Dimethylarginine dimethylaminohydrolase inhibition and asymmetric dimethylarginine accumulation contribute to endothelial dysfunction in rats exposed to glycosylated protein: effects of aminoguanidine.

OBJECTIVES To determine whether alterations of endogenous asymmetric dimethylarginine (ADMA) concentration and dimethylarginine dimethylaminohydrolase (DDAH) activity are involved in endothelial dysfunction induced by glycosylated bovine serum albumin (GBSA) in rats and effects of aminoguanidine on them. METHODS Endothelium-dependent relaxation of aortic rings from Sprague-Dawley rats after treatment with GBSA in vitro and in vivo was tested. Serum concentrations of ADMA, nitrite/nitrate, and activities of aortic DDAH, nitric oxide synthase (NOS) and superoxide dismutase were measured in GBSA-treated rats. Moreover, serum contents of glycosylated serum protein, and malondialdehyde were also assayed. RESULTS Endothelium-dependent relaxation was significantly impaired either by incubation of aortic rings with GBSA (1.70mmol/l) in vitro for 60min or by injection of GBSA (35mg/kg/d, i.v.) to normal rats for 4 weeks, and serum ADMA levels were remarkably elevated in GBSA-treated rats, which was accompanied by decreases of nitrite/nitrate concentrations, NOS and DDAH activities. Furthermore, elevated glycosylated serum protein, malondialdehyde levels, and reduced superoxide dismutase activity were also observed in GBSA-treated rats. Treatment with aminoguanidine not only improved impairment of endothelium-dependent relaxation but also prevented elevation of endogenous ADMA, which were concomitant with increases of nitrite/nitrate concentration, NOS and DDAH activity. Serum levels of glycosylated serum protein, malondialdehyde, and vascular superoxide dismutase activity were also normalized after aminoguanidine treatment. CONCLUSIONS Decreased DDAH activity and elevated endogenous ADMA is implicated in endothelial dysfunction of rats exposed to GBSA. Aminoguanidine can protect endothelium of rat aorta against injury induced by GBSA both in vitro and in vivo.