The iron chelators desferrioxamine and 1-alkyl-2-methyl-3-hydroxypyrid-4-ones inhibit vascular prostacyclin synthesis in vitro.
The iron chelators desferrioxamine (DFO), 1,2-dimethyl(L1)-, 1-ethyl-2-methyl(L1NEt)- and 1-propyl-2-methyl(L1NPr)-3-hydroxypyrid-4-ones inhibited rat aortic prostacyclin (PGI2) synthesis in vitro (rank order of potency: DFO greater than L1 greater than L1NEt greater than L1NPr) when stimulated with adrenaline, arachidonate and the Ca2+ ionophore A23187. The inhibitory action of the chelators was blocked by Fe3+ and Al3+ and reversed by washing and H2O2, but not by ascorbate. These data suggest that iron chelators inhibit prostanoid synthesis in intact tissue through the removal or binding of Fe3+ linked to cyclo-oxygenase. These iron chelators may be of therapeutic value in the treatment of inflammatory and other diseases via two mechanisms: (1) the inhibition of pro-inflammatory prostanoid synthesis and (2) the inhibition of toxic-free-radical generation by cyclo-oxygenase.
D000535:Aluminum / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D000077543:Deferiprone; D003676:Deferoxamine / Q000494:pharmacology*; D004837:Epinephrine / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007501:Iron / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000494:pharmacology; D008297:Male; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D001095:Arachidonic Acids; D007502:Iron Chelating Agents; D011728:Pyridones; D016718:Arachidonic Acid; D000077543:Deferiprone; C048630:1-ethyl-2-methyl-3-hydroxypyridin-4-one; C049969:1-propyl-2-methyl-3-hydroxypyrid-4-one; D000001:Calcimycin; D006861:Hydrogen Peroxide; D000535:Aluminum; D011464:Epoprostenol; D007501:Iron; D003676:Deferoxamine; D001205:Ascorbic Acid; D004837:Epinephrine