Abstract

We showed previously, using in vitro microdialysis, that activation of the nitric oxide (NO)/cyclic GMP pathway was the underlying mechanism of exogenous NO-induced dopamine (DA) secretion from PC12 cells. In this study, infusion of the potential peroxynitrite generator 3-morpholinosydnonimine (SIN-1, 1.0 mM for 60 min) induced a long-lasting decrease in dialysate DA þ 3-methoxytyramine (3- MT) in dialysates from PC12 cell suspensions. Ascorbic acid (0.2 mM) co-infusion allowed SIN-1 to increase dialysate DA þ 3-MT. SIN- 1 þ ascorbic acid effects were abolished by Ca²⁺ omission. Infusion of high K⁺ (75 mM) induced a 2.5-fold increase in dialysate DA þ 3- MT. The increase was inhibited by SIN-1 co-infusion. Conversely, co-infusion of ascorbic acid (0.2 mM) with SIN-1 þ high K⁺ resulted in a 3.5 fold increase in dialysate DA þ 3-MT. The L-type Ca²⁺ channel inhibitor nifedipine selectively inhibited the DA þ 3-MT increase pertaining to high K⁺, while the soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]-oxadiazolo[4,3]quinoxalin-1-one selectively inhibited the increase pertaining to SIN-1 effects. These results suggest that activation of the NO/sGC/cyclic GMP pathway is the underlying mechanism of extracellular Ca²⁺-dependent effects of SIN-1 on DA secretion from PC12 cells. Extracellular Ca²⁺ entry occurs through nifedipine-insensitive channels. Ascorbic acid is a key determinant in modulating the distinct profiles of SIN-1 effects.

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