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

Abstract

Abstract

The efficacy of N, N′-bis-(3-picolyl)-methoxyisophthalamide (picotamide) as an in vitro thromboxane synthetase inhibitor and its effect on endotoxin (LPS)-induced lethality in rats were assessed. Picotamide at 0.5 and 1.0 mM concentrations significantly (P < 0.05) inhibited basal and LPS-stimulated synthesis of TxA₂ measured by its stable immunoreactive (i) metabolite TxB₂ in rat peritoneal macrophages. This compound did not inhibit synthesis of i6-keto-PGF_1α, the stable metabolite of PGI₂, and produced significant shunting to i6-keto-PGF_1α. For lethality studies rats were pretreated, by gavage with picotamide, at either 75, 150, 300, or 600 mg/kg 2 hr prior to iv S. enteritidis (LPS, 20 mg/kg). Both 150 and 300 mg/kg doses of picotamide significantly (P < 0.05) improved survival in endotoxin shock at 48 hr. These studies demonstrate that picotamide is a selective thromboxane synthetase inhibitor, and that it may be useful during disease states characterized by increased TxA₂ synthesis.