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.