The therapeutic potential of targeting endogenous inhibitors of nitric oxide synthesis

Abstract

Asymmetric dimethylarginine (ADMA)--a naturally occurring amino acid that is a product of protein breakdown--is released into the cytoplasm following the post-translational methylation of arginine residues within proteins and the subsequent proteolysis of these arginine-methylated proteins. ADMA inhibits all three isoforms of nitric oxide synthase and therefore has the potential to produce diverse biological effects, particularly in the cardiovascular system. In addition to its renal clearance, endogenously produced ADMA is metabolized to L-citrulline and dimethylamine by the dimethylarginine dimethylaminohydrolase (DDAH) enzymes. Pharmacological modification of DDAH has therefore been proposed as a mechanism for manipulating endogenous ADMA concentrations and regulating the production of nitric oxide in situations where alterations in nitric oxide signalling have been shown to contribute to pathophysiology. This review describes the biology of ADMA and the potential therapeutic utility of manipulating DDAH activity.

Dimethylarginine Dimethylaminohydrolase 2 Gene Polymorphism and Its Association with Asymmetrical Dimethyl Arginine in Hemodialyzed Patients

“…Based on tissue messenger ribonucleic acid (mRNA) levels, it has been suggested that the expression pattern of DDAH 1 overlaps more closely with the expression pattern of neuronal NOS, whereas DDAH 2 expression has greater similarities with endothelial NOS expression [26,27]. However, it is still unclear which DDAH isoform represents the principal methylarginine-metabolizing enzyme.…”

“…The finding that the gene for DDAH is evolutionarily well conserved suggests that the enzyme confers an important survival advantage [10]. And it can be postulated that genetic variations in DDAH that affect the ability of the enzyme to metabolize ADMA might increase cardiovascular risk in patients with renal failure and might also determine, in part, the rate of disease progression [26].…”

“…Among the mechanisms for impaired NO synthesis is the accumulation of the endogenous NOS inhibitor asymmetric ADMA [7]. ADMA inhibits all three isoforms of nitric oxide synthase and therefore has the potential to produce diverse biological effects, particularly in the cardiovascular system [26,30]. Some studies of human subjects with essential HT report elevated plasma levels of ADMA [31,32].…”

<i>In vitro</i> anti-inflammatory and free radical scavenging activities of crude saponins extracted from <i>Albuca bracteata</i>Jacq. Bulb.

“…Because nitric oxide is essential for cellular signalling, it is involved in many physiological and pathological processes including inflammation (Leiper & Nandi, 2011), protection of liver ischemic damage (Yang et al, 2011), carcinogenesis and rheumatoid arthritis (Melchers et al, 2006). Therefore, inhibition of nitric oxide may suggest the mechanism of saponin against inflammation.…”

Hypoxia causes increased monocyte nitric oxide synthesis which is mediated by changes in dimethylarginine dimethylaminohydrolase 2 expression in animal and human models of normobaric hypoxia

“…In mammals there are three methylarginine species, ADMA, symmetrical dimethyarginine (SDMA) and L-NMMA. ADMA and L-NMMA competitively inhibit arginine binding to NOS and reduce NO production 20,21 . SDMA does not inhibit the activity of the NOS enzymes 22 .…”