The Role of Asymmetric Dimethylarginine and Arginine in the Failing Heart and its Vasculature

Marlieke Visser; Walter J. Paulus; Mechteld A.R. Vermeulen; Milan C. Richir; Mariska Davids; Willem Wisselink; Bas A.J.M. de Mol; Paul A.M. van Leeuwen


Eur J Heart Fail. 2010;12(12):1274-1281. 

In This Article

Asymmetric Dimethylarginine Metabolism

There are two compounds that can inhibit NOS, N-monomethyL-arginine (NMMA) and ADMA, which both reduce NO synthesis by competing with arginine for NOS binding.[2]N-monomethy L-arginine concentrations in plasma, however, are much lower compared with plasma ADMA concentrations. N-monomethy L-arginine is formed when protein-incorporated arginine is methylated by the enzymes protein arginine methyltransferases (PRMT)-1 or PRMT-2 (Figure 1). Protein arginine methyltransferases-1 can subsequently methylate NMMA, resulting in the formation of ADMA, whereas PRMT-2 can methylate NMMA into symmetric dimethylarginine (SDMA). After proteolysis, the methylated arginines are released as unbound forms in the cytosol where NMMA and ADMA are able to inhibit NOS. In contrast to ADMA, SDMA is not able to inhibit NOS. All methylated arginines are released from the cell into the circulation, via system y+-carriers of the cationic amino acid transporter (CAT) family, from which they can be taken up by other cells that use the same transporters. Cationic amino acid transporters also facilitate the transport of arginine across the cell membrane. All methylated arginine metabolites are considered to interfere with NO synthesis indirectly, because the methylated arginine analogues compete with arginine for transport via CAT. However, because SDMA lacks NOS inhibitory activity and only small amounts of NMMA are found in the plasma, ADMA is considered to be the major inhibitor of NO availability. Asymmetric dimethylarginine is excreted into the urine for <20%. The major part of the NOS inhibitor is cleared by the enzymes DDAH-1 and DDAH-2 resulting in the formation of citrulline and dimethylamine. Both the expression and the activity of DDAH seem to be regulated by NO through feedback mechanisms.[2]

Figure 1.

Synthesis and metabolism of asymmetric dimethylarginine and arginine. ADC, arginine decarboxylase; ADMA, asymmetric dimethylarginine; AGAT, arginine glycine amidinotransferase; ASL, argininosuccinate lyase; ASS, argininosuccinate synthase; ATS, arginyl-tRNA synthetase; CAT, cationic amino acid transporter; DDAH, dimethylarginine dimethylaminohydrolase; NMMA, N-monomethyl-arginine; NO, nitric oxide; NOS, nitric oxide synthase; OAT, ornithine aminotransferase; ODC, ornithine decarboxylase; PRMT, protein arginine methyltransferase; SDMA, symmetric dimethylarginine.


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