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Liquid Chromatography–Tandem Mass Spectrometry Method for the Analysis of Asymmetric Dimethylarginine in Human Plasma

¹ Institute of Experimental and Clinical Pharmacology, University Hospital Hamburg-Eppendorf, and² Institute of Pharmacy, University of Hamburg, Hamburg, Germany;

^aaddress correspondence to this author at: Institute of Experimental and Clinical Pharmacology, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany; fax 49-40-428039757, e-mail schwedhelm@uke.uni-hamburg.de

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Nitric oxide (NO) is essential in numerous physiologic processes and may be involved in related pathologic processes. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of isoforms of NO synthase in humans (1). ADMA originates from protein arginine methylation by protein arginine methyltransferases after protein hydrolysis (2). Enzymatic hydrolysis by dimethylarginine dimethylaminohydrolases to dimethylamine and citrulline is the major pathway for elimination of ADMA (3). Circulating ADMA is altered in patients with cardiovascular and neurologic diseases, erectile dysfunction, and many other disorders (4)(5)(6), and increased circulating ADMA independently predicts future cardiovascular events and mortality (7)(8). Short-time infusion of ADMA affects hemodynamics and cardiac function in humans (3)(9).

Analytical methods for the measurement of ADMA include HPLC, capillary electrophoresis, ELISA, and mass spectrometry (MS). The commonly used HPLC methods with fluorescence detection (10) measure o-phthaldialdehyde derivatives of ADMA. These derivatives are not stable and must be analyzed on-line. Moreover, ADMA must be separated by chromatographic means from its biologically inactive isomer, symmetric dimethylamine (SDMA). Thus, these HPLC methods have long analysis times of up to 45 min. Alternatively, ADMA and SDMA can be analyzed by gas chromatography–mass spectrometry (11)(12), which shows different fragmentation patterns for the respective ions. These methods include several extraction and derivatization steps and require considerable analysis times. Recently, Kirchherr and Kühn-Velten (13) developed a mass spectrometric method that omits derivatization procedures; however, chromatographic separation of ADMA from SDMA is still required for this method. Here we report a simple and rapid liquid chromatography–tandem MS (LC-MS/MS)-based method with 1 derivatization step and sample pretreatment consisting of protein precipitation. This is the first LC-MS–based method that separates methylated arginine derivatives by . . . [Full Text of this Article]

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