The 21-aminosteroid U-74389G enhances hepatic blood flow and preserves sinusoidal endothelial cell function and structure in endotoxin-shocked dogs

Background. 21-Aminosteroids are potent antiinflammatory and antioxidant dr ugs that provide remarkable endothelial protection in different models of t issue ischemia-reperfusion and inflammation. The effects of 21-aminosteroid s in sepsis, a highly inflammatory condition leading to panendothelial acti vation and injury, are largely uninvestigated. We therefore explored the ef fects of the al-aminosteroid U74386G on hepatic blood flow, endothelial cel l function, and sinusoidal structure in a canine model of fluid-resuscitate d, hyperdynamic endotoxic shock. Materials and methods. Following invasive hemodynamic monitoring and placem ent of ultrasonic flow probes around the common hepatic artery and the port al vein, 12 anesthetized dogs received 2 mg/kg iv of Escherichia coli endot oxin, followed by generous saline infusion, before randomization into two g roups. One group (N = 6) received U74389G as an iv bolus of 80 mu g/kg, fol lowed by a continuous infusion of 10 mu g/kg min. The other group (N = 6) r eceived an equivalent volume of vehicle. Hyaluronic acid was measured in pl asma for in vivo evaluation of endothelial cell function. Liver biopsies we re taken after 4 h of endotoxic shock and prepared for light and electron m icroscopic examination. Results. Compared with the vehicle-treated controls, U74389G; maintained a higher blood flow in the hepatic artery and in the portal vein, without mar kedly influencing the systemic hemodynamic response. The endotoxin-induced increase in plasma hyaluronic acid levels was significantly attenuated foll owing UT4389G; treatment (70 +/- 14 vs 188 +/- 24 ng/mL after 3 h of endoto xic 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. Conclusion. U74389G can preserve the functional and structural integrity of endothelial cells in the hepatic sinusoid during hyperdynamic endotoxic sh ock. This endothelial-protective effect was associated with a better mainta ined hepatic blood flow and a significant attenuation of inflammatory liver injury. (C) 1999 Academic Press.