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)