Defibrotide, by enhancing prostacyclin generation, prevents endothelin-1 induced contraction in human saphenous veins.
Spirals of human saphenous veins (HSV), mounted in a 5 ml organ bath containing Krebs-Henseleit solution (37 degrees C), when kept in contact with defibrotide (100-200 ug/ml) for 15 min, enhance (2 and 3 fold) their own basal release of 6-keto-PGF 1 alpha (61 +/- 1.3 pg/mg w.t. n = 12). The phenomenon was long lasting upon repeated washing and sensitive to indomethacin (1 ug/ml). Endothelin-1 (ET-1, 20-40 ng) induced a sustained contraction of HSV and concomitantly released from the venous tissue a proportional amount of 6-keto-PGF 1 alpha. Indomethacin (1 ug/ml), by inhibiting cyclo-oxygenase enzyme, potentiated the contractile activity of ET-1 in HSV whereas exogenous PGE2 (20 ng/ml) considerably reduced the tension developed by the peptide on this venous tissue. Defibrotide (200 ug/ml), by releasing 6-keto-PGF 1 alpha, and other vasoactive prostaglandins, antagonized the contractile effect ET-1 (20 ng) in HSV. This data indicates that the eicosanoid metabolism is involved in the modulation of the potent vasoconstrictor effect of ET-1 in HSV and that PGI2-releaser, such as defibrotide, may have therapeutical value against immoderate changes of venous tone.
Berti
F
F
Department of Pharmacology, University of Milan, Italy.
Rossoni
G
G
Biasi
G
G
Buschi
A
A
Mandelli
V
V
Tondo
C
C
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology*; D011464:Epoprostenol / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D011089:Polydeoxyribonucleotides / Q000494:pharmacology*; D012501:Saphenous Vein / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects
D016861:Cyclooxygenase Inhibitors; D016232:Endothelins; D011089:Polydeoxyribonucleotides; C036901:defibrotide; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol; D015232:Dinoprostone; D007213:Indomethacin