Regulation of Cytokine-Induced Nitric Oxide Synthesis by Asymmetric Dimethylarginine: Role of Dimethylarginine Dimethylaminohydrolase

In response to vascular insults, inflammatory cytokines stimulate vascular smooth muscle cells (SMCs) to express an inducible isoform of nitric oxide synthase (iNOS). Asymmetric dimethylarginine (ADMA), an endogenous NO synthase inhibitor, is metabolized by dimethylarginine dimethylaminohydrolase (DDAH). To determine whether the ADMA-DDAH system regulates cytokine-induced NO production, cultured rat SMCs were exposed to interleukin-1β (IL-1β). IL-1β (1 to 100 U/mL) dose-dependently stimulated not only iNOS but also DDAH expression and enzyme activity, accompanied by an increase in NO metabolite and by a decrease in ADMA content in culture media. A DDAH inhibitor (4124W, 5 mmol/L) augmented ADMA production ( P P