ADMA Levels Research Articles

Plasma asymmetric dimethylarginine, l-arginine and left ventricular structure and function in a community-based sample

Objective Increasing evidence indicates that cardiac structure and function are modulated by the nitric oxide (NO) system. Elevated plasma concentrations of asymmetric dimethylarginine (ADMA; a competitive inhibitor of NO synthase) have been reported in patients with end-stage renal disease. It is unclear if circulating ADMA and l-arginine levels are related to cardiac structure and function in the general population. Methods We related plasma ADMA and l-arginine (the amino acid precursor of NO) to echocardiographic left ventricular (LV) mass, left atrial (LA) size and fractional shortening (FS) using multivariable linear regression analyses in 1919 Framingham Offspring Study participants (mean age 57 years, 58% women). Results Overall, neither ADMA or l-arginine, nor their ratio was associated with LV mass, LA size and FS in multivariable models ( p > 0.10 for all). However, we observed effect modification by obesity of the relations of ADMA and LA size ( p for interaction p = 0.04): ADMA was positively related to LA size in obese individuals (adjusted- p = 0.0004 for trend across ADMA quartiles) but not in non-obese people. Conclusion In our large community-based sample, plasma ADMA and l-arginine concentrations were not related to cardiac structure or function. The observation of positive relations of LA size and ADMA in obese individuals warrants confirmation.

Letter by Stuehlinger et al Regarding Article, “Metabolic Profiling of Arginine and Nitric Oxide Pathways Predicts Hemodynamic Abnormalities and Mortality in Patients With Cardiogenic Shock After Acute Myocardial Infarction”

To the Editor: We read with great interest the article by Nicholls et al,1 which revealed alterations in the nitric oxide synthase pathway in patients with cardiogenic shock after myocardial infarction. Their intriguing data indicate that plasma concentrations of asymmetric dimethylarginine (ADMA, the endogenous nitric oxide synthase inhibitor) correlate with hemodynamic measurements in these patients. Moreover, of all clinical and laboratory parameters measured, plasma ADMA levels were the strongest determinant of 30-day mortality.1 We congratulate …

Review: The role of the L-arginine-nitric oxide pathway in preeclampsia

Preeclampsia (PE) is a major cause of maternal and perinatal mortality, especially in developing countries. Its etiology involves multiple factors, but no specific cause has been identified. Evidence suggests that clinical manifestations are caused by endothelial dysfunction. Nitric oxide (NO), which is synthesized from L-arginine in endothelial cells by the endothelial nitric oxide synthase (eNOS), provides a tonic dilator tone and regulates the adhesion of white blood cells and platelet aggregation. Alterations in the L-arginine-NO pathway have been associated with the development of PE. Various studies, reporting decreased, elevated or unchanged levels of nitrite (NO(2)) and nitrate (NO(3)), two end products of NO metabolism, have been published. Our group contributed to those contradictory reports describing cases of PE with both elevated and decreased levels of NO(2) and NO(3). Apparently, diminished levels of NO could be related to deficiencies in the ingestion of dietary calcium associated to low levels of plasma ionic calcium, which is crucial to the eNOS' activity. Also, low levels of NO could be associated with the presence of eNOS polymorphisms or the presence of increased levels of ADMA, the endogenous inhibitor of NO. High levels of NO associated to low levels of cGMP suggest a decreased bioactivity of NO, which is probably related to an increased degradation of NO caused by a high production of superoxide in states of infection and inflammation. The present article analyses and reviews the reported paradoxical roles of the L-arginine-NO pathway in PE and gives a possible explanation for these results.

Possible Indirect Detection of rHuEPO Administration in Human Urine by High-Performance Liquid Chromatography Tandem Mass Spectrometry

The present study is based on the assumption that changes in an ADMA-DDAH-NOS (ADMA-asymmetrical dimethylarginine; DDAH-dimethyl-arginine dimethylaminohydrolase; NOS-nitric oxide synthase) system could be employed as indirect markers for recombinant human erythropoietin (rHuEPO) administration in doping control. We assessed a predictive value of four proposed new markers for rHuEPO abuse. Preliminary data showed that concentrations of ADMA, symmetrical dimethylarginine (SDMA), citrulline and arginine in human urine were increased after administration of a single intravenous erythropoietin injection (2000 U day(-1), Epocrine, St-Petersburg, Russia). The study of variations of ADMA, SDMA, arginine and citrulline levels before and after rHuEPO administration was performed with two healthy male volunteers. Urine samples were collected before rHuEPO administration and urinary concentrations of ADMA and SDMA were determined at 10.0-40 microg mL(-1) and of arginine and citrulline at 0.5-10 microg mL(-1). A single dose injection of rHuEPO caused an increase in ADMA, SDMA, arginine and citrulline concentrations up to 40-270 microg mL(-1), 40-240 microg mL(-1), 10-60 microg mL(-1) and 12-140 microg mL(-1), respectively. These preliminary results indicated that an indirect approach could be used as a pre-screening of urine samples in order to decrease the number of samples with a low probability of rHuEPO abuse and, thus, save costs and human workload.

