Inhibition of [3H]MK‐801 Binding by Ferrous (II) but Not Ferric (III) Ions in a Manner Different from That by Sodium Nitroprusside (II) in Rat Brain Synaptic Membranes

: The addition of sodium nitroprusside (SNP) significantly inhibited binding of (+)‐5‐[3H]methyl‐10,11‐dihydro‐5H‐dibenzo[a,d]cyclohepten‐5,10‐imine ([3H]MK‐801) to an ion channel associated with the N‐methyl‐d‐aspartate (NMDA) receptor in a concentration‐dependent manner at concentrations of >1 µM in rat brain synaptic membranes not extensively washed. However, neither S‐nitroso‐N‐acetylpenicillamine nor S‐nitroso‐l‐glutathione inhibited binding even at 100 µM. Of the two compounds structurally related to SNP (II), similarly potent inhibition was induced by potassium ferrocyanide (II) but not by potassium ferricyanide (III). In addition, ferrous chloride (II) induced much more potent inhibition of binding than ferric chloride (III), at a similar concentration range. In contrast, iron chelators prevented the inhibition by ferrous chloride (II) without markedly affecting that by SNP (II) and potassium ferrocyanide (II). Pretreatment with ferrous chloride (II) also led to potent inhibition of [3H]MK‐801 binding in a manner insensitive to subsequent addition of the iron chelators. Pretreatment with Triton X‐100 resulted in significant potentiation of the ability of ferrous chloride (II) to inhibit [3H]MK‐801 binding irrespective of the addition of agonists, moreover, although binding of other radioligands to the non‐NMDA receptors was unaltered after pretreatment first with Triton X‐100 and then with ferrous chloride (II). These results suggest that ferrous ions (II) may interfere selectively with opening processes of the NMDA channel through mechanisms entirely different from those underlying the inhibition by both SNP (II) and potassium ferrocyanide (II) in rat brain.