Prostaglandin biosynthesis in rabbit kidney: Mepacrine inhibits renomedullary cyclooxygenase

Mepacrine was found to exert a dose-dependent inhibition of prostaglandin E₂ synthesis in rabbit kidney medulla slices and in medullary microsomes. Mepacrine at 0.5 mM produced 90% inhibition of microsomal prostaglandin E₂ biosynthesis from added arachidonic acid. This effect results from inhibition of medullary cyclooxygenase; the activities of the prostaglandin G₂ hydroperoxidase and the prostaglandin H₂ isomerases are unaffected. In experiments with medulla slices prelabelled with [¹⁴C]arachidonate, the effect of mepacrine on the inhibition of [¹⁴C]prostaglandin generation was significantly higher (2.5 to 3.5-fold) than its inhibition of [¹⁴C]arachidonate release. Hence, although mepacrine reduces prostaglandin production by decreasing the lipolytic release of arachidonate from medullary lipids, its inhibitory effect on prostaglandin cyclooxygenase activity is substantial and appears to contribute significantly to its overall inhibition of prostaglandin generation in kidney medulla. Mepacrine is thus not only a non-selective antilipolytic agent but also a potent cyclooxygenase inhibitor.