Novel beneficial mechanisms of defibrotide, a prostacyclin enhancing agent in splanchnic artery occlusion and reperfusion in rats.
To further clarify the protective mechanism(s) of defibrotide in splanchnic artery occlusion (SAO) shock, we observed the effect of defibrotide on polymorphonuclear leukocyte (PMN) accumulation in the intestinal tissue, gastric lysosomal hydrolases and endothelial function of the ischemia-reperfused superior mesenteric artery (SMA). Pentobarbital anesthetized rats were subjected to occlusion of both the celiac and superior mesenteric arteries for 90 min followed by 2 h reperfusion. The rats receiving only the vehicle for defibrotide exhibited a marked increase in intestinal myeloperoxidase (MPO) activity and a significant endothelial dysfunction manifested by the loss of endothelium-dependent vasorelaxation. Only 2 of 6 rats (33%) survived 2 h of reperfusion. In contrast, those rats treated with defibrotide exhibited significantly attenuated PMN accumulation in intestinal tissue, enhanced endothelium-dependent vasorelaxation in SMA rings, prolonged survival time and increased survival rate to 6 of 7 (i.e., 86%). However, addition of defibrotide in vitro had no direct effect on LTB4 activated PMN adherence to vascular endothelium. Moreover, defibrotide preserved gastric lysosomal membranes in vitro. These results indicate that the protective effect of intravenous administration of defibrotide on SAO shock may be related to its endothelial preserving effect reducing PMN adherence and protection of endothelial and lysosomal membrane integrity.
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Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA.
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D000818:Animals; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D007082:Ileum / Q000201:enzymology; D008297:Male; D008641:Mesenteric Vascular Occlusion / Q000188:drug therapy* / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011089:Polydeoxyribonucleotides / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D015424:Reperfusion; D012769:Shock / Q000201:enzymology / Q000378:metabolism
D005343:Fibrinolytic Agents; D011089:Polydeoxyribonucleotides; C036901:defibrotide; D009195:Peroxidase