PROTECTIVE EFFECTS OF BAY-U-3405, A THROMBOXANE-A(2) RECEPTOR ANTAGONIST, IN ENDOTOXIN-SHOCK

The present study was designed to investigate the effects of BAY U 340 5, a new thromboxane A(2) (TxA(2)) receptor antagonist, in endotoxin s hock. Endotoxin shock (ES) was induced in male rats by an i.v. injecti on of Salmonella enteritidis lipopolysaccharide (LPS; 20 mg kg(-1)). L PS administration caused animal death (survival=0%, 48 h after endotox in challenge), systemic hypotension, depressed phagocytosis and increa sed blood levels of TNF-alpha, TxB(2) and 6-keto-PGF1 alpha, reduced w hite blood cell (WBC) count (ES=5.9+/-1x10(3) mm(-3); CTRL=13.4+/-5x10 (3) mm(-3)) and enhanced myeloperoxidase (MPO) activity, studied as a quantitative means for assessing leukocyte accumulation, in the ileum (ES=0.24+/-0.7 U g(-1) fresh tissue; CTRL=0.13+/- 0.04 U g(-1) fresh t issue), in the heart (ES=0.41+/-0.1 U g(-1) fresh tissue; CTRL=0.16+/- 0.08 U g(-1) fresh tissue) and in the lung (ES=0.68+/-0.11 U g(-1) fr esh tissue; CTRL= 0.19+/-0.05 U g(-1) fresh tissue). Furthermore, endo toxin administration produced characteristic damage of the gastric muc osa consisting of haemmorrhagic infiltrates. BAY U 3405 (30 mg kg(-1) i.v., 30 min before endotoxin challenge) increased survival rate (45% survival rate 48 h after endotoxin challenge), reduced hypotension, de creased TNF-alpha levels in serum, enhanced phagocytic activity (ES=25 .6+/-1.9%, BAY U 3405=45.9+/-0.4%, P<0.001) and lowered MPO activity i n the ileum (0.14+/-0.05 U g(-1) fresh tissue), in the heart (0.18+/-0 .08 U g(-1) fresh tissue) and in the lung (0.44+/-0.09 U g(-1) fresh t issue). Finally, the gastric alterations were significantly reduced in rats pretreated with BAY U 3405. These data suggest that this thrombo xane receptor antagonist might be a useful drug in shock conditions.