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 study to inhibit (K(i) = 3 microM) glutathione reductase from bovine intestinal mucosa. As glutathione disulphide has been reported to inhibit guanylate cyclase irreversibly [Braughler, Biochem Pharmacol 32: 811-818, 1983], the inhibition of glutathione reductase should affect the activity of guanylate cyclase and may thus have physiological implications in the action of endothelium-derived relaxation factor and the design of muscle relaxants. LY83583 is reduced by NADPH and glutathione reductase in aerobic media and this may offer a route to the metabolic activation of LY83583. These results may have significant implications for the design of heart-regulating drugs (e.g. those used in angina), such as glyceryl trinitrate, which act via guanylate cyclase.
Lüönd
R M
RM
Department of Pharmacy, University of Manchester, U.K.
McKie
J H
JH
Douglas
K T
KT
D000634:Aminoquinolines / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D006152:Cyclic GMP / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015195:Drug Design; D005978:Glutathione / Q000378:metabolism*; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors*; D006162:Guanylate Cyclase / Q000378:metabolism; D007413:Intestinal Mucosa / Q000201:enzymology; D007700:Kinetics
D000634:Aminoquinolines; C041715:6-anilino-5,8-quinolinedione; D005980:Glutathione Reductase; D006162:Guanylate Cyclase; D005978:Glutathione; D006152:Cyclic GMP