Coronary endothelium-protective effects of defibrotide in ischaemia and reperfusion.
Defibrotide is known to enhance prostacyclin (PGI2) release from the vascular endothelium. We investigated the vasoactive effects of defibrotide in isolated rat hearts perfused at constant flow subjected to ischaemia and reperfusion. Defibrotide at 10 or 100 micrograms/ml did not exert any direct vasoactive effect on normal rats hearts. However, ischaemia and reperfusion resulted in an impaired vasodilation to acetylcholine, an endothelium-dependent vasodilator. In contrast, the vasodilator response to the endothelium-independent dilator, nitroglycerin, was unaffected. Defibrotide, at 10 or 100 micrograms/ml, markedly restored the vasodilation to acetylcholine 10 nmol/l to 1 mumol/l (P less than 0.01) without influencing the vasodilator response to nitroglycerin (2 to 200 micrograms/l). Haemoglobin (150 nmol/l) inhibited the dilation to acetylcholine in response to defibrotide. However, no evidence of PGI2 release was observed with acetylcholine-induced vasodilation in the presence or absence of defibrotide. Additionally, 10-100 micrograms/ml of defibrotide did not significantly decrease superoxide radicals generated by a xanthine-xanthine oxidase synthetic system under conditions in which superoxide dismutase was effective. Thus, defibrotide appears to exert an endothelium-protective effect preserving endothelium-derived relaxing factor (EDRF) without directly scavenging free signals.
Lefer
A M
AM
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107.
Aoki
N
N
Mulloy
D
D
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015121:6-Ketoprostaglandin F1 alpha / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D003327:Coronary Disease / Q000503:physiopathology*; D003331:Coronary Vessels / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects*; D011464:Epoprostenol / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D015425:Myocardial Reperfusion; D009569:Nitric Oxide / Q000494:pharmacology / Q000652:urine; D005996:Nitroglycerin / Q000494:pharmacology; D011089:Polydeoxyribonucleotides / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism
D005343:Fibrinolytic Agents; D011089:Polydeoxyribonucleotides; D011450:Prostaglandin Endoperoxides, Synthetic; D013481:Superoxides; D009569:Nitric Oxide; C036901:defibrotide; D015121:6-Ketoprostaglandin F1 alpha; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D011464:Epoprostenol; D013482:Superoxide Dismutase; D005996:Nitroglycerin; D000109:Acetylcholine