The irone 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 > L1 > L1NEt > 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.