Asymmetric dimethylarginine (ADMA) elicits superoxide production in isolated arterioles via NAD(P)H oxidase

Abstract

ADMA is thought to be an endogenous inhibitor of nitric oxide (NO) synthase, thus may decrease NO synthesis. However, our previous investigation showed that in isolated microvessels ADMA induced superoxide production, but the mechanisms remain unknown. We hypothesized that elevated level of exogenous ADMA, by activating vascular oxidases, elicits increased superoxide production, interfering with NO mediation of flow‐induced dilation. In the presence of indomethacin, isolated arterioles from rat gracilis muscle (∼ 150 m at 80 Hgmm) were incubated with ADMA (10−4 mol/L), which eliminated the dilations to increases in intraluminal flow (from max.: 28±1% to 7±2 %, p<0.05). However, in the presence of ADMA, the NAD(P)H oxidase inhibitor apocynin restored flow‐induced dilations, whereas the xanthine oxidase inhibitor oxypurinol was without effect. Superoxide dismutase plus catalase also restored dilations to flow, which were then abolished by inhibition of NOS. In addition, ADMA elicited significant constriction (from 162±4 μm to 143±4 μm at 80 Hgmm), which was prevented by prior incubation of arterioles with apocynin. Thus, we suggest that ADMA activates NAD(P)H oxidase, and the produced superoxide reduces the bioavailability of NO resulting in diminished flow‐induced dilation, a mechanism, which may contribute to the development of cardiovascular diseases associated with elevated levels of ADMA. (Grants: Hungarian Sci. Res. Funds/OTKA T48376, T67984; Health Sci. Council/ETT 364/2006 and Am. Heart Assoc. NE Aff. 0555897T, USA).