Does the Inhibitory Action of Asymmetric Dimethylarginine (ADMA) on the Endothelial Nitric Oxide Synthase Activity Explain Its Importance in the Cardiovascular System? The ADMA Paradox

Abstract

is endogenously produced by asymmetric dimethylation of the guanidine group of L-arginine residues. ADMA is generally considered a powerful cardiovascular risk factor, an Übermarker, due to its inhibitory action on the activity of nitric oxide synthase (NOS) isoforms. In the endothelium, the constitutively expressed and Ca 2+ /calmodulin-dependent NOS (eNOS) catalyzes the conversion of L-arginine to nitric oxide (NO). NO is one of the most potent endogenous activators of soluble guanylyl cyclase which produces the second messenger cyclic guanosine monophosphate (cGMP). There is experimental evidence from in vitro and in vivo experiments that challenges the extraordinary importance of ADMA as the culprit of NO-related cardiovascular diseases in the human circulation. Most notably, we present data showing that ADMA is a weak competitive inhibitor of recombinant endothelial NOS (eNOS) activity (K i 3.9 μM, IC 50 12 μM). Thus, at its relatively low concentrations of 0.4 to 0.5 μM in the human blood, ADMA is unlikely to inhibit NO synthesis in the endothelium to an extent sufficient enough to cause endothelium dysfunction. Furthermore, ADMA does not "uncouple" eNOS and does not diminish the bioavailability of NO through its reaction with superoxide radical anions produced by "uncoupled" eNOS. Consequently, the particular importance assigned to ADMA in the human circulation is likely to be due to other not yet recognized biological actions beyond inhibition of eNOS activity. This "ADMA paradox" remains to be solved.

An Ethnic Comparison of Arginine Dimethylation and Cardiometabolic Factors in Healthy Black and White Youth: The ASOS and African-PREDICT Studies

“…This action is generally believed to be responsible for their atherogenic and BP-enhancing effects. Given the weak inhibitory potency of ADMA and SDMA towards eNOS activity [11,19,41], we hypothesized that not free ADMA and SDMA, but rather their proteinic precursors may be responsible for the cardiovascular risk, which is associated with high blood circulating and low urinary concentrations of ADMA and SDMA in the general population. In South Africa, hypertension is a major public health problem.…”

Arginine Derivatives in Cerebrovascular Diseases: Mechanisms and Clinical Implications

“…Recently, the importance of ADMA for NO-synthesis in human circulation has been challenged. While ADMA has been shown to effectively inhibit nNOS, the inhibitory potential of ADMA in regard to eNOS seems to be by far weaker [22,136]. This might at least indicate a lack of sufficient knowledge regarding the role of ADMA in patients.…”

“…SDMA concentrations between 2-100µmol/L dose dependently enhanced ROS production in endothelial cells [82]. SDMA has been shown to be a weak nNOS inhibitor, while any data showing efficacy of SDMA for inhibition of other NOS isoforms are missing (for a review see Reference [136]). In monocytes SDMA increased ROS production by modulation of store-operated calcium channels [145].…”

Enhanced Nitric Oxide (NO) and Decreased ADMA Synthesis in Pediatric ADHD and Selective Potentiation of NO Synthesis by Methylphenidate

“…ADMA is a much stronger inhibitor of nNOS activity (IC 50 = 1.5 µM) than of eNOS activity (IC 50 ≈ 12 µM) and has been suggested to be a modulator of nociception [43]. In addition, nNOS is a much more abundant NO-producer than eNOS [44]. Hence, it is reasonable to assume that the higher circulating nitrite concentrations measured in the ADHD children of our study are likely to arise from NO produced from Arg by the catalytic action of nNOS in neuronal cells (Figure 1).…”

“…In addition to being an endogenous inhibitor of NOS activity, ADMA is supposed to exert NO-independent effects [44]. Thus, ADMA was found to be negatively correlated with growth in juveniles and seems to be an important factor in growth control [51,52].…”