Prostacyclin

Prostacyclin

Clinical data
Trade names	Flolan, Veletri
AHFS/Drugs.com	Monograph
License data	US DailyMed: Epoprostenol_sodium
Pregnancy category	AU: B1
ATC code	B01AC09 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) US: ℞-only
Pharmacokinetic data
Elimination half-life	42 seconds
Identifiers
IUPAC name (Z)-5-[(4R,5R)-5-Hydroxy-4-((S,E)-3-hydroxyoct-1-enyl)hexahydro-2H-cyclopenta[b]furan-2-ylidene]pentanoic acid
JSmol)	Interactive image
SMILES OC(=O)CCC\C=C1\C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]2O1
InChI InChI=1S/C20H32O5/c1-2-3-4-7-14(21)10-11-16-17-12-15(8-5-6-9-20(23)24)25-19(17)13-18(16)22/h8,10-11,14,16-19,21-22H,2-7,9,12-13H2,1H3,(H,23,24)/b11-10+,15-8-/t14-,16+,17+,18+,19-/m0/s1 N Key:KAQKFAOMNZTLHT-OZUDYXHBSA-N N
NY (what is this?)  (verify)

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

When used as a drug, it is also known as epoprostenol.^[1] The terms are sometimes used interchangeably.^[2]

Function

Prostacyclin chiefly prevents formation of the

Prostacyclin, which has a half-life of 42 seconds,^[7] is broken down into 6-keto-PGF₁, which is a much weaker vasodilator. A way to stabilize prostacyclin in its active form, especially during drug delivery, is to prepare prostacyclin in alkaline buffer. Even at physiological pH, prostacyclin can rapidly form the inactive hydration product 6-keto-prostaglandin F1α.^[8]

Mechanism

Prostacyclin effect		Mechanism	Cellular response
Classical functions	Vessel tone	↑cAMP, ↓ET-1 ↓Ca2+, ↑K+	↓SMC proliferation ↑Vasodilation
	Antiproliferative	↑cAMP ↑PPARgamma	↓Fibroblast growth ↑Apoptosis
	Antithrombotic	↓Thromboxane-A2 ↓PDGF	↓Platelet aggregation ↓Platelet adherence to vessel wall
Novel functions	Antiinflammatory	↓IL-1, IL-6 ↑IL-10	↓Proinflammatory cytokines ↑Antiinflammatory cytokines
	Antimitogenic	↓VEGF ↓TGF-β	↓Angiogenesis ↑ECM remodeling

As mentioned above, prostacyclin (PGI₂) is released by healthy endothelial cells and performs its function through a

Members[9]

Pharmacology

Synthetic prostacyclin analogues (iloprost, cisaprost) are used intravenously, subcutaneously or by inhalation:

• as a
  Raynaud's phenomenon or ischemia
  of a limb;
• in pulmonary hypertension.
• in primary pulmonary hypertension (PPH)

The production of prostacyclin is inhibited by the action of

In patients with pulmonary hypertension, inhaled epoprostenol reduces pulmonary pressure, and improves right ventricular stroke volume 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.^[10] The drug has been known to cause flushing, headaches and hypotension.^[11]

Synthesis

Biosynthesis

Prostacyclin is produced in endothelial cells, which line the walls of arteries and veins,^[12] 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). PGI₂, derived primarily from COX-2 in humans, is the major arachidonate metabolite released from the vascular endothelium. This is a controversial point, some assign COX 1 as the major prostacyclin producing cyclooxygenase in the endothelial cells of the blood vessels.^[13]

The series-3 prostaglandin PGH₃ also follows the prostacyclin synthase pathway, yielding another prostacyclin, PGI₃.^[14] 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.

Artificial synthesis

Prostacyclin can be

Because prostacyclin is so chemically labile, quantitation of their inactive metabolites, rather than the active compounds, is used to assess their rate of synthesis.[17]

History

During the 1960s, a UK 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, Vane 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.

A team at The Wellcome Foundation led by Salvador Moncada had identified a lipid mediator they called "PG-X," which inhibits platelet aggregation. PG-X, later known as prostacyclin, is 30 times more potent than any other then-known anti-aggregatory agent. They did this while searching for an enzyme that generates a fellow unstable prostanoid, Thromboxane A2^[18]

In 1976, Vane and fellow researchers Salvador Moncada, Ryszard Gryglewski, and Stuart Bunting published the first paper on prostacyclin in Nature.^[19] The collaboration produced a synthesized molecule, which was named epoprostenol. But, as with native prostacyclin, the epoprostenol molecule is unstable in solution and prone to rapid degradation.^{[citation needed]} This presented a challenge for both in vitro experiments and clinical applications.

To overcome this challenge, the research team that discovered prostacyclin continued the research. The research team synthesized nearly 1,000 analogues.^{[citation needed]}

References