PGI2

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

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). 

Both thromboxane A (TXA2) and prostacyclin (PGI2) are extremely unstable compounds. The iastabiUty of TXA2 (3) is due to the strained bicycHc acetal system. Hydrolysis of the acetal to give TXB2 (15) releases the strain. 

PGI2 (4) contains an acid-labHe enol ether which is readily hydrolyzed to generate 6-keto-PGp2Q, (16). 

As with TxA2, the reactivity of PGI2 — 3 min at pH 7.6 and 37°C) made isolation of the natural substance difficult, and a pure chemical sample was obtained only through chemical synthesis. PGI2 is stable under more alkaline conditions and can be isolated and stored as a salt. Additional information on the chemistry and stabiUty of TXA2 and PGI2 has been summarized (58). 

The PGs, PGI2 and TXA2 collectively exhibit a wide variety of biochemical and pharmacological activities and are iavolved ia both physiological and pathophysiological processes. However, the iadividual compounds show different overall activity profiles sometimes ia opposiag directions. Excellent reviews are available (59—64). A survey of some of the more important biological actions of the prostanoids foUow. 

Reproductive System. The primary PGs are intimately involved in reproductive physiology (67). PGE2 and PGP2Q, are potent contractors of the pregnant utems and intravenous infusion of either of these compounds to pregnant humans produces a dose-dependent increase in frequency and force of uterine contraction. PGI2 and TXA2 have mild relaxant and stimulatory effects, respectively, on uterine tissue. The primary PGs also play a role in parturition, ovulation, luteolysis, and lactation and have been impHcated in male infertility. 

Prostacyclin. The total syntheses of PGI2 (4) have been extensively reviewed (58,103). The first synthesis of PGI2 as its methyl ester and... 

Subsequent dehydrohalogenation afforded exclusively the desired (Z)-olefin of the PGI2 methyl ester. Conversion to the sodium salt was achieved by treatment with sodium hydroxide. The sodium salt is crystalline and, when protected from atmospheric moisture and carbon dioxide, is indefinitely stable. A variation of this synthesis started with a C-5 acetylenic PGF derivative and used a mercury salt cataly2ed cyclization reaction (219). Although natural PGI has not been identified, the syntheses of both (6R)- and (65)-PGl2, [62777-90-6] and [62770-60-7], respectively, have been described, as has that of PGI3 (104,216). 

The 5-(E)-isomer of PGI2 was also unambiguously synthesized in two different approaches (Ref. 2, 3). 

Research and development of Beraprost sodium, a stable modified prostaglandin PGI2 possessing cyclopenta[d]benzofuran fragment 96YGK1055,97YZ509. 

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. 

The ETa receptor activates G proteins of the Gq/n and G12/i3 family. The ETB receptor stimulates G proteins of the G and Gq/11 family. In endothelial cells, activation of the ETB receptor stimulates the release of NO and prostacyclin (PGI2) via pertussis toxin-sensitive G proteins. In smooth muscle cells, the activation of ETA receptors leads to an increase of intracellular calcium via pertussis toxin-insensitive G proteins of the Gq/11 family and to an activation of Rho proteins most likely via G proteins of the Gi2/i3 family. Increase of intracellular calcium results in a calmodulin-dependent activation of the myosin light chain kinase (MLCK, Fig. 2). MLCK phosphorylates the 20 kDa myosin light chain (MLC-20), which then stimulates actin-myosin interaction of vascular smooth muscle cells resulting in vasoconstriction. Since activated Rho... 

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