Effects of the arachidonate 5-lipoxygenase synthesis inhibitor A-64077 in intestinal ischemia-reperfusion injury.
This study was designed to characterize the role of arachidonate 5-lipoxygenase metabolism during experimental intestinal ischemia-reperfusion (I/R) injury. Canines were subjected to 3 hr of intestinal ischemia followed by 1 hr of normobaric reperfusion. Intestinal ischemia followed by 1 hr of normobaric reperfusion. Intestinal mucosal leukotriene B4 and leukotriene C4 synthesis tripled after ischemia and ischemia-reperfusion, relative to non-ischemic intestinal mucosa. The flux of fluid and protein from the capillary to the lumen also increased 3-fold after I/R. The selective 5-lipoxygenase synthesis inhibitor A-64077 (Ziluten, 5 mg/kg, p.o.) abolished I/R-induced leukotriene synthesis and reduced transluminal protein flux (50%) but did not influence the lumenal accumulation of fluid after I/R. In animals treated with the leukotriene synthesis inhibitor, intestinal vascular resistance significantly declined during the imposed ischemia period and after 60 min of reperfusion. Mucosal myeloperoxidase activity, a biochemical marker for tissue neutrophils, rose significantly after I/R, and these increases were prevented with the 5-lipoxygenase synthesis inhibitor. In other experiments, the lipoxygenase inhibitor nondihydroguaretic acid produced similar results to those of A64077. In an attempt to determine the source of mucosal leukotrienes during intestinal I/R, we imposed in vitro ischemia and reperfusion on normal mucosal tissue in a blood-free environment. Mucosal tissue was incubated in Krebs buffer under oxygen for 3 hr to simulate the control condition, under nitrogen for 3 hr to simulate ischemia and under nitrogen for 2 hr followed by oxygen for 1 hr to simulate I/R.(ABSTRACT TRUNCATED AT 250 WORDS)
Mangino
M J
MJ
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
Murphy
M K
MK
Anderson
C B
CB
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis*; D004285:Dogs; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism; D007422:Intestines / Q000098:blood supply* / Q000201:enzymology*; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D015289:Leukotrienes / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008954:Models, Biological; D009504:Neutrophils / Q000166:cytology; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology*
D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase; C063449:zileuton; D006918:Hydroxyurea