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/kg iv of Escherichia coli endotoxin, followed 30 min later by saline infusion. Group 3 was given U-74006F as an intravenous bolus of 80 micrograms/kg followed by an infusion of 10 micrograms.kg-1.min-1, and group 2 received an equivalent volume of vehicle. Tamponade was induced 30 min later to study the oxygen extraction capabilities of the animals. Compared with the endotoxin-alone group, the U-74006F-treated dogs maintained higher mean arterial pressure, cardiac index, stroke volume index, and left ventricular stroke work index and lower pulmonary vascular resistance. They also showed a higher fractional blood flow to mesenteric and renal beds. Endotoxin administration increased whole body critical oxygen delivery (DO2crit) from 7.7 +/- 2.4 to 12.0 +/- 1.9 ml.kg-1.min-1 (P < 0.05), but U-74006F decreased DO2crit to 7.8 +/- 2.0 ml.kg-1.min-1 (P < 0.05 vs. endotoxin alone). Endotoxin decreased critical oxygen extraction ratio (O2ERcrit) from 75.0 +/- 12.7 to 44.3 +/- 8.7% (P < 0.05), but U-74006F increased O2ERcrit to 64.1 +/- 11.2% (P < 0.05 vs. endotoxin alone). U-74006F also decreased endotoxin-induced elevation of mesenteric and renal DO2crit and markedly increased regional O2ERcrit. Systemic and regional blood lactate concentrations were lower in the U-74006F-treated animals