prostaglandin I2

WordNet

1. the 9th letter of the Roman alphabet (同)i
2. a potent substance that acts like a hormone and is found in many bodily tissues (and especially in semen); produced in response to trauma and may affect blood pressure and metabolism and smooth muscle activity

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1. 『私は』私が
2. iodineの化学記号

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/09/29 21:25:02」(JST)

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Prostacyclin

Systematic (IUPAC) name
(Z)-5-[(4R,5R)-5-hydroxy-4-((S,E)-3-hydroxyoct-1-enyl)hexahydro-2H-cyclopenta[b]furan-2-ylidene]pentanoic acid
Clinical data
AHFS/Drugs.com	monograph
Pregnancy cat.	?
Legal status	?
Identifiers
CAS number	35121-78-9 Y
ATC code	B01AC09
PubChem	CID 5282411
DrugBank	DB01240
ChemSpider	4445566 N
ChEMBL	CHEMBL962 N
Chemical data
Formula	C20H32O5
Mol. mass	352.465 g/mol
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
N (what is this?)  (verify)

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

Eicosanoid synthesis. (Prostacyclin near bottom center.)

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

Prostacyclin effect		Mechanism	Cellular response
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
Novel functions	Antiinflammatory	↓IL-1, IL-6 ↑IL-10	↓Proinflammatory cytokines ↑Antiinflammatory cytokines
	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.

Members

PROSTACYCLINS
Flolan (epoprostenol sodium) for Injection	Continuously infused	2 ng/kg/min to start, increased by 2 ng/kg/min every 15 minutes or longer until suitable efficacy/tolerability balance is achieved	Class III Class IV
Veletri (epoprostenol) for Injection	Continuously infused	2 ng/kg/min to start, increased by 2 ng/kg/min every 15 minutes or longer until suitable efficacy/tolerability balance is achieved	Class III Class IV
Remodulin SC§ (treprostinil sodium) Injection	Continuously infused	1.25 ng/kg/min to start, increased by up to 1.25 ng/kg/min per week for 4 weeks, then up to 2.5 ng/kg/min per week until suitable efficacy/tolerability balance is achieved	Class II Class III Class IV
Ventavis (iloprost) Inhalation Solution	Inhaled 6–9 times daily	2.5 mcg 6–9 times daily to start, increased to 5.0 mcg 6–9 times daily if well tolerated	Class III Class IV

Pharmacology

Ball-and-stick model of prostacyclin

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.

See also

• Essential fatty acid

References

UpToDate Contents

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• 1. 成人における肺高血圧症の治療 treatment of pulmonary hypertension in adults
• 2. 止血の概要 overview of hemostasis
• 3. 下肢末梢動脈疾患の症状を治療するための試験的治療 investigational therapies for treating symptoms of lower extremity peripheral artery disease
• 4. COX-2選択的阻害剤：有害な心血管系への影響 cox 2 selective inhibitors adverse cardiovascular effects
• 5. 血液透析中の抗凝固療法 hemodialysis anticoagulation

English Journal

• H2S inhibition of chemical hypoxia-induced proliferation of HPASMCs is mediated by the upregulation of COX-2/PGI2.

• Li Y1, Liu G2, Cai D2, Pan B3, Lin Y1, Li X1, Li S1, Zhu L1, Liao X4, Wang H1.Author information 1Department of Pediatric Cardiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.2Department of Physiology, Guangzhou Medical University, Guangzhou, Guangdong 510182, P.R. China.3Division II of General Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, P.R. China.4Department of Hypertension and Vascular Diseases, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.AbstractThe hypoxia-induced proliferation of pulmonary artery smooth muscle cells (PASMCs) is the main cause of pulmonary arterial hypertension (PAH), in which oxidative stress, cyclooxygenase (COX)-2 and hydrogen sulfide (H2S) all play an important role. In the present study, we aimed to examine the effects of H2S on the hypoxia-induced proliferation of human PASMCs (HPASMCs) and to elucidate the underlying mechanisms. The HPASMCs were treated with cobalt chloride (CoCl2), a hypoxia-mimicking agent, to establish a cellular model of hypoxic PAH. Prior to treatment with CoCl2, the cells were pre-conditioned with sodium hydrosulfide (NaHS), a donor of H2S. Cell proliferation, reactive oxygen species (ROS) production, COX-2 expression, prostacyclin (also known as prostaglandin I2 or PGI2) secretion and H2S levels were detected in the cells. The exposure of the HPASMCs to CoCl2 markedly increased cell proliferation, accompanied by a decrease in COX-2 expression, PGI2 secretion and H2S levels; however, the levels of ROS were not altered. Although the exogenous ROS donor, H2O2, triggered similar degrees of proliferation to CoCl2, the ROS scavenger, N-acetyl-L-cysteine (NAC), markedly abolished the H2O2‑induced cell proliferation, as opposed to the CoCl2-induced proliferation. The CoCl2-induced proliferation of HPASMCs was suppressed by exogenously applied PGI2. The addition of H2S (NaHS) attenuated the CoCl2-induced cell proliferation through the increase in the intercellular content of H2S. Importantly, the exposure of the cells to H2S suppressed the CoCl2-induced downregulation in COX-2 expression and PGI2 secretion from the HPASMCs. In conclusion, the results from the current study suggest that H2S enhances hypoxia-induced cell proliferation through the upregulation of COX-2/PGI2, as opposed to ROS.
• International journal of molecular medicine.Int J Mol Med.2013 Dec 9. doi: 10.3892/ijmm.2013.1579. [Epub ahead of print]
• The hypoxia-induced proliferation of pulmonary artery smooth muscle cells (PASMCs) is the main cause of pulmonary arterial hypertension (PAH), in which oxidative stress, cyclooxygenase (COX)-2 and hydrogen sulfide (H2S) all play an important role. In the present study, we aimed to examine the effect
• PMID 24337227

• Geometry of the randomized evidence for treatments of pulmonary hypertension.

