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1Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor; 2College of Literature, Science, and The Arts and 3College of Engineering, University of Michigan, Ann Arbor, Michigan; 4Department of Nutritional Science, Faculty of Health and Welfare Science, Okayama Prefectural University, Kuboki, Soja, Okayama, Japan; 5Macromolecular Structure Facility, Michigan State University, East Lansing; 6Department of Surgery (Vascular), University of Michigan Medical School, Ann Arbor; and 7William Beaumont Hospital, Department of Surgery, Royal Oak, Michigan
Submitted 16 January 2006 ; accepted in final form 11 April 2006
The endogenous nitric oxide (NO) synthase (NOS) inhibitor asymmetrical dimethylarginine (ADMA) is elevated in many patients and may contribute to the initiation and progression of their disease. While some mechanistic pathways have been identified, tissue-specific contributions to ADMA control remain unclear. We sought to determine if whole blood (WB) could participate in ADMA control ex vivo. Anesthetized male Sprague-Dawley rats underwent exsanguinations, and WB preparations were incubated at 37°C for 5 h. ADMA and symmetrical dimethylarginine were analyzed by high-pressure liquid chromatography. Incubation of lysed red blood cell (RBC) supernatant yielded a significant decrease in ADMA that was blocked by 4124W, a synthetic inhibitor of dimethylarginine dimethylaminohydrolase, the only reported enzyme to hydrolyze ADMA. Hydrolysis of ADMA was diminished by addition of physiologically relevant concentrations of zinc (i.e., 20 µM). Conversely, when rat WB or WB supernatant was incubated at 37°C, it liberated quantities of free ADMA (1–2 µM) that in vivo would likely have pathological consequences. Addition of arginine methyltransferase inhibitors to these incubations did not reduce ADMA release, indicating no dominant role for active protein methylation during these incubations. This ADMA liberation was significantly reduced by addition of protease inhibitors, indicating a dependence on peptide bond hydrolysis. Total ADMA (protein incorporated plus free) was determined by acid hydrolysis and found to be 43.18 ± 4.79 µM in WB with 
95% of this in RBCs. These ex vivo data demonstrate the potential of blood to control the NO-NOS system by modulating free ADMA.
nitric oxide; protein arginine methyltransferase; symmetrical dimethylarginine; protease
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