TIRILAZAD MESYLATE (U-74006F) INHIBITS EFFECTS OF ENDOTOXIN IN DOGS

The present study explored the effects of a potent antioxidant, the 21 -aminosteroid U-74006F, on the systemic and regional hemodynamics and the oxygen extraction capabilities during endotoxic shock. Twenty-four anesthetized dogs were randomized into three groups. Group 1 (n = 8) served as control. Group 2 (n = 8) and group 3 (n = 8) received 2 mg/k g iv of Escherichia coli endotoxin, followed 30 min later by saline in fusion. Group 3 was given U-74006F as an intravenous bolus of 80 mu g/ kg followed by an infusion of 10 mu g . kg(-1). min(-1), and group 2 r eceived an equivalent volume of vehicle. Tamponade was induced 30 min later to study the oxygen extraction capabilities of the animals. Comp ared with the endotoxin-alone group, the U-74006F-treated dogs maintai ned higher mean arterial pressure, cardiac index, stroke volume index, and left ventricular stroke work index and lower pulmonary vascular r esistance. They also showed a higher fractional blood flow to mesenter ic and renal beds. Endotoxin administration increased whole body criti cal oxygen delivery (Do(2crit)) from 7.7 +/- 2.4 to 12.0 +/- 1.9 ml . kg(-1). min(-1) (P < 0.05), but U-74006F decreased Do(2crit) to 7.8 +/ - 2.0 ml . kg(-1) . min(-1) (P < 0.05 vs. endotoxin alone). Endotoxin decreased critical oxygen extraction ratio (O(2)ER(crit) from 75.0 +/- 12.7 to 44.3 +/- 8.7% (P < 0.05), but U-74006F increased O(2)ER(crit) to 64.1 +/- 11.2% CP < 0.05 vs. endotoxin alone). U-74006F also decre ased endotoxin-induced elevation of mesenteric and renal Do(2crit) and markedly increased regional O(2)ER(crit). Systemic and regional blood lactate concentrations were lower in the U-74006F-treated animals. U- 74006F also largely attenuated the endotoxin-induced release of tumor necrosis factor and plasma nitrite. We conclude that during endotoxic shock, U-74006F can enhance myocardial function, increase mesenteric a nd renal blood flow, and improve whole body and regional oxygen extrac tion capabilities.