Effects of a pyridine derivative thromboxane synthetase inhibitor and its inactive isomer in endotoxic shock in the rat.
1 We investigated the effects of a pyridine derivative thromboxane synthetase inhibitor and its inactive ortho isomer on arachidonic acid metabolism and pathophysiological sequelae of endotoxic shock. In vehicle-treated rats, 30 min after intravenous S. enteritidis endotoxin (15 mg/kg), plasma iTxB2 (the stable metabolite of thromboxane A2) increased from non-detectable levels (less than 100 pg/ml) to 763 +/- 250 pg/ml (n = 10). Plasma i6-keto-PGF1 alpha (the stable metabolite of prostacyclin, PGI2) increased to 1850 +/- 426 pg/ml, (n = 9) and plasma iPGE increased to 2350 = 560 (n = 5). Pretreatment with the pyridine active (PA) meta isomer (30 mg/kg i.p.) significantly (P less than 0.05) suppressed iTxB2 to 390 +/- 31 pg/ml (n = 10) although 6-keto-PGF1 alpha levels (1294 +/- 358 pg/ml, n = 5) and plasma iPGE (2847 +/- 1103 pg/ml, n = 5) were not significantly different from the shocked control values. In contrast, pretreatment with, the pyridine inactive (PI) ortho isomer did not significantly affect endotoxin-induced iTxB2 (1431 +/- 194 pg/ml, n = 5) or i6-keto-PGF1 alpha synthesis (628 +/- 266 pg/ml, n = 5). 2 Pretreatment of rats with the Tx synthetase inhibitor, PA, significantly enhanced (P less than 0.05) survival and prevented splanchnic infarction relative to both endotoxin shocked control rats and those pretreated with the PI isomer. 3 Significantly reduced lysosomal labilization, hepatocellular dysfunction and elevations in serum fibrin/fibrinogen degradation products were seen only in groups pretreated with the PA isomer. 4 The beneficial effects of the latter compound in endotoxic shock thus appear to be due to inhibition of Tx synthesis, since its ortho isomer did not inhibit TxA2 synthesis nor did it protect against endotoxic shock.
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D062365:Aminobenzoates / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D008297:Male; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011458:Prostaglandins E / Q000097:blood; D011863:Radioimmunoassay; D051381:Rats; D012772:Shock, Septic / Q000097:blood / Q000503:physiopathology*; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D062365:Aminobenzoates; D001786:Blood Glucose; D011458:Prostaglandins E; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C037943:4-((2-pyridinylmethyl)amino)benzoic acid; C037942:4-((3-pyridinylmethyl)amino)benzoic acid; D010088:Oxidoreductases; D013930:Thromboxane-A Synthase