Diabetes mellitus increases plasma levels of the endogenous nitric oxide synthase inhibitor

Plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), are elevated in hypercholesterolemic as well as atherosclerotic humans. However, it is unclear as to whether plasma ADMA is also elevated in diabetes mellitus (DM). Furthermore, the mechanism of ADMA elevation is not understood. Accordingly, the purpose of this study is to examine whether plasma ADMA is elevated in a rat model of DM, and whether the activity of the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which is known to degrade ADMA, is altered. Male Sprague-Dawley rats were assigned to one of the following four groups: normal chow (control), high-fat diet (high-fat), high-fat diet and 35 mg/kg streptozotocin (STZ) injection (high-fat + STZ 35) and high-fat diet and 40 mg/kg STZ injection (high-fat + STZ 40). After 4 weeks, plasma was drawn for biochemical measurements, and abdominal aortae were harvested. Plasma ADMA was measured by high-performance liquid chromatography (HPLC). The activity of DDAH was evaluated by measurement of citrulline formation from ADMA. Hyperglycemia was induced in high-fat + STZ 35 and 40. Plasma ADMA levels were significantly (p<0.05) elevated in high-fat + STZ 35 and 40, when compared with control. There was a significant (p<0.05) positive correlation between plasma glucose and ADMA. In high-fat + STZ 35 and 40, DDAH activity was significantly (p<0.05) decreased, although the protein expression was unchanged by Western analysis. These results suggest that hyperglycemia may increase plasma ADMA by reducing the activity of DDAH in rats. This is the first description of a novel mechanism for suppression of the NOS pathway in DM.