Prostacyclin arachidonic acid

The enzyme system responsible for the biosynthesis of PGs is widely distributed in mammalian tissues and has been extensively studied (2). It is referred to as prostaglandin H synthase (PGHS) and exhibits both cyclooxygenase and peroxidase activity. In addition to the classical PGs two other prostanoid products, thromboxane [57576-52-0] (TxA ) (3) and prostacyclin [35121 -78-9] (PGI2) (4) are also derived from the action of the enzyme system on arachidonic acid (Fig. 1). 

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

Cyclooxygenases. Figure 1 Pathways for the formation of prostanoids from arachidonic acid. Arachidonic acid is converted by cyclooxygenase to endoperoxides, which are acted upon by various synthesases to form the prostanoids. Prostacyclin and thromboxane are relatively unstable and break down rapidly to form the inactive metabolites 6-oxo-PGF1a and thromboxane B2, respectively. 

CYP8A1 is the complementary enzyme to CYP5 in that it synthesizes prostacyclin in the arachidonic acid cascade. CYP8B1 catalyzes the steroid 12-alpha hydroxylation in the cholic acid biosynthesis. 

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. 

Lipids have multiple roles in cells. Recent discoveries show that the same lipid may have both structural and regulatory roles in the cell. For example, while arachidonic acid (20 4co6) is a major constituent of brain inositides and PtdEtn, the free acid is also a precursor of a number of important bio messengers, the eicosanoids, such as prostaglandins, prostacyclins, leukotrienes and thromboxanes... 

F i g u re 18.1 One pathway of arachidonic acid metabolism. The branches of this pathway lead to the prostaglandins (PGs), prostacyclins (PGIs), and thromboxanes (TxBs). The key reaction is the formation of PGH2, creating five chiral centers from an achiral molecule. (Modified from D. Voet and J. G. Voet, Biochemistry, 3rd edn, 2004. Reprinted with permission John Wiley and Sons Inc.)... 

Cyclooxygenase converts arachidonic acid first to prostaglandin G (PGG) and then to PGH prior to formation of prostaglandins, thromboxanes and prostacyclins. The structures of the intermediates and some of the end-products of these conversions are provided in Figure 11.28. 

The major omega-3 fatty acid in hsh oil is eicosapentae-noic acid, which contains hve double bonds compared with only four present in the omega-6 fatty acid, arachidonic acid. When eicosapentaenoic acid is substrate for eico-sanoid production, it gives rise to prostacyclins and thromboxanes of the three series (Figure 22.9(a)) whereas when arachidonic acid is substrate, it gives rise to the two series, thromboxane A2 and prostacyclin I2. Thromboxane A3 has... 

Sources of prostaglandins are the fatty acids of omega-3 and omega-6 classes. Both of these fatty acid classes are compulsory components of cell membranes however, their metaholism and action are sufficiently different. Fatty acids such as linoleic acid and arachidonic acid are sources of prostacyclin as well as thromhoxane. The fatty acids of the omega-3 family with 20 carhon atoms or more displace the balance of prostacyclin... 

Prostacyclin, a potent inhibitor of platelet aggregation, is derived from metabo-lisation of arachidonic acid by endothelial cells, and shear stress increases its production rate [12]. It is postulated that this effect is due to perturbations of the permeability of the plasma membrane changing the cytosolic Ca + content and leading to an increase in phospholipase C activity (through the by-passing of the receptor requirement), which contributes to a higher production of arachidonic metabolites. 

K. C. Nicolaou, J. B. Smith (1979). Prostacyclin, thromboxane and the arachidonic acid cascade ... 

EICOSANOID. Any of a number of biochemically active compounds resulting from enzymic oxidation of arachidonic acid. e.g.. prostaglandins, thromboxanes, prostacyclin, and leukotrienes As a group they compose what is known arachidonic acid cascade. They have many pharmacological and medical possibilities. 

Phospholipase A2 has an important role in the production of arachidonic acid. This is the precursor of some very important signal molecules such as the prostaglandins, prostacyclins, thromboxanes and leukotrienes. Most of the arachidonic acid in cells is attached at the 2-position of certain phospholipids, and is released by the action of phospholipase A2. The role of Ca2+ in the secretion of these signal molecules will be discussed in the next section. 

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