Abstract
Asymmetric dimethylarginine (ADMA, NG, NG-dimethyl-L-arginine) 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 Ca2+/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 (Ki 3.9 μM, IC50 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.
Cited by
17 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献