- Prostacyclin
drugbox
IUPAC_name = 5- [7-hydroxy-8- (3-hydroxyoct-1-enyl) -4-oxabicyclo [3.3.0] oct-3-ylidene] pentanoic acid
width=200px
CAS_number = 35121-78-9
ATC_prefix = B01
ATC_suffix = AC09
ATC_supplemental =
PubChem = 114805
DrugBank = APRD00949
C=20 | H=32 | O=5
molecular_weight = 352.465 g/mol
bioavailability =
protein_bound =
metabolism =
elimination_half-life =
pregnancy_category =
legal_status =
routes_of_administration =
smiles = OC(=O)CCCC=C1C [C@@H] 2 [C@@H] (/C=C/ [C@@H] (O)CCCCC) [C@H] (O)C [C@@H] 2O1Prostacyclin (or PGI2) is a member of the family of
lipid molecule s known aseicosanoids .Production
).
The series-3 prostaglandin PGH3 also follows the prostacyclin synthase pathway, yielding another prostacyclin, PGI3.(Fischer, 1985) 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.Degradation
Prostacyclin, which has a
half-life of seconds, is broken down into 6-keto-PGF1 which is a much weaker vasodilator.Mode of action
Prostacyclin (PGI2) is released by healthy endothelial cells and performs its function through a
paracrine signaling cascade that involvesG protein-coupled receptor s 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 which would result fromthromboxane A2 (TXA2) binding (leading to platelet activation and subsequentcoagulation ). PGI2 also binds to endothelialprostacyclin receptor s and in the same manner raise cAMP levels in the cytosol. This cAMP then goes on to activateprotein kinase A (PKA). PKA then continues the cascade by activatingmyosin light-chain kinase which leads tosmooth muscle relaxation andvasodilation . Notably, PGI2 and TXA2 work as antagonists.Function
Prostacyclin (PGI2) chiefly prevents formation of the
platelet plug involved in primaryhemostasis (a part ofblood clot formation). It is also an effectivevasodilator . Prostacyclin's interactions in contrast tothromboxane (TXA2), another eicosanoid, strongly suggest a mechanism of cardiovascularhomeostasis between the two hormones in relation to vascular damage.Pharmacology
Synthetic prostacyclin analogues (
iloprost , cisaprost) are used intravenously, subcutaneously or by inhalation:
* as avasodilator in severeRaynaud's phenomenon orischemia of a limb;
* inpulmonary hypertension .Its production is inhibited indirectly by NSAIDs, which inhibit the
cyclooxygenase enzymes COX1 and COX2. These convertarachidonic acid toprostaglandin H2 (PGH2), the immediate precursor of prostacyclin. Since thromboxane (aneicosanoid stimulator of platelet aggregation ) is also downstream of COX enzymes, one would think that the effect of NSAIDs would balance out. 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 thromboxane predominates). 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 tocatalyze the formation of PGI2. In contrast, TXA2 is primarily released by anucleated plateles which are unable to respond to NSAID COX inhibition with additionaltranscription of the COX gene because they lackDNA material necessary to perform such a task. This allows NSAIDs to result in PGI2 dominance that promotes circulation and retardsthrombosis .References
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*
ee also
*
Essential fatty acid
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