Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P50583 (asymmetrical)
12,197 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypertension is a major healthcare problem afflicting nearly 50 million individuals in the United States. Despite its strong causal association with cardiovascular disease complications including myocardial infarction, heart failure, and stroke, the majority of patients with hypertension do not achieve optimal blood pressure control. The prevalence of hypertension is expected to increase with the aging population, growing obesity epidemic, and rising incidence of metabolic syndrome. Endothelial dysfunction and reduced nitric oxide (NO) bioactivity represent prominent pathophysiological abnormalities associated with hypertensive cardiovascular disease. Individuals with hypertension exhibit blunted epicardial and resistance vascular dilation to endothelium-derived nitric oxide (EDNO) agonists in the peripheral and coronary circulation that likely contributes to mechanisms of altered vascular tone in hypertension. The amino acid L-arginine serves as the principal substrate for vascular NO production. Numerous studies, though not uniformly, demonstrate a beneficial effect of acute and chronic L-arginine supplementation on EDNO production and endothelial function, and L-arginine has been shown to reduce systemic blood pressure in some forms of experimental hypertension. This brief review discusses the potential role of L-arginine in hypertension, and reviews possible mechanisms of L-arginine action including modulation of EDNO production, alteration of asymmetrical dimethylarginine (ADMA):L-arginine balance, and possible improvement of insulin sensitivity. In view of the rising prevalence of hypertension, randomized human clinical studies investigating the potential therapeutic role of L-arginine may be warranted.
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PMID:L-arginine and hypertension. 1546 90

The endogenous nitric oxide-synthase inhibitor asymmetrical dimethyl-L-arginine (ADMA) is elevated in patients with increased risk for arteriosclerosis. Obesity is a risk factor for cardiovascular disease. We measured plasma ADMA concentrations in morbidly obese women before and after weight loss following gastroplastic surgery. ADMA and symmetrical dimethyl-L-arginine concentrations were analyzed by HPLC from 34 female patients (age 41 +/- 7 yr) with a body mass index (BMI) of 49 +/- 1 kg/m2 before and 14 months after vertical ring gastroplasty. Age-matched healthy women (BMI < 25 kg/m2; n = 24) were studied as controls. After gastroplastic surgery, BMI decreased to 34 +/- 1 kg/m2 in obese women (P < 0.00001), and ADMA concentrations were reduced from 1.06 +/- 0.06 micromol/liter at baseline to 0.81 +/- 0.04 micromol/liter after weight loss (P < 0.00001). Symmetrical dimethyl-L-arginine plasma levels were not affected. ADMA correlated with high-sensitivity C-reactive protein at baseline (r = 0.42; P < 0.05) and after weight loss (r = 0.56; P < 0.005). No association with blood pressure or plasma lipids could be observed. ADMA concentrations were lower in controls (0.68 +/- 0.04 micromol/liter; P < 0.05) compared with obese patients before or after weight reduction. The decrease of highly elevated ADMA concentrations in morbidly obese patients is paralleled by improvement of parameters associated with the metabolic syndrome after weight loss.
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PMID:Weight loss reduces circulating asymmetrical dimethylarginine concentrations in morbidly obese women. 1557 89

Vascular dysfunction in chronic renal failure may be linked to reduced nitric oxide (NO) bioactivity and increased circulating concentrations of the endogenous NO synthase inhibitor asymmetrical dimethyl L-arginine (ADMA). The association between ADMA and basal endothelial NO release and endothelium-dependent vasodilation in resistance arteries of chronic renal failure patients is unknown. Forearm blood flow responses to the endothelium-dependent vasodilator acetylcholine, the endothelium-independent vasodilator nitroglycerine, and the endothelium-dependent vasoconstrictor N(G)-monomethyl-L-arginine (L-NMMA) were assessed in 37 peritoneal dialysis patients. L-arginine and ADMA plasma concentrations were measured by HPLC. ADMA (mean +/- SEM: 0.68 +/- 0.02 micromol/L) was associated with basal forearm blood flow (r = -0.33; P < 0.05) and L-NMMA induced vasoconstriction (r = -0.55; P < 0.0005), but not with dilator effects of acetylcholine or nitroglycerine. L-arginine (68 +/- 3 micromol/L) tended to correlate with acetylcholine-induced vasodilation (r = 0.32; P = 0.05) but was not associated with other parameters. ADMA is related to basal but not to acetylcholine-stimulated NO bioactivity in patients on peritoneal dialysis. Impaired endothelium-dependent vasodilation found in chronic renal failure is not explained by elevated circulating NO synthase inhibitors in renal failure.
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PMID:Asymmetrical dimethylarginine plasma concentrations are related to basal nitric oxide release but not endothelium-dependent vasodilation of resistance arteries in peritoneal dialysis patients. 1585 20

