Effects of a pyridine derivative thromboxane synthetase inhibitor and its inactive isomer in endotoxic shock in the rat

Abstract

1We 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 (< 100 pg/ml) to 763 ± 250 pg/ml (n = 10). Plasma i6-keto-PGF1,, (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<0.05) suppressed iTxB2 to 390±31 pg/ml (n= 10) although 6-keto-PGF1,l 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,, synthesis (628 ± 266 pg/ml, n = 5).2 Pretreatment of rats with the Tx synthetase inhibitor, PA, significantly enhanced (P <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 tndotoxic 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.

Selective Thromboxane Synthetase Inhibition by Picotamide and Effects on Endotoxin-Induced Lethality

“…The latter data demonstrate both selectivity of picotamide on inhibition of thromboxane synthetase and cellular shunting of endoperoxide metabolites through prostacyclin synthetase. This shunting phenomenon, following thromboxane inhibition in macrophages, concurs with previous in vitro studies with dazoxiben ( 10) and pyridine derivatives ( 12).…”

“…TxA2, a potent vasoconstrictor, bronchoconstrictor, and platelet aggregator, has been implicated as a possible mediator of certain pathogenic sequelae of endotoxic shock (3,4). Several specific thromboxane synthetase inhibitors including imidazole (9), 7-IHA ( lo), Dazoxiben ( 1 1 ), pyridine derivatives ( 12), and OKY-158 1 ( 13) have been tested in experimental endotoxic shock in the rat. These compounds have been shown to ameliorate many of the deleterious effects of endotoxemia such as reductions in systemic coagulopathies (4), reduced lysosomal labialization (9,13), improved cardiac output and tissue perfusion ( 14), and enhanced survival (9,10,13).…”

Eicosanoids as Risk and Prognostic Factors for Acute Respiratory Distress Syndrome in Sepsis Patients

“…Receptor antagonist and/or synthetase inhibitor analysis have been carried out in patients with ARDS. Thromboxane synthesis inhibitors and/or antagonists improved the acute cardiopulmonary effects of bolus endotoxin [13][14][15] and increased patient survival [16][17][18]. The thromboxane A 2 synthesis inhibitor ketoconazole was found to significantly reduce the rate of ARDS development in sepsis patients and decrease their mortality rate [19].…”

Syntheses ofN‐[3‐(1‐methyl‐1H‐2‐imidazolyl)propyl]benzamides andN‐[3‐(1‐methyl‐1H‐2‐imidazolyl)propyl]benzenesulfonamides

“…In addition, TXA 2 has been shown to be the most potent endogenous vasoconstrictor known, it was hoped that some TX inhibitors might have antihypertensive activity in certain forms of hypertension where in TX maintains blood pressure [8]. Several laboratories have investigated the selective inhibitors of thromboxane synthetase (TXS) such as dazoxiben [9] (I), 4'-(1H-imidazol-1-yl)acetophenone [10] and 4-[(2-pyridylmethyl)-amino]benzoic acid [11]. Also, the syntheses of N- [3-(1H-imidazol-1-yl)propyl]benzamides (II) as TXS inhibitor have been reported [8].…”