Modulation of venous endothelial activity and transcellular calcium transport by defibrotide: the adenosine hypothesis.
Defibrotide is a polydeoxyribonucleotide that possesses profibrinolytic and cytoprotective activities. These properties have been associated with its capacity to induce the release of prostacyclin and tissue plasminogen activator (t-PA) from endothelial cells. In the present study, the bolus administration of defibrotide in humans was able to induce (100-800 mg) a dose-dependent decrease in plasminogen activator inhibitor (PAI) (from 19.4 +/- 7.11 to 7.20 +/- 6.41 AU/mL) and an increase in t-PA (from 3.70 +/- 0.96 to 4.50 +/- 1.20 IU/mL) and in the stable prostacyclin derivative 6-keto-PGF1 alpha (from 18.83 +/- 3.83 to 26.75 +/- 8.48 pg/0.1 mL) in the venous blood. In a second part of the study, defibrotide has been shown to inhibit dose-dependently (10-100 microns) neutrophil activation in vitro: it decreased lysosomal enzyme release and superoxide anion and chemiluminescence production induced by the oligopeptide fMLP and the ionophores A23187 and ionomycin. The increase in extracellular calcium concentration from 0.5 to 2 mm antagonized the inhibitory effect of the drug. Defibrotide was able to reduce the cytosolic free calcium increase induced by specific stimuli by blunting calcium entry. Such an inhibitory activity of defibrotide was antagonized by theophylline, an adenosine receptor antagonist. The study confirms some pharmacological activities of defibrotide (release of t-PA and prostacyclin in vivo), and it also suggests that the compound blocks Ca2+ entry into the cells, possibly by interfering with the adenosine receptors.
Pasini
F L
FL
Instituto di Clinica Medica Generale e Terapia Medica, Università di Siena, Italy.
Frigerio
C
C
Capecchi
P L
PL
Ceccatelli
L
L
Messa
G L
GL
Franchi
M
M
Di Perri
T
T
D000241:Adenosine / Q000502:physiology*; D000933:Antifibrinolytic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011089:Polydeoxyribonucleotides / Q000494:pharmacology*
D000933:Antifibrinolytic Agents; D002121:Calcium Channel Blockers; D011089:Polydeoxyribonucleotides; C036901:defibrotide; D000241:Adenosine; D002118:Calcium