Protective effects of trans-13-APT, a thromboxane receptor antagonist, in endotoxemia.
The effect of the thromboxane A2/prostaglandin H2 (TxA2/PGH2) receptor antagonist trans-7[2-(p-hydroxyphenethylamino)-cyclopentyl]-heptanoic acid (trans-13-APT) on certain pathogenic sequelae of endotoxic shock and associated changes in arachidonic acid metabolism in the rat was investigated. trans-13-APT, an analog of 13-azaprostanoic acid, was synthesized and found to block human platelet aggregation induced by the thromboxane mimetic U46619. Pretreatment with trans-13-APT did not significantly alter the elevations in plasma immunoreactive (i) TxB2 or iPGE, 0.5 or 4 h after the intravenous administration of Salmonella enteritidis endotoxin. However, in the trans-13-APT-pretreated group, 4 h after administration of the endotoxin, plasma i6-keto-PGF1 alpha was significantly (p less than 0.05) reduced to 1.2 +/- 0.3 ng/ml (n = 17) compared with vehicle-treated rats (2.4 +/- 0.5 ng/ml; n = 18). The elevation in plasma i6-keto-PGF1 alpha seen 0.5 h (n = 17/group) after endotoxin infusion was not altered by trans-13-APT. trans-13-APT also significantly (p less than 0.05) attenuated the endotoxin-induced fall in platelet count (135 +/- 27 X 10(3)/mm3 vs. 350 +/- 65 X 10(3)/mm3 and hypoglycemia (73 +/- 9 vs. 97 +/- 7 mg/dl), but not the leukopenia. Since the reticuloendothelial system may be an important source of iTxB2 and i6-keto-PGF1 alpha during endotoxemia, in vitro studies were conducted with adherent peritoneal cells. High concentrations of trans-13-APT (50 and 100 microM) significantly reduced (p less than 0.05) basal but not endotoxin-induced synthesis of iTxB2 and i6-keto-PGF1 alpha by isolated adherent rat peritoneal cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Olanoff
L S
LS
Cook
J A
JA
Eller
T
T
Knapp
D R
DR
Halushka
P V
PV
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis / Q000097:blood; D000818:Animals; D004731:Endotoxins / Q000097:blood*; D011464:Epoprostenol / Q000096:biosynthesis; D066298:In Vitro Techniques; D008264:Macrophages / Q000378:metabolism; D008297:Male; D010627:Phenethylamines / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D011458:Prostaglandins E / Q000097:blood; D051381:Rats; D011956:Receptors, Cell Surface / Q000187:drug effects*; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D013929:Thromboxane B2 / Q000096:biosynthesis / Q000097:blood
D004731:Endotoxins; D010627:Phenethylamines; D011458:Prostaglandins E; D011956:Receptors, Cell Surface; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C045021:7-(2-(4-hydroxyphenethylamino)cyclopentyl)heptanoic acid; D011464:Epoprostenol