2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic-acid and 1-benzylimidazole

PAF-receptor antagonists are known to inhibit gastrointestinal damage induced by endotoxin. In the present study, the interaction between the biosynthesis of PAF and thromboxane (TX) A2, as putative mediators of the acute intestinal damage induced by endotoxin, has been investigated in the anaesthetised rat. Bolus intravenous administration of lipopolysaccharide from E. coli (5-50 mg/kg) induced dose-related jejunal damage, assessed using both macroscopic and histological techniques. This damage was accompanied by significant increases in the jejunal formation of PAF determined by bioassay, and of TXB2, determined by radioimmunoassay. Pretreatment with the structurally-unrelated thromboxane synthase inhibitors, 1-benzyl imidazole (10-50 mg/kg) or OKY 1581 (25 mg/kg) substantially reduced both jejunal damage and TXB2 formation, but did not inhibit PAF formation. Likewise, pretreatment with indomethacin (5 mg/kg) or BW 755C (50 mg/kg) reduced jejunal damage and TXB2 formation but did not affect PAF formation. Pretreatment (2h) with dexamethasone (4 mg/kg) reduced jejunal damage and the formation of both TXB2 and PAF. Intravenous infusion of PAF (100 ng/kg/min for 10 min) induced jejunal damage and significantly increased the formation of TXB2, whereas non-specific jejunal damage induced by oral administration of ethanol did not augment PAF formation. The present findings that inhibition of jejunal thromboxane formation is associated with a substantial reduction in jejunal damage, with no corresponding inhibition in PAF formation, therefore suggests a complex interaction or sequential release of these tissue destructive mediators underlying the intestinal damage induced by endotoxin.

Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Escherichia coli; Ethanol; Imidazoles; Indomethacin; Jejunum; Lipopolysaccharides; Male; Methacrylates; Platelet Activating Factor; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Rats, Inbred Strains; Shock, Septic; Thromboxane A2; Thromboxane-A Synthase

Selective inhibitors of thromboxane (TX) formation have potential utility in the treatment of hypertension, atherosclerosis, thrombosis, myocardial ischemia, cancer metastasis, etc. This class of compounds not only removes TX, a potent vasoconstrictor and inducer of platelet aggregation, but may also enhance the production of a potent vasodilator and inhibitor of platelet aggregation, viz., prostacyclin (epoprostenol, PGI2). The specific thromboxane synthetase (TXS) inhibitor 1-benzylimidazole (1-BI) demonstrated a weak and OKY-1581 (OKY) a potent inhibition of TX formation in SHR-derived platelets in vitro. The acute antihypertensive effects produced by 1-BI were marked while those of OKY were less significant in SHR. 1-BI and OKY did not demonstrate an inhibition of PGI2 formation in SHR-derived aortic rings in vitro. Indomethacin (I), which inhibits the formation of both TX and PGI2, was not antihypertensive and did not antagonize the blood pressure lowering effects of 1-BI in the present studies. Oral and intravenous dosing with 1-BI, unlike OKY, produced epinephrine reversal in SHR, indicating the blockade of alpha-adrenoceptors. In conclusion, the acute antihypertensive effects of 1-BI in SHR result mainly from alpha-adrenoceptor blockade, not inhibition of TXS activity.

Topics: Adrenergic alpha-Antagonists; Animals; Blood Pressure; Epoprostenol; Hypertension; Imidazoles; In Vitro Techniques; Methacrylates; Oxidoreductases; Rats; Thromboxane-A Synthase; Thromboxanes