The present study was undertaken to explore involvement of nitric oxide (NO) in the experimental models of Parkinson's disease. Neurodegeneration was induced by unilateral injections of 6-hydroxydopamine (6-OHDA) or lipopolysaccharide (LPS) in the right striatum. Lesions were functionally evaluated by amphetamine-induced asymmetrical behaviour and by decrease in the tyrosine hydroxylase (TH) immunostaining. An induction in the expression of iNOS and augmentation in nitrite content was observed in both the models. The extent of increase in iNOS expression was, however, different but the elevation in the nitrite content was comparable in both the models. The increase in iNOS expression inversely correlated with the tyrosine hydroxylase (TH) immunolabeling. Animals pretreated with a NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), exhibited complete protection against amphetamine induced rotations in both the models. Thus, augmented NO availability subsequent to iNOS induction seems to play an important role in the initial phase of neurodegeneration.
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PMID:Involvement of nitric oxide in neurodegeneration: a study on the experimental models of Parkinson's disease. 1594 31

We examined whether endothelial function of the renal microcirculation was impaired in a model of chronic renal failure (CRF), and further assessed the role of asymmetrical dimethylarginine (ADMA) and its degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH), in mediating the deranged nitric oxide (NO) synthesis in CRF. CRF was established in male mongrel dogs by subtotal nephrectomy, and the animals were used in experiments after a period of 4 weeks. The endothelial function of the renal afferent and efferent arterioles was evaluated according to the response to acetylcholine, using an intravital needle-lens charge-coupled device camera. Intrarenal arterial infusion of acetylcholine (0.01 microg/kg/min) elicited 22+/-2% and 20+/-2% dilation of the afferent and efferent arterioles in normal dogs. In dogs with CRF, this vasodilation was attenuated (afferent, 12+/-2%; efferent, 11+/-1%), and the attenuation paralleled the diminished increments in urinary nitrite+nitrate excretion. In the animals with CRF, plasma concentrations of homocysteine (12.2+/-0.7 vs. 6.8+/-0.4 micromol/l) and ADMA were elevated (2.60+/-0.13 vs. 1.50+/-0.08 micromol/l). The inhibition of S-adenosylmethionine-dependent protein arginine N-methyltransferase by adenosine dialdehyde decreased plasma ADMA levels, and improved the acetylcholine-induced changes in urinary nitrite+nitrate excretion and arteriolar vasodilation. Acute methionine loading impaired the acetylcholine-induced renal arteriolar vasodilation in CRF, but not normal dogs, and the impairment in CRF dogs coincided with the changes in plasma ADMA levels. Real-time polymerase chain reaction revealed downregulation of the mRNA expression of DDAH-II in the dogs with CRF. Collectively, these results provide direct in vivo evidence of endothelial dysfunction in canine CRF kidneys. The endothelial dysfunction was attributed to the inhibition of the NO production by elevated ADMA, which involved the downregulation of DDAH-II. The deranged NO metabolic pathway including ADMA and DDAH is a novel mechanism for the aggravation of renal function.
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PMID:Role of asymmetrical dimethylarginine in renal microvascular endothelial dysfunction in chronic renal failure with hypertension. 1602 46

The nitric oxide generating neurons of the nucleus accumbens exert a powerful influence over striatal function, in addition, these nitrergic inputs are in a position to regulate the dopaminergic and glutamatergic inputs on striatal projection neurons. It was the aim of this study to establish the source of the glutamatergic drive to nitric oxide synthase interneurons of the nucleus accumbens. The nucleus accumbens nitric oxide-generating neurons receive asymmetrical, excitatory, presumably glutamatergic inputs. Possible sources of these inputs could be the limbic and cortical regions known to project to this area. To identify sources of the excitatory inputs to the nitric oxide synthase-containing interneurons of the nucleus accumbens in the rat we first examined the ultrastructural morphology of asymmetrical synaptic specializations contacting nitric oxide synthase-immunohistochemically labeled interneurons in the nucleus accumbens. Neurons were selected from different regions of the nucleus accumbens, drawn using camera lucida, processed for electron microscopic analysis, and the boutons contacting nitric oxide synthase-labeled dendrites were photographed and correlated to the drawings. Using vesicle size as the criterion the source was predicted to be either the prefrontal cortex or the ventral subiculum of the hippocampus. To examine this prediction, a further study used anterograde tracing from both the prefrontal cortex and the ventral subiculum, and nitric oxide synthase immunohistochemistry with correlated light and electron microscopy. Based on appositions by anterogradely labeled fibers, selected nitric oxide synthase-labeled neurons within the nucleus accumbens, were examined with electron microscopic analysis. With this technique we confirmed the prediction that subicular afferent boutons make synaptic contact with nitric oxide synthase interneurons, and demonstrated anatomically that nitric oxide synthase boutons make synaptic contact with the dendritic arbors of nitric oxide synthase interneurons. We suggest that the subicular input may excite the nitric oxide synthase neurons synaptically, while the nitric oxide synthase-nitric oxide synthase interactions underlie a nitric oxide signaling network which propagates hippocampal information, and expands the hippocampus's influence on 'gating' information flow across the nucleus accumbens.
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PMID:Nucleus accumbens nitric oxide immunoreactive interneurons receive nitric oxide and ventral subicular afferents in rats. 1608 59

