Effects of defibrotide on prostacyclin release from isolated rabbit kidneys and protection from post-ischemic acute renal failure in vivo.
We evaluated whether defibrotide, a single-stranded polydeoxyribonucleotide that enhances prostacyclin (PGI2) release from various isolated organs, could also release PGI2 from the rabbit kidney and prove effective against renal ischemic injury. Isolated perfused kidneys responded to defibrotide (100, 250 and 500 micrograms ml-1 min-1) with a dose-dependent release of immunoreactive 6-keto-PGF1 alpha (4-fold increase at highest dose), which was prevented by indomethacin pre-treatment. In vivo, venous blood withdrawn from heparinized rabbits (and representative of renal outflow) was conveyed over a collagen matrix, onto which platelets adhered and aggregated. Recording the weight increase of the matrix was used as a bioassay to follow the time-course of released PGI2. We observed that renal outflowing blood from defibrotide treated animals (50 mgKg-1 i.v.) displayed lower (P less than 0.05 versus controls) platelet activation, consistent with enhanced PGI2 release from the kidneys. Furthermore, the duration of this effect was longer lasting than that predicted from the known plasma half-life of the drug. After transient (30 min) occlusion of the renal arteries, glomerular filtration rate (GFR) dropped by about 50% (P less than 0.01) during the first reperfusion hour in control animals, with only mild recovery having occurred 4 h later. Defibrotide (16 mgKg-1 bolus + 16 mgKg-1h-1, i.v.) could not antagonize the initial impairment (40% GFR reduction), but allowed full recovery at the end of the observation period (P less than 0.05 vs controls). Indomethacin, instead, caused a dramatic reduction of GFR (70%) during early reperfusion, with no subsequent recovery.(ABSTRACT TRUNCATED AT 250 WORDS)
Berti
F
F
Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan Medical School, Italy.
Rossoni
G
G
Bianchi
G
G
Alberico
P
P
Tettamanti
R
R
Calvani
A B
AB
Mantovani
M
M
Prino
G
G
D058186:Acute Kidney Injury / Q000209:etiology / Q000517:prevention & control*; D000818:Animals; D011464:Epoprostenol / Q000378:metabolism*; D005343:Fibrinolytic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007511:Ischemia / Q000150:complications; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010477:Perfusion; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D011089:Polydeoxyribonucleotides / Q000494:pharmacology*; D011817:Rabbits
D005343:Fibrinolytic Agents; D011089:Polydeoxyribonucleotides; C036901:defibrotide; D011464:Epoprostenol