Prostacyclin

Prostacyclin, also known as prostaglandin I2 or PGI2, is a vasodilatory and thrombocyte aggregation-inhibiting eicosanoid (C20 fatty acid), which is mainly produced by the vascular endothelia.

The chemically unstable prostacyclin (PGI2) belongs to the series 2 prostaglandins which are formed from arachidonic acid and, in a second step, by enzymatic conversion from the PG endoperoxides (PGH2/ PGG2).

Prostacyclin receptor: Prostacyclin binds to its own IP receptor. This is a G-protein coupled membrane receptor. Furthermore, PGI2 binds to a second receptor, the "peroxisome proliferator-activated receptor" PPAR.

Platelet aggregation inhibition: PGI2 inhibits platelet aggregation induced by different stimuli (ADP, collagen, thrombin, thrombboxane). Depending on the agonists involved, the antiaggregatory effect of PGI2 is already triggered in a concentration range of 0.5-2.0 nmol/l. This is 20-40 times more active than PGE1 or PGD2. PGI2 also inhibits other effects of platelet activation such as shape changes, adhesion and degranulation. In children, it was proven that the substance has a"heparin-saving" effect.

Inflammation: Release of prostacyclin activates and maintains local inflammatory reactions together with prostaglandin E2 (PGE2).

Vasodilation: Prostacyclin increases vascular permeability (local tissue swelling). Together with the EDRF (endothelium relaxing factor), which is also formed by endothelia, it binds to the smooth vascular muscles via its receptor. There, stimulation of the adenylate cyclase cAMP induces smooth muscle relaxation (leading to local vasodilation).

Pain engraving: Prostacyclin, when injected locally, engraves the inflammatory pain induced by other cytokines. The substance sensitizes afferences to the effect of chemical and mechanical stimuli. This induces a state of hyperalgesia.

Degradation and elimination: Prostacyclin hydrolyses with a half-life of 3 minutes to the biologically inactive 6-keto-PGF1alpha. In contrast to the prostaglandins of the E and F series, it is not absorbed into the lung cells and is inactivated there. Prostacyclin is mainly metabolized hepatic and 70% renally eliminated.

Vascular system: PGI2 (prostacyclin) is biologically important for a balanced homeostasis between vascular flow and thrombus formation. Endogenous prostacyclin is mainly produced in the vascular endothelium and the smooth vascular muscles. The vascular endothelia form several prostaglandins. However, since the prostaglandin I synthase responsible for the formation of PGI2 is found in endothelia, PGI2 is formed predominantly. PGI2 is a ligand for a proprietary G-protein-coupled prostacyclin receptor of the smooth vascular muscle cells. It inhibits vasoconstriction by increasing the intracellular cAMP and thus has a vasodilatory effect. PGI2 is an antagonist of the thrombboxanes preferentially formed in the thrombocytes. Furthermore, PGI2 inhibits platelet aggregation and is therefore also a functional antagonist of the thrombboxane.

Lungs: PGI2 also leads to vasodilation in the lungs. It prevents microthrombi. Furthermore, the substance is a weak bronchodilator. PGI2 is an established, highly potent therapeutic for pulmonary hypertension. Furthermore, the substance is apparently able to initiate the endothelial regeneration of the lung parenchyma.

Gastrointestinal secretion: Prostacyclin (PGI2) as well as PGE1 and PGE2 inhibit the secretion of gastric juice after various stimuli such as feeding, gastrin, etc. There is a reduction in acid and pepsin secretion. On the other hand, mucus and bicarbonate secretion is increased.

Kidney: Prostacyclin (PGI2) as well as PGE2 and PGD2 release renin from the renal cortex. Prostacyclin (PGI2) and PGE2 increase renal blood flow and diuresis. They inhibit the effect of the antidiuretic hormone (ADH = vasopressin)

Iloprost, an approved drug consists of a chemically stable prostacyclin analogue. Iloprost inhibits the aggregation, adhesion and release reaction of the thrombocytes. It leads to dilatation of arterioles and venules, increases capillary density and reduces increased vascular permeability in the microcirculation. Furthermore, the substance stimulates the endogenous fibrinolysis potential, inhibits the adhesion of leukocytes after endothelial lesion and leukocyte accumulation in injured tissue. The molecule is mainly metabolized via β oxidation of the carboxyl side chain. Unchanged active substance is not excreted. The excretion of iloprost metabolites is 80% renal and 20% biliary. Iloprost is used as a therapeutic agent in systemic scleroderma. It is also used in Raynaud's syndrome, pulmonary arterial hypertension. It is effective in the aseptic bone necrosis of the child.

Systemic prostacyclin levels rise to 15-20 times the norm in patients under general anesthesia and ventilation.

Alkukhun L et al (2014) Subcutaneous to intravenous prostacyclin analogous transition in pulmonary hypertension. J Cardiovasc Pharmacol 63:4-8.

Chen Y et al (2014) Prostacyclin analogue beraprost inhibits cardiac fibroblast proliferation depending on prostacyclin receptor activation through a TGF β-Smad signal pathway. PLoS One 9(5):e98483.

Clapp LH det al. (2015) The mechanistic basis of prostacyclin and its stable analogues in pulmonary arterial hypertension: Role of membrane versus nuclear receptors. Prostaglandins Other Lipid Media 120:56-71.

Deep A et al (2017) Prostacyclin as an Anticoagulant for Continuous Renal Replacement Therapy in Children. Blood Purif 43:279-289

Lackner H et al (2005) Aseptic osteonecrosis in children and adolescents treated for hemato-oncologic diseases: a 13-year longitudinal observational study. J Pediatr Hematol Oncol 27:259-263.

Rasmussen R et al (2012) The effects of continuous prostacyclin infusion on regional blood flow and cerebral vasospasm following subarachnoid haemorrhage: study protocol for a randomised controlled trial.Trials 13:102.