Diphenylamine-2-carboxylate (DPC) inhibits both Cl− conductance and cyclooxygenase of canine tracheal epithelium

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Abstract
Diphenylamine-2-carboxylate (DPC) decreases Cl− conductance (G Cl) in epithelia and cells of several tissues, an effect which has been ascribed to blockade of conductive Cl− channels. However, one DPC derivative, flufenamic acid, is a clinically useful non-steroidal antiinflammatory agent, the mechanism of action of which involves the blockade of arachidonic acid metabolism by cyclooxygenase. BecauseG Cl in canine tracheal epithelium is stimulated by exogenous prostaglandins and induction of cyclooxygenase activity, we tested the hypothesi that DPC inhibits dog tracheal epitheliumG Cl through inhibition of cyclooxygenase. DPC inhibited the short circuit current of amiloride-pretreated tissues by 50% at 0.138 mmol/l and by more than 95% at 3 mmol/l. Isoproterenol reversed the inhibition seen at 0.1 mmol/l DPC and stimulated current above control (indomethacin-pretreated) levels. Higher concentrations of DPC diminished the stimulation of current by subsequent exposure to isoproterenol, such that there was little effect of isoproterenol in the presence of 3 mmol/l DPC. DPC, 0.1 mmol/l, also blocked stimulation of current by exogenous arachidonic acid, but not of exogenous prostaglandins PGE or PGD. The metabolism of3H-arachidonic acid to3H-PGD2, monitored by HPLC, was completely blocked by 0.1 mmol/l DPC. We conclude that the isoproterenol/prostaglandin reversible blockade ofG Cl by DPC can be attributed to inhibition of arachidonic acid metabolism.