Asymmetrical Dimethylarginine Inhibits Shear Stress–Induced Nitric Oxide Release and Dilation and Elicits Superoxide-Mediated Increase in Arteriolar Tone

Abstract

Abstract-L-arginine is the substrate used by NO synthase to produce the vasodilator NO. However, in several human diseases, such as hyperhomocysteinemia, diabetes mellitus, and hypertension, there is an increase in serum levels of methylated L-arginines, such as asymmetrical dimethylarginine (ADMA), which cannot be used by NO synthase to produce NO. Yet, the functional consequence of increased levels of ADMA on the vasomotor function of resistance vessels has not been delineated. We hypothesized that elevated levels of exogenous ADMA inhibit NO mediation of flow/shear stress-dependent dilation of isolated arterioles. In the presence of indomethacin, isolated arterioles from rat gracilis muscle (Ϸ165 m at 80 mm Hg) were incubated with ADMA (10 Ϫ4 mol/L), which eliminated the dilations to increases in intraluminal flow (control: from 164Ϯ5.4 to 188Ϯ3.8 m versus ADMA: from 171Ϯ6.1 to 173Ϯ6.3 m at 20 L/min). ADMA did not affect dilations to nifedipine (10 Ϫ6 mol/L; control: 63.4Ϯ2%, ADMA: 65.8Ϯ3%) or 8-bromo cGMP (10 Ϫ4 mol/L; control: 51.2Ϯ2.1%, ADMA: 49.3Ϯ3.4%). In addition, ADMA elicited significant constriction of arterioles (from 173Ϯ17 m to 138Ϯ16 m at 80 mm Hg), which was prevented by previous incubation of arterioles with polyethylene-glycol (PEG) superoxide dismutase (SOD; 120 U/mL, control: 155Ϯ11 m versus ADMA: 150Ϯ14 m). Correspondingly, ADMA increased PEG-SOD reversible manner the production of vascular superoxide assessed by lucigenin-enhanced chemiluminescence and ethidium bromide fluorescence. Thus, increased levels of ADMA in various diseases could inhibit the regulation of arteriolar resistance by shear stress-induced release of NO and elicit superoxide-mediated increase in basal tone, both of which favor the development of hypertension. Key Words: ADMA Ⅲ flow-dependent dilation Ⅲ superoxide Ⅲ nitric oxide Ⅲ arteriolar tone T he production of the important signaling molecule NO is regulated and modulated by several physiological and pathological mechanisms. 1 It has been well established that L-arginine is the physiological substrate of NO synthase (NOS) to produce the vasodilator substance NO. 1 Supporting this conclusion, we have found previously that exogenous L-arginine increases the synthesis of NO and augments NO-mediated arteriolar vasodilation. 2 In 1992, Vallance et al 3 described that Ͼ10 mg of methylated L-arginines, such as asymmetrical dimethylarginine (ADMA), is excreted in urine in 24 hours indicating that these forms of L-arginine exist in vivo. Further studies revealed that in several human diseases, such as hyperhomocysteinemia, 4 diabetes mellitus, 5 hypertension, 6 coronary artery disease, 7 peripheral arterial occlusive disease, 8 and pulmonary hypertension, 9 and as result of smoking, 10 there is an increase in the serum level of methylated L-arginines, such as ADMA. The pathological importance of these findings is underscored by the biochemical mechanism showing that NOS cannot use ADMA to produce NO. 3 Interestingly, a significant positive correlation between age and ADMA le...

Salt Sensitivity in Blacks

“…Asymmetrical dimethylarginine (ADMA) is a major endogenous inhibitor of vasodilatation by inhibiting the endothelial synthesis of NO, which relaxes vascular smooth muscle. 7,8 In isolated rat arterioles, 9 and likely in small resistance arteries, 10 ADMA inhibits vasodilatation otherwise induced by increased flow/shear stress. Intravenously administered ADMA acutely increases systemic vascular resistance (SVR) and BP in humans and animals.…”

Review article: Asymmetric dimethylarginine as a mediator of vascular dysfunction and a marker of cardiovascular disease and mortality: an intriguing interaction with diabetes mellitus

“…Superoxide production was increased in human umbilical vein endothelial cells (HUVEC) and isolated arterioles from rat gracilis muscle after incubation with ADMA. [119][120] Moreover, elevated ADMA levels as a result of decreased DDAH activity in lipopolysaccharide (LPS)-treated mice were accompanied by increased production of superoxide which was blocked by treatment with L-NMMA, indicating an uncoupled NOS as the source of superoxide. 121 Evidence from a clinical study in which elevated ADMA levels were correlated with increased NOS-derived production of reactive oxygen species (ROS) in the vasculature of patients undergoing coronary bypass surgery supports this idea; 119 however, definite proof for a causal relationship in diabetes mellitus is still lacking.…”

Leptin-induced endothelial dysfunction in obesity

“…It has been suggested that increased free fatty acid concentration in obesity may be related to increased levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase (2). L-Arginine competes with ADMA for the eNOS enzyme (29). Therefore, an increase in NO production after supplementation with L-arginine to obese mice may be due in part to an increase of the arginineto-ADMA ratio in endothelial cells and the reduction of the ADMA inhibitory effect.…”