Metabolic fate of S-nitrosoglutathione after oral administration: Where does NO go?

Abstract

Increasing the gastric mucosal perfusion by nitric oxide (NO) action can reduce the gastric injuries caused by non-steroidal anti-inflammatory drugs (NSAIDs). We have shown previously that topical administration of the NO donor S-nitrosoglutathione (GSNO) on the gastric mucosa of rats increases gastric blood flow, pointing to a possible oral therapeutic approach for treating NSAIDs side effects. In the present study, we found that oral administration of GSNO solutions (7–365 μmol/kg) to Swiss mice leads to a significant dose–response increase in the plasmatic levels of nitrite and nitrate (NOx) measured by chemiluminescence, with peak levels (160 mM) achieved after 1 h. At the same time, intact GSNO could not be detected in the plasma of the GSNO-treated animals by high-sensitivity Ultra Performance Liquid Chromatography (UPLC), 1 h after oral administration. These results indicate that gastric vasodilatation is not associated with a direct action of GSNO molecules, what is in accordance with the fact that GSNO vanishes completely 1 h after incubation in human plasma, as shown by UPLC analysis. In addition, no signal of free NO could be detected after incubation of human plasma with GSNO 50 μM by using a nanomolar-sensitive NO selective electrode (ISO-NOP and APOLLO 4000), over a 1 h period. These findings strongly suggest that the fate of GSNO after contact with the biological milieu involves its primary reaction with proteins by S-nitrosation or/and S-nitrosylation with the transfer of its NO moiety to other effector molecules, which are ultimately responsible for the observed increase in gastric blood flow.