Prostacyclin inhibition

PHHj is converted to prosta-cycline (PGI2) in vessel walls and other tissues. Unlike the thromboxanes, which induce platelet aggregation, prostacyclin inhibits it. 

The inhibition of platelet activation is a critical component in the treatment and prevention of cardiovascular diseases and cerebral ischemia/thrombotic disorders. Nitric oxide and prostacyclins inhibit platelet activation by elevating intracellular levels of both cGMP and cAMP, respectively. In platelets, the most abundant PDE is PDE3A, which lowers the intracellular concentration of cAMP. Inhibitors of PDE3A serve as potential antiplatelet agents by elevating cAMP levels. One PDE3-type selective inhibitor cilostazol, which has both antiplatelet, antithrombotic, and vasodilatory effects, is used for the treatment of intermittent claudication and for the prevention of short- and medium-term vessel closure (22). 

Sulphur analogue of Prostacyclin. Inhibits blood platelet aggregation and is a potent vasoconstrictor. 

Lastly, diabetic platelets showed a refractoriness to prostacyclin and prostaglandin Ei inhibition. Either in the presence of prostacyclin synthetase or prostacyclin, inhibition of collagen-induced platelet aggregation was lower in diabetics than in controls. These results were observed with PRP (table VI) as well as with isolated platelets (table VII). 

Lapetina EG, Schmitges CJ, Chandrabose K and Cuatrecasas P. Cyclic AMP and prostacyclin inhibit platelet membrane phospholipase. Biochem. Biophys. Res. Commun. 76, 828-835, 1977. 

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). 

Okabe, T., Meyer, J. S., Amano, T., Okayasu, H., Mortel, K., 198T Prostacyclin inhibition and cerebrovascular hemodynamics in normal and ischemic human brain. J. Cereb. Blood Flow Metab. 3, 115-121. 

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). 

COX-2 synthesises PGI2 (prostacyclin) and the high incidence of myocardial infarctions with selective COX-2 inhibitors has been attributed to inhibition of COX-2 in vascular tissues. Prostacyclin, made by blood vessel walls, inhibits aggregation of platelets and maintains a balance with thromboxane. Thromboxane, which is released by platelets, promotes clotting. Prostacyclin is synthesised mostly by COX-1, but in humans selective COX-2 inhibition reduces its biosynthesis in vivo. This reduced synthesis may lead to an overactive thromboxane system and increased risk of thromboembolism. 

Inhibition of phospholipase A2, thromboxane B4 and enhancement of prostacyclin production (Raederstorff et al., 2002 Qureshi and Qureshi, 1992). 

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. 

The vascular endothelium produces a number of substances that are released basally into the blood vessel wall to alter vascular smooth muscle tone. One such substance is endothelin (ET-1). Endothelin exerts its effects throughout the body, causing vasoconstriction as well as positive inotropic and chronotropic effects on the heart. The resulting increases in TPR and CO contribute to an increase in MAP. Synthesis of endothelin appears to be enhanced by many stimuli, including Ag II, vasopressin, and the mechanical stress of blood flow on the endothelium. Synthesis is inhibited by vasodilator substances such as prostacyclin, nitric oxide, and atrial natriuretic peptide. There is evidence that endothelin is involved with the pathophysiology of many cardiovascular diseases, including hypertension, heart failure, and myocardial infarction. Endothelin receptor antagonists are currently available for research use only. 

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. 

The aggregation of platelets contributes to the development of atherosclerosis and to the formation of acute thrombus. The activated platelets that adhere to the vascular endothelium generate lipid peroxides and oxygen free radicals, inhibiting the endothelial formation of prostacyclin and nitric oxide. 

The answer is d, (Hardman, p 617. Katzung, p 318.) Most NSAlDs inhibit both cyclooxygenase I and II, resulting in decreased synthesis of prostaglandins, prostacyclins, and thromboxanes. 

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