ADMA Impairs Nitric Oxide-Mediated Arteriolar Function Due to Increased Superoxide Production by Angiotensin II-NAD(P)H Oxidase Pathway

Asymmetrical dimethylarginine (ADMA) is thought to be an endogenous regulator of arteriolar tone by inhibiting NO synthase. However, our previous studies showed that, in isolated arterioles, ADMA induced superoxide production as well. Thus, the mechanisms by which ADMA affects arteriolar tone remain obscure. We hypothesized that ADMA, by activating NAD(P)H oxidase, increases superoxide production, interfering with NO mediation of flow-induced dilation. In the presence of indomethacin, isolated arterioles from rat gracilis muscle (approximate to 160 mu m at 80 mm Hg) were incubated with ADMA (10(-4) mol/L), which elicited significant constriction (from 162 +/- 4 to 143 +/- 4 mu m) and eliminated the dilations to increases in intraluminal flow (from a maximum 31 +/- 2% to 3 +/- 1%; P<0.05). In the presence of ADMA, superoxide dismutase plus catalase restored dilations to flow (from a maximum 3 +/- 1% to 28 +/- 2%). Endothelial denudation or incubation of arterioles with the NAD(P) H oxidase inhibitor apocynin or the angiotensin-converting enzyme inhibitor quinapril inhibited ADMA-induced constriction. In addition, apocynin, quinapril, or the angiotensin type 1 receptor blocker losartan restored flow-induced dilations reduced by ADMA. Furthermore, inhibition of NO synthase abolished the "superoxide dismutase/catalase-restored" flow-induced dilation in the presence of ADMA. ADMA-induced increased production of superoxide, assessed by dihydroethidium fluorescence, was inhibited by apocynin, quinapril, or losartan. We suggest that ADMA activates the local renin-angiotensin system, and the angiotensin II released activates NAD(P) H oxidase; superoxide produced interferes with the bioavailability of NO, resulting in diminished flow-induced dilation, a mechanism that may contribute to the development of arteriolar dysfunction and increased tone associated with elevated ADMA levels. (Hypertension. 2008;52:960-966.)