Asymmetric dimethylarginine (ADMA) in vascular, renal and hepatic disease and the regulatory role of l-arginine on its metabolism

Asymmetric dimethylarginine (ADMA), an inhibitor of nitric oxide synthase (NOS), has been identified as a new and emerging contributor to, or marker for, cardiovascular risk. The ADMA-mediated regulation of nitric oxide (NO) production is determined by the quantitative bioavailability of intracellular and extracellular ADMA. Dimethylarginine dimethylaminohydrolase (DDAH), which is ubiquitously expressed in tissues, especially liver and kidney, converts the majority of the ADMA to citrulline. In this review, we discuss a new regulatory mechanism for the metabolism of ADMA in which l-arginine acts as a competitive inhibitor of DDAH activity. This novel regulatory pathway is consistent with ADMA contributing to cardiovascular risk when levels are increased but not when levels are within the normal range. The pathway then has a physiological role in the regulation of NO production by preventing overproduction of NO. The regulatory role of l-arginine on ADMA may explain the unexpected outcomes in some l-arginine supplementation studies. This paper also reviews associations between the metabolism of ADMA and insulin resistance, smoking and homocysteine which are all associated with an increased risk of vascular disease.