• Tonelli AR, Zein J, Ioannidis JP.Author information Department of Pulmonary, Allergy, and Critical Care Medicine, Respiratory Institute, Cleveland, OH, USA.AbstractOBJECTIVE: We studied the entire agenda of randomized clinical trials in pulmonary hypertension (PH) using sociological methods. We explored the geometry of the PH network to interpret the evidence on multiple competing treatments for the same indication.
• Cardiovascular therapeutics.Cardiovasc Ther.2013 Dec;31(6):e138-46. doi: 10.1111/1755-5922.12050.
• OBJECTIVE: We studied the entire agenda of randomized clinical trials in pulmonary hypertension (PH) using sociological methods. We explored the geometry of the PH network to interpret the evidence on multiple competing treatments for the same indication.DESIGN: We searched MEDLINE, Embase and Cochr
• PMID 24112824

• Parenteral and inhaled prostanoid therapy in the treatment of pulmonary arterial hypertension.

• McLaughlin VV, Palevsky HI.Author information Pulmonary Hypertension Program, Cardiovascular Center, University of Michigan Hospital and Health Systems, 1500 East Medical Center Drive, Room 2392, Ann Arbor, MI 48109-5853, USA.AbstractSince continuous IV epoprostenol was approved in the U.S., parenteral prostanoid therapy has remained the gold standard for the treatment of patients with advanced pulmonary arterial hypertension (PAH). Prostanoid agents can be administered as continuous intravenous infusions, as continuous subcutaneous infusions and by intermittent nebulization therapy. This article presents data from clinical trials of available prostanoid agents, and their varied routes of administration. The varied routes of administration allow for the incremental use of this class of agents in advanced PAH, and if PAH progresses. Prostanoids will remain a major component of PAH therapy for the foreseeable future.
• Clinics in chest medicine.Clin Chest Med.2013 Dec;34(4):825-40. doi: 10.1016/j.ccm.2013.09.003. Epub 2013 Oct 18.
• Since continuous IV epoprostenol was approved in the U.S., parenteral prostanoid therapy has remained the gold standard for the treatment of patients with advanced pulmonary arterial hypertension (PAH). Prostanoid agents can be administered as continuous intravenous infusions, as continuous subcutan
• PMID 24267307

Japanese Journal

• Thromboxane A2 synthase inhibitors prevent production of infectious hepatitis C virus in mice with humanized livers.

• Abe Yuichi,Aly Hussein Hassan,Hiraga Nobuhiko,Imamura Michio,Wakita Takaji,Shimotohno Kunitada,Chayama Kazuaki,Hijikata Makoto
• Gastroenterology 145(3), 658-667.e11, 2013-09
• … [Results]Microarray analysis showed that cells cultured under 2-dimensional vs 3D conditions expressed different levels of messenger RNAs encoding prostaglandin synthases. … The TXAS inhibitor and a prostaglandin I2 receptor agonist, which has effects that are opposite those of thromboxane A2, reduced serum levels of HCV and inhibited the infection of human hepatocytes by blood-borne HCV in mice. …
• NAID 120005324909

• Linoleic Acid Attenuates Endothelium-Derived Relaxing Factor Production by Suppressing cAMP-Hydrolyzing Phosphodiesterase Activity

• Wei Jiazhang,Takeuchi Kazuhiko,Watanabe Hiroshi
• Circulation Journal 77(11), 2823-2830, 2013
• … These molecules are restrained by endothelium-derived relaxing factors (EDRFs), such as nitric oxide (NO) and prostaglandin I2 (PGI2). …
• NAID 130003361824

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Related Pictures

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★リンクテーブル★

リンク元	「エポプロステノール」「PGI2」
拡張検索	「prostaglandin I2 receptor」
関連記事	「I」「prostaglandin」「I2」「prostaglandins」

「エポプロステノール」

　　[★]

英

epoprostenol

化

エポプロステノールナトリウム epoprostenol sodium

商

フローラン

関

プロスタサイクリン prostacyclin、プロスタグランジンI2 prostaglandin I2 PGI2

肺高血圧

「PGI2」

　　[★] プロスタグランジンI2

同

prostaglandin I2

「prostaglandin I2 receptor」

　　[★]

• プロスタグランジンI2受容体、プロスタグランジンI2レセプター

関

epoprostenol receptor、PGI2 receptor、prostacyclin receptor

「I」

　　[★]

• イソロイシン isoleucine
• イノシン inosine
• 阻害剤 inhibitor
• iodine
• ヨード iodide
• I因子 factor I

　 　 　

「prostaglandin」

　　[★] プロスタグランジン prostaglandins PG

　

「I2」

　　[★] ヨウ素

関

I、iodide、iodine

「prostaglandins」

　　[★] プロスタグランジン