Prostacyclins

Prostacyclin (also called prostaglandin I2 or PGI2) is a prostaglandin member of the family of lipid molecules known as eicosanoids. It inhibits platelet activation and is also an effective vasodilator.

As a drug, it is also known as "epoprostenol". The terms are sometimes used interchangeably.

History
During the 1960s, a U.K. research team, headed by Professor John Vane, began to explore the role of prostaglandins in anaphylaxis and respiratory diseases. Working with a team from the Royal College of Surgeons, Sir John discovered that aspirin and other oral anti-inflammatory drugs work by inhibiting the synthesis of prostaglandins. This critical finding opened the door to a broader understanding of the role of prostaglandins in the body.

Sir John and a team from the Wellcome Foundation, had identified a lipid mediator they called “PG-X,” which inhibits platelet aggregation. PG-X, which later would become known as prostacyclin, is 30 times more potent than any other then-known anti-aggregatory agent.

By 1976, Sir John and fellow researchers Salvador Moncada, Ryszard Gryglewski and Stuart Bunting published the first paper on prostacyclin, in the scientific journal Nature. The collaboration produced a synthesized molecule, which was given the name epoprostenol. But, as with native prostacyclin, the structure of the epoprostenol molecule proved to be unstable in solution, prone to rapid degradation. This presented a challenge for both in vitro experiments and clinical applications. To overcome this challenge, the research team that discovered prostacyclin was determined to continue the research in an attempt to build upon the success they had seen with the prototype molecule. The research team synthesized nearly 1,000 analogues.

Through innovative work done by researcher Lucy Clapp, treprostinil has demonstrated a unique effect on PPAR gamma, a transcription factor important in vascular pathogenesis as a mediator of proliferation, inflammation, and apoptosis. Through a complementary, yet cyclic AMP-independent pathway, treprostinil activates PPARs, another mechanism that contributes to the anti-growth benefits of the prostacyclin class.

Production
Prostacyclin is produced in endothelial cells from prostaglandin H2 (PGH2) by the action of the enzyme prostacyclin synthase. Although prostacyclin is considered an independent mediator, it is called PGI2 (prostaglandin I2) in eicosanoid nomenclature, and is a member of the prostanoids (together with the prostaglandins and thromboxane).

The series-3 prostaglandin PGH3 also follows the prostacyclin synthase pathway, yielding another prostacyclin, PGI3. The unqualified term 'prostacyclin' usually refers to PGI2. PGI2 is derived from the ω-6 arachidonic acid. PGI3 is derived from the ω-3 EPA.

Function
Prostacyclin (PGI2) chiefly prevents formation of the platelet plug involved in primary hemostasis (a part of blood clot formation). It does this by inhibiting platelet activation. It is also an effective vasodilator. Prostacyclin's interactions in contrast to thromboxane (TXA2), another eicosanoid, strongly suggest a mechanism of cardiovascular homeostasis between the two hormones in relation to vascular damage.

Degradation
Prostacyclin, which has a half-life of 42 seconds, is broken down into 6-keto-PGF1, which is a much weaker vasodilator.

Mode of action

 * {| class=wikitable

!colspan=2|Prostacyclin effect !Mechanism !Cellular response
 * rowspan=3|Classical functions
 * Vessel tone
 * ↑cAMP, ↓ET-1 ↓Ca2+, ↑K+
 * ↓SMC proliferation ↑Vasodilation
 * Antiproliferative
 * ↑cAMP &earr;PPAR
 * ↓Fibroblast growth ↑Apoptosis
 * Antithrombotic
 * ↓Thromboxane-A2 ↓PDGF
 * ↓Platelet aggregation ↓Platelet adherence to vessel wall
 * rowspan=2|Novel functions
 * Antiinflammatory
 * ↓IL-1, IL-6 ↑IL-10
 * ↓Proinflammatory cytokines ↑Antiinflammatory cytokines
 * Antimitogenic
 * ↓VEGF ↓TGF-β
 * ↓Angiogenesis ↑ECM remodeling
 * }
 * Antimitogenic
 * ↓VEGF ↓TGF-β
 * ↓Angiogenesis ↑ECM remodeling
 * }
 * }

Prostacyclin (PGI2) is released by healthy endothelial cells and performs its function through a paracrine signaling cascade that involves G protein-coupled receptors on nearby platelets and endothelial cells. The platelet Gs protein-coupled receptor (prostacyclin receptor) is activated when it binds to PGI2. This activation, in turn, signals adenylyl cyclase to produce cAMP. cAMP goes on to inhibit any undue platelet activation (in order to promote circulation) and also counteracts any increase in cytosolic calcium levels that would result from thromboxane A2 (TXA2) binding (leading to platelet activation and subsequent coagulation). PGI2 also binds to endothelial prostacyclin receptors and in the same manner raise cAMP levels in the cytosol. This cAMP then goes on to activate protein kinase A (PKA). PKA then continues the cascade by phosphorylating and inhibiting myosin light-chain kinase, which leads to smooth muscle relaxation and vasodilation. It can be noted that PGI2 and TXA2 work as physiological antagonists.

Pharmacology
Synthetic prostacyclin analogues (iloprost, cisaprost) are used intravenously, subcutaneously or by inhalation:
 * as a vasodilator in severe Raynaud's phenomenon or ischemia of a limb;
 * in pulmonary hypertension.
 * in primary pulmonary hypertension (PPH)

Its production is inhibited indirectly by NSAIDs, which inhibit the cyclooxygenase enzymes COX1 and COX2. These convert arachidonic acid to prostaglandin H2 (PGH2), the immediate precursor of prostacyclin. Since thromboxane (an eicosanoid stimulator of platelet aggregation) is also downstream of COX enzymes, one might think that the effect of NSAIDs would act to balance. However, prostacyclin concentrations recover much faster than thromboxane levels, so aspirin administration initially has little to no effect but eventually prevents platelet aggregation (the effect of prostaglandins predominates as they are regenerated). This is explained by understanding the cells that produce each molecule, TXA2 and PGI2. Since PGI2 is primarily produced in a nucleated endothelial cell, the COX inhibition by NSAID can be overcome with time by increased COX gene activation and subsequent production of more COX enzymes to catalyze the formation of PGI2. In contrast, TXA2 is released primarily by anucleated platelets, which are unable to respond to NSAID COX inhibition with additional transcription of the COX gene because they lack DNA material necessary to perform such a task. This allows NSAIDs to result in PGI2 dominance that promotes circulation and retards thrombosis.

In patients with pulmonary hypertension, inhaled epoprostenol reduces pulmonary pressure, and improves right ventricular stroke work in patients undergoing cardiac surgery. A dose of 60 µg is hemodynamically safe, and its effect is completely reversed after 25 minutes. No evidence of platelet dysfunction or an increase in surgical bleeding after administration of inhaled epoprostenol has been found.