Prostacyclin
From Wikipedia, the free encyclopedia
 |
|
|
Prostacyclin
|
|
| Systematic (IUPAC) name | |
| 5-[7-hydroxy-8- (3-hydroxyoct-1-enyl) -4-oxabicyclo[3.3.0]oct-3-ylidene] pentanoic acid | |
| Identifiers | |
| CAS number | |
| ATC code | B01 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C20H32O5 |
| Mol. mass | 352.465 g/mol |
| SMILES | & |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Metabolism | ? |
| Half life | ? |
| Excretion | ? |
| Therapeutic considerations | |
| Pregnancy cat. |
? |
| Legal status | |
| Routes | ? |
Prostacyclin (or PGI2) is a member of the family of lipid molecules known as eicosanoids.
Contents |
[edit] Production
It 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.(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.
[edit] Degradation
Prostacyclin, which has a half-life of seconds, is broken down into 6-keto-PGF1 which is a much weaker vasodilator.
[edit] Mode of action
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 which 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 activating myosin light-chain kinase which leads to smooth muscle relaxation and vasodilation. Notably, PGI2 and TXA2 work as antagonists.
[edit] Function
Prostacyclin (PGI2) chiefly prevents formation of the platelet plug involved in primary hemostasis (a part of blood clot formation). 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.
[edit] 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.
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 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 to catalyze the formation of PGI2. In contrast, TXA2 is primarily released by anucleated plateles 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.
[edit] References
- Dorlands Medical Dictionary. epoprostenol. Retrieved on February 10, 2006.
- Fischer S, Weber PC (1985). "Thromboxane (TX)A3 and prostaglandin (PG)I3 are formed in man after dietary eicosapentaenoic acid: identification and quantification by capillary gas chromatography-electron impact mass spectrometry". Biomed. Mass Spectrom. 12 (9): 470-6. doi:. PMID 2996649.
[edit] See also
|
||||||||||||||||||||||||||
|
||||||||||||||
|
||||||||
