Asymmetric Dimethylarginine Reduces Nitric Oxide Donor-Mediated Dilation of Arterioles by Activating the Vascular Renin-Angiotensin System and Reactive Oxygen Species

Abstract

Introduction: We tested the hypothesis that asymmetric dimethylarginine (ADMA) interferes with other mechanisms in addition to inhibition of nitric oxide synthase (NOS). Thus, in skeletal muscle arterioles, in the presence of ADMA, we investigated the dilator effect of an NO donor and increases in flow and aimed to elucidate the underlying mechanisms, including the role of oxidative stress, which is known to reduce the bioavailability of NO. Methods and Results: In isolated rat gracilis skeletal muscle arterioles (∼160 µm at 80 mm Hg), ADMA (similarly to pyrogallol) reduced dilations to sodium nitroprusside (SNP), which was significantly prevented by the presence of superoxide dismutase (SOD) and catalase (CAT): SNP 10^–8M; control: 43.2 ± 3%, ADMA: 4.9 ± 1%, ADMA + SOD/CAT: 30.2 ± 9% (p < 0.05). Also, ADMA reduced basal diameter and flow-induced dilations, which were not restored by L-arginine, but prevented by SOD/CAT and by inhibition of NAD(P)H oxidase (but not xanthine oxidase) and by an angiotensin-converting enzyme inhibitor or an angiotensin type 1 receptor blocker (ARB). ADMA increased the production of reactive oxygen species detected by lucigenin-enhanced chemiluminescence, which was significantly inhibited by SNP or ARB. Conclusion: We suggest that by activating the vascular renin-angiotensin-NAD(P)H oxidase pathway, ADMA elicits oxidative stress, which interferes with the bioavailability of NO and consequently reduces NO-mediated dilations.

Angiotensin-converting Enzyme Inhibition Improves the Effectiveness of Transcutaneous Carbon Dioxide Treatment

“…Only a few studies have investigated the relation between ADMA and ACEIs. Veresh et al showed that ADMA activates the renin-angiotensin-aldosterone system (RAAS), which leads to vasoconstriction and increased oxidative stress (19). Moreover, Ito et al found reduced ADMA levels among hypertensive patients after being treated with ACEIs (20).…”

Short-Term Esmolol Improves Coronary Artery Remodeling in Spontaneously Hypertensive Rats through Increased Nitric Oxide Bioavailability and Superoxide Dismutase Activity

“…On the other hand, the reduced asymmetric dimethylarginine (ADMA) concentration in SHR treated with nebivolol, a third-generation β -blocker, has been associated with endothelial NO synthase (eNOS) agonist properties and increased bioavailability of NO [32]. In addition, ADMA has been shown to increase ROS level in arterioles in vitro by activation of the vascular renin-angiotensin system [35]. In our study, we showed that SOSA, which includes low-molecular weight antioxidant (scavengers) and superoxide dismutase, increased as a result of treatment with esmolol.…”

Elevated Levels of Asymmetric Dimethylarginine (ADMA) in the Pericardial Fluid of Cardiac Patients Correlate with Cardiac Hypertrophy

“…Previous studies established that asymmetric dimethylarginine (ADMA), being a false substrate limits the activity of endothelial nitric oxide (NO) synthase thus production of NO. In addition, our previous studies and others revealed that elevated levels of ADMA elicits the release of reactive oxygen species (ROS) by activation of the renin angiotensin system (RAS) leading to vascular dysfunction [ 18 – 20 ]. ADMA can accumulate due to enhanced production or reduced catabolism and excretion [ 21 ].…”

“…Furthermore, ADMA has been identified as a risk factor for endothelial dysfunction and was shown to accelerating the progression of several cardiovascular diseases [ 23 ]. Thus, ADMA may serve as a biomarker indicating reduced bioavailability of NO [ 18 – 20 ]. Previous studies have shown that ADMA is partly excreted by the kidneys, and suggested that low urinary ADMA level predicts impaired cardiac function [ 24 ].…”