, a platelet aggregation... 

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. 

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