Angiotensin II inhibitor DuP753 attenuates burn- and endotoxin-induced gutischemia, lipid peroxidation, mucosal permeability, and bacterial translocation

T. Tadros et al., Angiotensin II inhibitor DuP753 attenuates burn- and endotoxin-induced gutischemia, lipid peroxidation, mucosal permeability, and bacterial translocation, ANN SURG, 231(4), 2000, pp. 566-576
Citations number
Categorie Soggetti
Surgery,"Medical Research Diagnosis & Treatment
Journal title
ISSN journal
0003-4932 → ACNP
Year of publication
566 - 576
SICI code
Objective To investigate the role of angiotensin II as a mediator of burn- and sepsis -induced gut ischemia and reperfusion injury and to determine whether treat ment with the angiotensin II inhibitor DuP753 can attenuate mucosal injury and bacterial translocation in a burn/endotoxemia porcine model. Summary Background Data Thermal injuries and endotoxemia have been shown to induce ischemia and rep erfusion injury to the intestine, leading to increased mucosal permeability and bacterial translocation. Angiotensin II, the production of which has b een reported to increase after burn, is thought to be one of the primary me diators of postburn mesenteric vasoconstriction. Methods An ultrasonic flow probe was inserted into the superior mesenteric artery a nd a catheter into the superior mesenteric vein in 21 female pigs. After 5 days, all animals were anesthetized, and 14 received 40% total body surface area third-degree burn. DuP753 was administered intravenously at 1 mu g/kg to seven pigs immediately after burn. Eighteen hours after burn, 100 mu g/ kg Escherichia coil lipopolysaccharide (LPS) was intravenously administered . Systemic and splanchnic hemodynamics were measured and blood samples were drawn for blood gas analysis. Plasma conjugated dienes (PCDs), an index of lipid per oxidation, were measured every 6 hours. Intestinal permeability was assessed every 6 hours by measuring the lactulose/mannitol excretion ra tio. At the end of the study (42 hours), tissue samples were harvested for bacteriologic cultures. Results Burn caused a significant decrease in mesenteric blood flow, to approximate ly 58% of baseline. Postburn endotoxemia significantly reduced the blood fl ow in the superior mesenteric artery to 53% of baseline. Treatment with DuP 753 prevented postburn vasoconstriction and subsequently abrogated the impa ct of postburn endotoxemia on blood now in the superior mesenteric artery. Mesenteric oxygen supply was significantly reduced after burn and endotoxin to 60% and 51% of baseline levels, respectively. DuP753 administration sig nificantly improved mesenteric oxygen supply after both insults. Burn- and LPS-induced mesenteric hypoxia, as indicated by decreased mesenteric oxygen consumption, was also ameliorated by DuP753 treatment. PCD levels were sig nificantly elevated 8 hours after burn, LPS caused a higher and prolonged i ncrease in PCD levels. Treatment with DuP753 significantly reduced PCD leve ls after burn and after LPS. Intestinal permeability, as assessed by the la ctulose/mannitol ratio, showed 6-fold and 12-fold increases after thermal i njury and IFS, respectively, In contrast, the lactulose/mannitol ratio was only doubled in DuP753-treated animals. Bacterial translocation was signifi cantly increased after burn and endotoxin, The incidence of bacterial trans location in the DuP753-treated animals was similar to that in the sham grou p, Conclusions Angiotensin II appears to play a pivotal role in the burn- and endotoxin-in duced intestinal ischemia and reperfusion injury, with subsequent increases in permeability and bacterial translocation. Postburn administration of th e angiotensin II receptor antagonist DuP753 significantly reduces the exten t of these events.