The endogenous nitric oxide (NO) synthase (NOS) inhibitor asymmetrical dimethylarginine (ADMA) is elevated in many patients and may contribute to the initiation and progression of their disease. While some mechanistic pathways have been identified, tissue-specific contributions to ADMA control remain unclear. We sought to determine if whole blood (WB) could participate in ADMA control ex vivo. Anesthetized male Sprague-Dawley rats underwent exsanguinations, and WB preparations were incubated at 37 degrees C for 5 h. ADMA and symmetrical dimethylarginine were analyzed by high-pressure liquid chromatography. Incubation of lysed red blood cell (RBC) supernatant yielded a significant decrease in ADMA that was blocked by 4124W, a synthetic inhibitor of dimethylarginine dimethylaminohydrolase, the only reported enzyme to hydrolyze ADMA. Hydrolysis of ADMA was diminished by addition of physiologically relevant concentrations of zinc (i.e., 20 microM). Conversely, when rat WB or WB supernatant was incubated at 37 degrees C, it liberated quantities of free ADMA (1-2 microM) that in vivo would likely have pathological consequences. Addition of arginine methyltransferase inhibitors to these incubations did not reduce ADMA release, indicating no dominant role for active protein methylation during these incubations. This ADMA liberation was significantly reduced by addition of protease inhibitors, indicating a dependence on peptide bond hydrolysis. Total ADMA (protein incorporated plus free) was determined by acid hydrolysis and found to be 43.18 +/- 4.79 microM in WB with approximately 95% of this in RBCs. These ex vivo data demonstrate the potential of blood to control the NO-NOS system by modulating free ADMA.
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PMID:Contribution of whole blood to the control of plasma asymmetrical dimethylarginine. 1663 50

Genetics, oxidative stress: superoxide anion (O2*-) and hydrogen peroxide (H2O2), endothelial nitric oxide (eNO), lipid peroxides, anti-oxidants, endothelin, angiotensin converting enzyme (ACE) activity, angiotensinII, transforming growth factor-beta (TGF-beta), insulin, homocysteine, asymmetrical dimethyl arginine, proinflammatory cytokines: interleukin-6 (IL-6), tumor necrosis factor-a (TNF-alpha), C-reactive protein (hs-CRP), and long-chain polyunsaturated fatty acids (LCPUFAs), and activity of NAD(P)H oxidase have a role in human essential hypertension. There is a close interaction between endogenous molecules: eNO, endothelin, cytokines, and nutrients: folic acid, L-arginine, tetrahydrobiopterin (H4B), vitamin B6, vitamin B12, vitamin C, and LCPUFAs. Statins mediate some, if not all, of their actions through LCPUFAs, whereas these fatty acids (especially omega-3 fatty acids) suppress cyclo-oxygenase activity and the synthesis of pro-inflammatory cytokines, and activate parasympathetic nervous system, actions that reduce the risk of major vascular events. Some LCPUFAs form precursors to lipoxins and resolvins that have anti-inflammatory actions. Low-grade systemic inflammation seen in hypertension seems to have its origins in the perinatal period and availability of adequate amounts of LCPUFAs during the critical periods of brain growth prevents the development of hypertension. This indicates that preventive strategies aimed at decreasing the incidence of hypertension and its associated conditions such as atherosclerosis, type 2 diabetes, coronary heart disease (CHD), and cardiac failure in adulthood need to be instituted during the perinatal period if they are to be effective.
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PMID:Hypertension as a low-grade systemic inflammatory condition that has its origins in the perinatal period. 1671 19

In 1992, asymmetrical dimethylarginine (ADMA) was first described as an endogenous inhibitor of the arginine-nitric oxide (NO) pathway. From then, its role in regulating NO production has attracted increasing attention. Nowadays, ADMA is regarded as a novel cardiovascular risk factor. The role of the kidney and the liver in the metabolism of ADMA has been extensively studied and both organs have proven to play a key role in the elimination of ADMA. Although the liver removes ADMA exclusively via degradation by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), the kidney uses both metabolic degradation via DDAH and urinary excretion to eliminate ADMA. Modulating activity and/or expression of DDAH is still under research and may be a potential therapeutic approach to influence ADMA plasma levels. Interestingly, next to its association with cardiovascular disease, ADMA also seems to play a role in other clinical conditions, such as critical illness, hepatic failure, and preeclampsia. To elucidate the clinical significance of ADMA in these conditions, the field of research must be enlarged.
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PMID:The clinical significance of asymmetric dimethylarginine. 1684 5

Nitric oxide (NO) is a potent vasodilator. NO is synthesized by NO synthases (NOS) and NOS are inhibited by asymmetrical dimethylarginine (ADMA). ADMA is metabolized by dimethylarginine dimethylaminohydrolase (DDAH) and excreted in the kidneys. Lower ADMA levels in pregnant women compared to non-pregnant controls suggest that ADMA has a role in vascular dilatation and blood pressure changes. Several studies show an increase in ADMA levels in pregnancies complicated with preeclampsia. Elevated ADMA levels in preeclampsia are seen before clinical symptoms have developed; these findings suggest that ADMA has a role in the pathogenesis of preeclampsia.
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PMID:Endogenous inhibitors of nitric oxide and preeclampsia: a review. 1696 8


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