The 21-aminosteroid U74389G enhances hepatic blood flow and preserves sinusoidal endothelial cell function and structure in endotoxin-shocked dogs.
BACKGROUND
21-Aminosteroids are potent anti-inflammatory and antioxidant drugs that provide remarkable endothelial protection in different models of tissue ischemia-reperfusion and inflammation. The effects of 21-aminosteroids in sepsis, a highly inflammatory condition leading to panendothelial activation and injury, are largely uninvestigated. We therefore explored the effects of the 21-aminosteroid U74386G on hepatic blood flow, endothelial cell function, and sinusoidal structure in a canine model of fluid-resuscitated, hyperdynamic endotoxic shock.


METHODS
Following invasive hemodynamic monitoring and placement of ultrasonic flow probes around the common hepatic artery and the portal vein, 12 anesthetized dogs received 2 mg/kg iv of Escherichia coli endotoxin, followed by generous saline infusion, before randomization into two groups. One group (N = 6) received U74389G as an iv bolus of 80 microg/kg, followed by a continuous infusion of 10 microg/kg. min. The other group (N = 6) received an equivalent volume of vehicle. Hyaluronic acid was measured in plasma for in vivo evaluation of endothelial cell function. Liver biopsies were taken after 4 h of endotoxic shock and prepared for light and electron microscopic examination.


RESULTS
Compared with the vehicle-treated controls, U74389G maintained a higher blood flow in the hepatic artery and in the portal vein, without markedly influencing the systemic hemodynamic response. The endotoxin-induced increase in plasma hyaluronic acid levels was significantly attenuated following U74389G treatment (70 +/- 14 vs 188 +/- 24 ng/mL after 3 h of endotoxic shock; P < 0.05). Morphological studies showed that the U74389G-treated group had less sinusoidal endothelial cell damage together with a dramatic reduction of neutrophil infiltration into the liver tissue.


CONCLUSIONS
U74389G can preserve the functional and structural integrity of endothelial cells in the hepatic sinusoid during hyperdynamic endotoxic shock. This endothelial-protective effect was associated with a better maintained hepatic blood flow and a significant attenuation of inflammatory liver injury.
Spapen
H
H
Department of Intensive Care, Erasme University Hospital, Free University of Brussels (ULB), Belgium.
Zhang
H
H
Wisse
E
E
Baekeland
M
M
Seynaeve
C
C
Eddouks
M
M
Vincent
J L
JL
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D004285:Dogs; D004727:Endothelium / Q000473:pathology / Q000503:physiopathology; D005440:Fluid Therapy; D008099:Liver / Q000473:pathology / Q000503:physiopathology*; D008102:Liver Circulation / Q000187:drug effects*; D008854:Microscopy, Electron; D011281:Pregnatrienes / Q000494:pharmacology*; D012151:Resuscitation; D012772:Shock, Septic / Q000473:pathology* / Q000503:physiopathology*
D000975:Antioxidants; D011281:Pregnatrienes; C074965:U 74389F