Role of dimethylarginine dimethylaminohydrolase activity in regulation of tissue and plasma concentrations of asymmetric dimethylarginine in an animal model of prolonged critical illness.

High plasma concentrations of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, are associated with adverse outcome in critically ill patients. Asymmetric dimethylarginine is released within cells during proteolysis of methylated proteins and is either degraded by dimethylarginine dimethylaminohydrolase (DDAH) or exported to the circulation via cationic amino acid transporters. We aimed to establish the role of DDAH activity in the regulation of tissue and plasma concentrations of ADMA. In 33 critically ill rabbits, we measured DDAH activity in kidney, liver, heart, and skeletal muscle and related these values to concentrations of ADMA in these tissues and in the circulation. Both DDAH activity and ADMA concentration were highest in kidney and lowest in skeletal muscle, with intermediate values for liver and heart. Whereas ADMA content was significantly correlated between tissues (r = 0.40-0.78), DDAH activity was not. Significant inverse associations between DDAH activity and ADMA content were only observed in heart and liver. Plasma ADMA was significantly associated with ADMA in the liver (r = 0.41), but not in the other tissues. In a multivariable regression model, DDAH activities in muscle, kidney, and liver, but not in heart, were negatively associated with plasma ADMA concentration, together explaining approximately 50% of its variation. In critical illness, plasma ADMA poorly reflects intracellular ADMA. Furthermore, tissue DDAH activity is a stronger predictor of plasma ADMA than of intracellular ADMA, indicating that, compared with DDAH activity, generation of ADMA and cationic amino acid transporter-mediated exchange may be more important regulators of intracellular ADMA.

Davids M ，Richir MC ，Visser M ，Ellger B ，van den Berghe G ，van Leeuwen PA ，Teerlink T ... -  《-》

Glycemic control modulates arginine and asymmetrical-dimethylarginine levels during critical illness by preserving dimethylarginine-dimethylaminohydrolase activity.

Ellger B ，Richir MC ，van Leeuwen PA ，Debaveye Y ，Langouche L ，Vanhorebeek I ，Teerlink T ，Van den Berghe G ... -  《-》

Molecular mechanism for elevation of asymmetric dimethylarginine and its role for hypertension in chronic kidney disease.

Matsuguma K ，Ueda S ，Yamagishi S ，Matsumoto Y ，Kaneyuki U ，Shibata R ，Fujimura T ，Matsuoka H ，Kimoto M ，Kato S ，Imaizumi T ，Okuda S ... -  《JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY》

Liver plays a central role in asymmetric dimethylarginine-mediated organ injury.

Ferrigno A ，Di Pasqua LG ，Berardo C ，Richelmi P ，Vairetti M ... -  《-》

Human recombinant erythropoietin augments serum asymmetric dimethylarginine concentrations but does not compromise nitric oxide generation in mice.

Desai A ，Zhao Y ，Warren JS 《-》