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

Abstract

Abstract-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 (Ϸ160 m at 80 mm Hg) were incubated with ADMA (10 Ϫ4 mol/L), which elicited significant constriction (from 162Ϯ4 to 143Ϯ4 m) and eliminated the dilations to increases in intraluminal flow (from a maximum 31Ϯ2% to 3Ϯ1%; PϽ0.05). In the presence of ADMA, superoxide dismutase plus catalase restored dilations to flow (from a maximum 3Ϯ1% to 28Ϯ2%). 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. Key Words: ADMA Ⅲ regional blood flow Ⅲ flow-dependent dilation Ⅲ NO Ⅲ oxidative stress Ⅲ ACE A symmetrical dimethylarginine (ADMA) is a naturally occurring L-arginine analogue derived from the proteolysis of proteins containing methylated arginine residues. 1-3 By now, numerous studies suggest that an elevated plasma level of ADMA is associated with endothelial dysfunction and is a risk factor for several human diseases, 4 such as hyperhomocysteinanemia, 5 hypertension, 6 coronary artery disease, 7 peripheral arterial occlusive disease, 8 pulmonary hypertension, 9 and preeclampsia. 10 In our previous studies in isolated arterioles we have found that elevated levels of exogenous ADMA impair the regulation of arteriolar resistance by interfering with the NO mediation of flow/shear stress-induced dilation. 11 Previous studies have found that ADMA inhibits purified NO synthase (NOS) catalytic activity, thus, release of NO and NOmediated vascular responses. 12,13 In addition, however, we have also found that ADMA elicits the release of reactive oxygen species, primarily superoxide, because superoxide dismutase reversed the ADMA-elicited reduction in basal diameter and ethidium bromide...

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

“…Additionally, ADMA increases oxidative stress by uncoupling electron transport between NO synthase and l ‐arginine, which can lead to decreased production and availability of endothelium‐derived NO 13, 14, 15. Furthermore, we have growing evidence for a contribution of ROS to ADMA‐mediated pathological effects, so activation of NOX signaling might be required for ADMA involved in the pathogenesis of cardiovascular and metabolic disease 48, 49, 50. Recently, targeting vascular NOX‐ROS signaling is considered a novel antioxidant strategy for inhibiting oxidative stress–induced pathological events 49, 50.…”

“…Furthermore, we have growing evidence for a contribution of ROS to ADMA‐mediated pathological effects, so activation of NOX signaling might be required for ADMA involved in the pathogenesis of cardiovascular and metabolic disease 48, 49, 50. Recently, targeting vascular NOX‐ROS signaling is considered a novel antioxidant strategy for inhibiting oxidative stress–induced pathological events 49, 50. Statins are known to have an inhibitory effect on upstream signaling of NOX activation, which contributes to the clinical benefis in CAD patients 3, 4, 8.…”

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Left ventricular hypertrophy is associated with inflammation in sodium loaded subtotal nephrectomized rats

“…Furthermore, over-expression of the ADMA degrading enzyme-dimethylarginine dimethylaminohydrolase (DDAH-1 and DDAH-2), which were mainly located in proximal tubules and endothelium (16)-decreased plasma levels of ADMA, prevented hypertension, and blocked the progression of renal dysfunction in the SNx rats (13). As a mechanism of ADMA to induce renal damage, ADMA was shown to be involved in production of IL-6 and chemokines in renal proximal tubular cells (25) through the activation of NAD(P)H oxidase (23).…”