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1 Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States
2 College of Literature, Science and Arts, University of Michigan, Ann Arbor, Michigan, United States
3 College of Engineering, University of Michigan, Ann Arbor, Michigan, United States
4 Nutritional Science, Okayama Prefectural University, Okayama, Soja, Japan
5 Macromolecular Structure Facility, Michigan State University, East Lansing, Michigan, United States
6 Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States; Surgery, University of Michigan, Ann Arbor, Michigan, United States; Surgery, William Beaumont Hospital, Royal Oak, Michigan, United States
* To whom correspondence should be addressed. E-mail: lgdalecy{at}umich.edu.
The endogenous nitric oxide 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 hours. ADMA and symmetrical dimethylarginine (SDMA) were analyzed by high-pressure liquid chromatography (HPLC). 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 (DDAH), 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 to 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 approximately 95% of this in RBCs. These ex vivo data demonstrate the potential of blood to control the NO-NOS system by modulating free ADMA.
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