Protective effect of imidaprilat, a new angiotensin-converting enzyme inhibitor against 1-methyl-4-phenylpyridinium ion-induced ⋅OH generation in rat striatum

Abstract

We examined the antioxidant effects of angiotensin-converting enzyme inhibitor on 1-methyl-4-phenylpyridinium ion (MPP +)-induced hydroxyl radical (⋅OH) formation in extracellular fluid of rat striatum. Rats were anesthetized and sodium salicylate in Ringer's solution (0.5 nmol μl −1 min −1) was infused through a microdialysis probe to detect the generation of ⋅OH, as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. MPP + clearly produced an increase in ⋅OH formation in a concentration-dependent manner. When imidaprilat was infused in MPP +-pre-treated animals, the formation of dopamine and 2,3-DHBA significantly decreased, as compared with that in the MPP +-only-treated group. We compared the ability of two non-SH-containing angiotensin-converting enzyme inhibitors (imidaprilat and enalaprilat) with an SH-containing angiotensin-converting enzyme inhibitor (captopril) to scavenge ⋅OH. All three angiotensin-converting enzyme inhibitors were able to scavenge ⋅OH generated by the action of MPP +. However, the changes produced by captopril and enalaprilat were not significant. When dopamine was administered to the MPP +-pre-treatment group, a marked elevation was observed, showing a positive linear correlation between dopamine and ⋅OH formation (2,3-DHBA) in the dialysate. Moreover, when iron (II) was administered to the MPP +-pre-treatment group, the same results were obtained: a positive linear correlation ( R 2=0.989) between the release of dopamine and 2,3-DHBA ( R 2=0.989) in the dialysate. When corresponding experiments were performed with imidaprilat-pre-treated animals, the level of 2,3-DHBA decreased. These results suggested that angiotensin-converting enzyme inhibitors may protect against MPP +-induced ⋅OH formation in the rat striatum.