A DIRECT LINK BETWEEN LY83583, A SELECTIVE REPRESSOR OF CYCLIC-GMP FORMATION, AND GLUTATHIONE METABOLISM

LY83583 (6-anilino-5,8-quinolinedione), considered to be a relatively specific repressor of cyclic GMP formation, is shown in the present st udy to inhibit (K(i) = 3 muM) glutathione reductase from bovine intest inal mucosa. As glutathione disulphide has been reported to inhibit gu anylate cyclase irreversibly [Braughler, Biochem Pharmacol 32: 811-818 , 1983], the inhibition of glutathione reductase should affect the act ivity of guanylate cyclase and may thus have physiological implication s in the action of endothelium-derived relaxation factor and the desig n of muscle relaxants. LY83583 is reduced by NADPH and glutathione red uctase in aerobic media and this may offer a route to the metabolic ac tivation of LY83583. These results may have significant implications f or the design of heart-regulating drugs (e.g. those used in angina), s uch as glyceryl trinitrate, which act via guanylate cyclase.