Trauma- and sepsis-induced hepatic ischemia and reperfusion injury: role of angiotensin II.
OBJECTIVE
We hypothesized that angiotensin II, a potent vasoconstrictor, is involved in the occurrence of hepatic ischemia after burn and sepsis, and that administration of angiotensin II antagonist DuP753 would ameliorate this process.


METHODS
Randomized animal study.


METHODS
University laboratory, investigational intensive care unit, University of Texas Medical Branch, Galveston.


METHODS
Female pigs (n = 18, weighing 20-25 kg).


METHODS
All animals were prepared with ultrasonic flow probes on the portal vein and the common hepatic artery. Catheters were inserted in the superior mesenteric and left hepatic veins. After 5 days all animals were anesthetized and 12 of them received 40% total body surface area third-degree burn. Escherichia coli lipopolysaccharide (100 microg/kg) was intravenously administered at 18 hours postburn DuP753 was administered intravenously in a dose of 1 microg/kg to 6 pigs immediately after the burn. All animals were studied for 42 hours.


METHODS
Systemic and hepatic hemodynamics were measured and blood samples were drawn for determinations of arterial, mixed venous, and portal blood gases at baseline and at 14 consecutive time points, starting 1 hour after the burn.


RESULTS
Burn caused a 4.6-fold increase in hepatic arterial vascular resistance and a 49% decrease in hepatic arterial blood flow. Postburn administration of angiotensin II receptor blocker DuP753 yielded a significant improvement in the hepatic arterial hemodynamics (only 12% increase in hepatic arterial vascular resistance and 8% decrease in hepatic arterial blood flow, P<.05 vs nontreated group, analysis of variance [ANOVA]). Postlipopolysaccharide hepatic arterial blood flow was significantly reduced (12% of baseline, P<.05, ANOVA), in contrast to DuP753-treated animals (64% of baseline, P<.05 vs nontreated group, ANOVA). Postburn blocking of angiotensin II receptors yielded a significant improvement in postlipopolysaccharide portal venous blood flow (85% of baseline vs 48% of baseline in nontreated animals, P<.05, ANOVA ). Postburn endotoxemia resulted in a significant decrease of hepatic oxygen delivery (22% of baseline) and hepatic oxygen consumption (30% of baseline), while no marked changes were observed in the DuP753-treated group (P<.05 vs nontreated group, ANOVA).


CONCLUSIONS
Angiotensin II seems to play a pivotal role in burn- and sepsis-induced hepatic ischemia and reperfusion injury. Blocking angiotensin II receptors by DuP753 seems to abrogate this adverse effect of thermal injuries and sepsis on hepatic perfusion and oxygenation.
Tadros
T
T
Shriners Burns Institute and the University of Texas Medical Branch, Galveston, USA. tadros@hlkd.azr.nl
Traber
D L
DL
Herndon
D N
DN
D000704:Analysis of Variance; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D002056:Burns / Q000150:complications; D004353:Drug Evaluation, Preclinical; D004926:Escherichia coli; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007511:Ischemia / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology; D008070:Lipopolysaccharides; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000503:physiopathology; D019808:Losartan / Q000627:therapeutic use; D011897:Random Allocation; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D018805:Sepsis / Q000150:complications*; D013552:Swine; D013556:Swine, Miniature; D014947:Wounds and Injuries / Q000150:complications*
D008070:Lipopolysaccharides; D000804:Angiotensin II; D019808:Losartan