Coronary endothelium-protective effects of defibrotide in ischaemia and reperfusion

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Abstract
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 10−7 or 100 μg/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 10−7 or 100 μg/ml, markedly restored the vasodilation to acetylcholine 10−7 nmol/l to 1 μmol/l (P < 0.01) without influencing the vasodilator response to nitroglycerin (2 to 200 μg/1). 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 μg/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.