Protective effects of BAY U 3405, a thromboxane A2 receptor antagonist, in endotoxin shock.
The present study was designed to investigate the effects of BAY U 3405, a new thromboxane A2 (TxA2) receptor antagonist, in endotoxin shock. Endotoxin shock (ES) was induced in male rats by an i.v. injection of Salmonella enteritidis lipopolysaccharide (LPS; 20 mg kg-1). LPS administration caused animal death (survival = 0%, 48 h after endotoxin challenge), systemic hypotension, depressed phagocytosis and increased blood levels of TNF-alpha, TxB2 and 6-keto-PGF1 alpha, reduced white blood cell (WBC) count (ES = 5.9 +/- 1 x 10(3) mm-3; CTRL = 13.4 +/- 5 x 10(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 tissue), 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 fresh tissue; CTRL = 0.19 +/- 0.05 U g-1 fresh tissue). Furthermore, endotoxin administration produced characteristic damage of the gastric mucosa 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, decreased 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 in 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 tissue). Finally, the gastric alterations were significantly reduced in rats pretreated with BAY U 3405. These data suggest that this thromboxane receptor antagonist might be a useful drug in shock conditions.
Altavilla
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D
Institute of Pharmacology, School of Medicine, University of Messina, Italy.
Canale
P
P
Squadrito
F
F
Sardella
A
A
Ammendolia
L
L
Urna
G
G
Ioculano
M
M
Squadrito
G
G
Caputi
A P
AP
D000704:Analysis of Variance; D000818:Animals; D001095:Arachidonic Acids / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D002227:Carbazoles / Q000627:therapeutic use*; D004731:Endotoxins; D007958:Leukocyte Count / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D012772:Shock, Septic / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D013449:Sulfonamides / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001095:Arachidonic Acids; D002227:Carbazoles; D004731:Endotoxins; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; C063119:ramatroban