Modulation of arginine and asymmetric dimethylarginine concentrations in liver and plasma by exogenous hydrogen sulfide in LPS-induced endotoxemia

Abstract

Plasma levels of asymmetric dimethylarginine (ADMA) are known to be elevated under pathological conditions, but reports on intracellular ADMA levels are scarce. In this study, we investigated whether lipopolysaccharide (LPS)-induced endotoxemia alters the intra-and extra-cellular partition of L-arginine and ADMA. The effect of H2S pretreatment was also researched. Wistar rats were given sodium hydrogen sulfide (NaHS, 1 mg.(kg body mass)(-1)) one hour before the LPS injections (20 mg.kg(-1)). Six hours after the LPS treatment, the animals were sacrificed. Myeloperoxidase (MPO) and dimethylarginine dimethylaminohydrolase (DDAH) activities and levels of hypoxia-inducible factor (HIF)-1 alpha were measured in the liver. ADMA and arginine levels were determined using HPLC. LPS injection caused liver injury, as evidenced by the activities of alanine transaminase, aspartate transaminase, and arginase. LPS increased L-arginine content and decreased DDAH activity in the rat liver. MPO activity and HIF-1 alpha levels indicated inflammation and hypoxia. Despite the accumulation of ADMA in the plasma, the level remained unchanged in the liver. NaHS pretreatment restored both the DDAH activity and intracellular L-arginine levels. It is concluded that increased H2S generation has a potency to restore hepatic L-arginine levels and ADMA handling in endotoxemia. Extra-and intra-cellular partitions of ADMA seem to depend on transport proteins as well as the DDAH activity.