Defibrotide has antiischemic activity in perfused rabbit hearts, preventing tissue Ca++ overloading.
Defibrotide (D), a polydeoxyribonucleotide obtained from mammalian lungs, reduced the ischemic contracture due to low perfusion (0.2 ml/min) of the isovolumic left heart of the rabbit and abolished the irregularity of the rhythm of the heart, thereby restoring the cardiomechanical activity upon reperfusion (20 ml/min). D stimulated the release of PG-like material. Indomethacin infusion completely prevented both the antiischemic activity of D and its ability to increase the generation of prostaglandins in the rabbit heart. Measurement by atomic absorption spectroscopy of calcium content in ischemic heart tissue and its mitochondrial fraction indicated that the ischemic procedure significantly increased tissue calcium content in both. D, Prostacyclin (PGI2) and Nifedipine protected the heart from ischemic ventricular contracture and prevented accumulation of calcium in the heart. The effect of D on preventing Ca++ overload was completely abolished by indomethacin infusion. The results indicate that the beneficial effects of Defibrotide in experimental ischemia are primarily due to a release of Prostaglandin E2 (PGE2) and PGI2, which in turn may inhibit the detrimental effects of calcium overload in myocytes and mitochondria.
Berti
F
F
Department of Pharmacology, University of Milan, Italy.
Rossoni
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G
Galli
G
G
Magni
F
F
Mantovani
M
M
Calvani
A B
AB
Porta
R
R
Prino
G
G
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003327:Coronary Disease / Q000188:drug therapy* / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D010477:Perfusion; D011089:Polydeoxyribonucleotides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011817:Rabbits
D005343:Fibrinolytic Agents; D011089:Polydeoxyribonucleotides; C036901:defibrotide; D011464:Epoprostenol; D015232:Dinoprostone; D002118:Calcium; D007213:Indomethacin