A comparative study of the effects of molsidomine and 3-morpholinosydnonimine on the redox status of rat erythrocytes and reticulocytes

Abstract

After enzymic biotransformation, molsidomine (MO) acts via the metabolite 3-morpholmosydnonimine (SIN-1) through spontaneous liberation of nitric oxide (NO) and superoxide (O-2(.-)). The aim of this study was to compare the effects of MO and its active metabolite SIN-1 on the redox status of rat erythrocytes and reticulocytes. Rat erythrocyte as well as reticulocyte-rich red blood cell (RBC) suspensions were aerobically incubated (2h, 37 degrees C) without (control) or in the presence of different concentrations of MO or SIN-1. In rat erythrocytes, biotransformation of MO resulted in the production of NO and nitroxyl (NO-). Endogenous superoxide anion (O-2(.-)) participated in peroxynitrite generation. SIN-1 simultaneously liberated NO and O-2(.-), which formed peroxynitrite (at least in part), but the liberated NO predominantly reacted with haemoglobin, forming methaemoglobin in erythrocytes. In reticulocytes, MO and SIN-1 caused an increase in the levels of both nitrite and 3-nitrotyrosine (an indicator of peroxynitrite), whereas they decreased the level of O-2(.-). In reticulocytes, MO was metabolized into SIN-1 which led to the generation of NO, which reacted with O-2(.-) (endogenous or exogenous) forming reactive nitrogen species. In conclusion, there are two metabolic pathways for MO biotransformation: one causing NO and NO- generation predominantly in erythrocytes and the other, via SINA metabolism, in reticulocytes. The main difference between the action of MO and SIN-1 was that the latter caused oxidative damage in RBCs. Copyright (c) 2006 John Wiley & Sons, Ltd.