Prostacyclin and the mechanism of action of defibrotide.
Defibrotide (DEF) is a product of the controlled hydrolysis of DNA from mammalian lungs. In vitro DEF (1-2000 micrograms/ml) neither inhibited the aggregation of human, rabbit and cat platelets nor released PGI2 from cultured porcine aortic endothelial cells. Preincubated with platelet preparations, DEF (10 micrograms/ml) lowered the IC50 for the anti-aggregatory action of PGI2 from 2.1-6.5 nM to 0.6-2.4 nM. In vivo DEF (2-20 mg/kg i.v. or 0.1-10 micrograms/ml locally o.t.) dispersed platelet thrombi in the extracorporeal circulation of anaesthetized heparinized cats. In contrast to an immediate and reversible action of PGI2 (0.3-3 micrograms/kg i.v. or 1-3 ng/ml locally o.t.), the delayed and irreversible dispersion of thrombi by DEF in vivo was inhibited by aspirin (50 mg/kg i.v.), indomethacin (10 mg/kg i.v.) or dexamethasone (2 mg/kg i.v.). After pretreatment with these drugs DEF, although deprived of its own effect on thrombi, still enhanced their dispersion by exogenous and endogenous PGI2. Similarly, at its subthreshold effective concentration (10 ng/ml, o.t.) DEF potentiated the thrombolytic action of PGI2 (1 microgram/kg, i.v.), dazoxiben (1 mg/kg, i.v.) and nicotinamide (100 mg/kg i.v.). It is concluded that DEF potentiates the action of PGI2 on platelets. In vivo DEF may facilitate an interaction between platelets and endothelium, leading to augmented generation of PGI2 or of its biologically active products, which are endowed with fibrinolytic properties.
Gryglewski
R J
RJ
Department of Pharmacology, Copernicus Academy of Medicine, Cracow, Poland.
Marcinkiewicz
E
E
Radomski
M
M
Swies
J
J
D000818:Animals; D002415:Cats; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D011089:Polydeoxyribonucleotides / Q000494:pharmacology*; D011817:Rabbits; D013927:Thrombosis / Q000188:drug therapy / Q000503:physiopathology
D005343:Fibrinolytic Agents; D011089:Polydeoxyribonucleotides; C036901:defibrotide; D011464:Epoprostenol