Abstract
1. E3040 (6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl)benzothiazole), is a novel dual inhibitor of 5-lipoxygenase (5-LOX) and thromboxane synthase (Tx synthase). Here, we examined the effects of E3040 sulphate, a sulphate conjugate of E3040, on these enzyme activities in cell-free systems and on the thromboxane A2 (TxA2)-mediated Cl- secretion induced by platelet-activating factor (PAF) in isolated rat colons. 2. E3040 sulphate inhibited Tx synthase activity in a concentration-dependent manner (IC50=0.013 microM), whereas it induced little effects on 5-LOX and cyclo-oxygenase activities (IC50>100 microM) with the cell-free enzyme assay. 3. With isolated rat colonic mucosa, E3040 sulphate in a concentration-dependent manner (IC50=1.8 microM) inhibited the Cl- secretion induced by 10 microM PAF. On the other hand, E3040 sulphate (30 microM) induced no effect on the prostaglandin E2 (0.5 microM)- and leukotriene D4 (1 microM)-induced Cl- secretion in the colon. 4. PAF (10 microM) increased a release of TxB2, a stable metabolite of TxA2, from the colonic mucosa. This increase was significantly inhibited by subsequent addition of E3040 sulphate (30 microM). 5. Probenecid (100 microM), an inhibitor of organic anion transporter, abolished the inhibitory effect of E3040 sulphate on the PAF-induced Cl- secretion. Another inhibitor, sulphobromophthalein (30 microM) partially but significantly attenuated the effect of E3040 sulphate. p-aminohippuric acid (1 mM) had no effect. 6. These findings suggest that E3040 sulphate is a novel Tx synthase inhibitor, and that E3040 sulphate taken up into the colonic cells by organic anion transporters inhibits the PAF-induced Cl- secretion by blocking a release of TxA2.
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