Tirilazad mesylate (u74006f) inhibits the effects of endotoxin in dogs.
Zhang, Haibo, Herbert Spapen, Panayotis Manikis, Peter Rogiers,
Ga[diaeresis]etane Metz,
Wim A. Buurman, and Jean-Louis Vincent.
Department of Intensive Care, Erasme University Hospital, Laboratory of
Immunulogy, Faculty of Medicine, Free University of Brussels, Belgium,
Department of Surgery (Immunology Laboratory), Rijksuniversiteit Limburg,
6200 MD Maastricht, The Netherlands
APStracts 2:0001H, 1995.
The present study explored the effects of a potent antioxidant, the 21
-aminosteroid U74006F, 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 a 2 mg/kg of
Escherichia coli endotoxin intravenously, followed 30 min later by saline
infusion. Group 3 was given U74006F as an iv bolus of 80 [mu]g/kg followed by
an infusion of 10 [mu]g/kg.min, and Group 2 received an equivalent volume of
vehicle. Tamponade was induced 30 min later to study the oxygen extraction
capabilities of the animals. As compared to the endotoxin alone group, the
U74006F-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.min (p < 0.05) but U74006F decreased DO2crit to 7.8 +/- 2.0 ml/kg.min (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 U74006F
increased O2ERcrit to 64.1 +/- 11.2 % (p < 0.05 vs. endotoxin alone). U74006F
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 U74006F-treated animals. U74006F also
largely attenuated the endotoxin-induced release of tumor necrosis factor and
plasma nitrite. We conclude that during endotoxic shock, U74006F can enhance
myocardial function, increase mesenteric and renal blood flow, improve whole
body and regional oxygen extraction capabilities.
Received 7 September 1994; accepted in final form 4 January 1995.
APS Manuscript Number H0802-4.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 24 February 1995.