3, 4, 5, 6‐Tetrahydroxyxanthone protects against hypoxia/ reoxygenation‐induced apoptosis of PC12 cells: role of the DDAH/ADMA pathway

Objective To observe the inhibitory effect of 3,4,5,6-tetrahydroxyxanthone(Xan) on hypoxia/reoxygenation(H/R)-induced apoptosis in PC12(pheochromocytoma) cells and to investigate the relationship between antiapoptotic action of Xan and the DDAH/ADMA pathway.Methods The apoptosis of PC12 was detected by Hoechst33342 staining or flow cytometry(FCM) with Annecin V + Propidium Iodide(PI).The activity of DDAH and level of ADMA were measured by high-performance liquid chromatography(HPLC).The activity of reactive oxygen species(ROS) and caspase-3 were determined by fluorescent ROS detection kit and colorimetric caspase-3 assay kit,respectively.Results Six-hour hypoxia(1% O2) and consequent 24-hour reoxygenation significantly increased the apoptotic death of PC12 cells,concomitantly with increasing intracellular ROS production and caspase-3 activity,which was attenuated by pretreatment with Xan(3,10 or 30 μmol·L-1).The decrease in DDAH activity and the increase in ADMA level were also observed after H/R treatment.Furthermore,incubation with exogenous ADMA could increase caspase3 activity and induce the apoptosis of PC12 cells.Pretreatment with Xan could markedly attenuate the decrease in DDAH activity and the increase in ADMA level.Conclusion Xan protects against H/R-induced apoptosis via inhibiting caspase-3-dependent apoptotic signaling pathway,which may be related to improving the DDAH/ADMA pathway by reduction of oxidative stress.

Study of the correlation between clinical efficiency of impaza and serum ADMA level

Correlation between superlow-dose antibodies to endothelial NO synthase (Impaza) and serum level of ADMA was evaluated in a double blind placebo-controlled study. The reduction of ADMA in patients with erectile dysfunction after impaza treatment was paralleled by improvement of clinical symptoms. No clear-cut correlation between ADMA level and impaza effect was detected.

O013 HYPOGLYCEMIA DETECTION USING A NON-INVASIVE CONTINUOUS BLOOD GLUCOSE MONITORING DEVICE IN INTENSIVE CARE

glycemic control. Blood samples were taken at 1st, 3rd, 6th, 9th and 12th days. We determined the circulating levels of ADMA, SDMA, arginine, interleukin-6, tumornecrosis-factor alpha and c-reactive-protein. At each sampling time the sequential organ failure assessment (SOFA) was scored. All data were analyzed on an intention-to-treat basis, and differences between groups and over time were assessed by means of a linear mixed model for repeated measures. Results: The control and treatment groups did not differ at admission; during the study they received the same energy intake (20.3±16.3 vs 18.9±2.7 kcal/kg/day, p = 0.74). Glycemia (110.4±17.3 vs 163.0±28.9mg/dl, p < 0.001) and insuline supply (74.5±141.1 vs 38.8±44.8 IU/day, p = 0.02) were statistically different. No differences were found in high plasma levels of ADMA (TGC 1.08±0.42 vs control 1.08±0.41mmol/L, p = 0.812) and SDMA (TGC 2.37±1.53 vs control 2.07±1.63mmol/L, p = 0.374) during the ICU stay. The clinical course, as indicated by markers of inflammation, average and maximum SOFA, ICU stay, and ICU and 90-day mortality were not different between groups. Conclusion: TGC, while achieving glucose control, did not reduce ADMA or SDMA in high-risk septic patients, fed with no more than 25 kcal/kg per day to limit ventilatory demand and to simplify glucose control.

Anti-hypertensive effects of Rosuvastatin are associated with decreased inflammation and oxidative stress markers in hypertensive rats

Among their pleiotropic effects, statins exert antioxidant and anti-inflammatory properties. The aim of this study was to evaluate in normotensive (WKY) and in spontaneously hypertensive rats (SHR) the effect of rosuvastatin (ROSU) treatment on (1) plasma inflammation markers and endogenous NO synthase inhibitor (ADMA) levels, (2) reactive oxygen species (ROS) generated by circulating leukocytes and (3) vascular oxidative stress and tissue inflammation markers. Plasma cytokines were higher in SHR than in WKY, except for IL-4, which was lower in SHR than in WKY. SHR monocytes exhibited higher production of ROS than did WKY monocytes. In the experimental conditions, ROSU did not modify plasma cholesterol levels in SHR but attenuated the increase in systolic blood pressure. In SHR only, ROSU lessened pro-inflammatory cytokines and ADMA levels, increased IL-4 and reduced ROS production in circulating monocytes. These results demonstrate the beneficial effects of ROSU in SHR, independently of any lowering of cholesterol levels.

Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals

Hydronephrotic animals develop renal injury and hypertension, which is associated with an abnormal tubuloglomerular feedback (TGF). The TGF sensitivity is coupled to nitric oxide (NO) in the macula densa. The involvement of reduced NO availability in the development of hypertension in hydronephrosis was investigated. Hydronephrosis was induced by ureteral obstruction in young rats. Blood pressure and renal excretion were measured in adulthood, under different sodium conditions, and before and after chronic administration of either N(G)-nitro-l-arginine methyl ester (l-NAME) or l-arginine. Blood samples for ADMA, SDMA, and l-arginine analysis were taken and the renal tissue was used for histology and determination of NO synthase (NOS) proteins. TGF characteristics were determined by stop-flow pressure technique before and after administration of 7-nitroindazole (7-NI) or l-arginine. Hydronephrotic animals developed salt-sensitive hypertension, which was associated with pressure natriuresis and diuresis. The blood pressure response to l-NAME was attenuated and l-arginine supplementation decreased blood pressure in hydronephrotic animals, but not in the controls. Under control conditions, reactivity and sensitivity of the TGF response were greater in the hydronephrotic group. 7-NI administration increased TGF reactivity and sensitivity in control animals, whereas, in hydronephrotic animals, neuronal NOS (nNOS) inhibition had no effect. l-Arginine attenuated TGF response more in hydronephrotic kidneys than in controls. The hydronephrotic animals displayed various degrees of histopathological changes. ADMA and SDMA levels were higher and the renal expressions of nNOS and endothelial NOS proteins were lower in animals with hydronephrosis. Reduced NO availability in the diseased kidney in hydronephrosis, and subsequent resetting of the TGF mechanism, plays an important role in the development of hypertension.

Metabolic Profiling of Arginine and Nitric Oxide Pathways Predicts Hemodynamic Abnormalities and Mortality in Patients With Cardiogenic Shock After Acute Myocardial Infarction

It is unclear whether abnormalities of arginine and nitric oxide metabolism are related to hemodynamic dysfunction and mortality in patients with cardiogenic shock (CS) after acute myocardial infarction. Plasma metabolites reflecting arginine bioavailability, nitric oxide metabolism, and protein oxidation were analyzed by mass spectrometry in patients with CS (n=79) and age- and gender-matched patients with coronary artery disease and normal left ventricular function (n=79). CS patients had higher levels of asymmetric dimethylarginine (ADMA; P<0.0001), symmetric dimethylarginine (P<0.0001), monomethylarginine (P=0.0003), nitrotyrosine (P<0.0001), and bromotyrosine (P<0.0001) and lower levels of arginine (P<0.0001), ratio of arginine to ornithine (P=0.03), and ratio of arginine to ornithine plus citrulline) (P=0.0003). CS patients with elevated ADMA levels were 3.5-fold (95% confidence interval, 1.4 to 11.3; P=0.02) more likely to die in 30 days than patients with low ADMA levels. ADMA remained the only independent predictor of mortality on multiple logistic regression analysis. In patients with normal renal function, symmetric dimethylarginine levels inversely correlated with mean arterial pressure and systemic vascular resistance, whereas levels of ADMA correlated with pulmonary capillary wedge pressure and both systolic and diastolic pulmonary artery pressures. Despite dramatic elevations, levels of protein oxidation products did not predict hemodynamic dysfunction or mortality in CS patients. CS is characterized by an arginine-deficient and highly specific pro-oxidant state, with elevated levels of methylated arginine derivatives, including endogenous nitric oxide synthase inhibitors. Levels of methylated arginine derivatives strongly correlate with hemodynamic dysfunction. Among all clinical and laboratory parameters monitored, ADMA levels were the strongest independent predictor of 30-day mortality.

Abstract 3745: Asymmetric Dimethylarginine and Mortality after Acute Myocardial Infarction

Background . From a prospective cohort of patients with acute myocardial infarction (MI), we aimed to analyse the predictive value of ADMA concentrations on mortality at 1 year follow-up. ADMA is an endogenous competitive inhibitor of NO synthases. Patients . Blood samples from 204 consecutive patients hospitalised for acute MI &lt; 24 hr were taken on admission. Serum levels of ADMA, its stereoisomer, symmetric dimethylarginine (SDMA), were determined using high-performance liquid chromatography and fluorescence. Results . The mean (SD) ADMA level was 1.07(0.37) μmol/L. ADMA was positively related to age, homocysteine, SDMA and L-arginine. The glomerular filtration rate (GFR) showed a trend toward an inverse relation with ADMA. ADMA concentrations showed a trend towards a higher level in women than in men (p=.101) and were lower in current smokers vs past or non smokers (p=0.022). Baseline ADMA and SDMA levels were higher in patients who had died than in patients who were alive at 1 year follow-up (respectively 1.22(1.06–1.54) vs 0.98(0.78–1.24), p=0.012 and 0.77(0.54–1.03) vs 0.47(0.35–0.64), p&lt;0.001). By Cox stepwise multivariate analysis, high levels of ADMA were one of the strongest predictors for mortality (HR(95%CI), 6.63(2.55–17.21)), even when adjusted for potential confounders, such as biological and clinical factors, and reperfusion. In contrast, SDMA failed to independently predict the outcome (HR(95%CI): 1.88(0.33–10.70). Conclusion . Our study suggests that measurement of ADMA levels at baseline improves cardiovascular risk prediction after acute MI, beyond traditional risk factors and biomarkers. ADMA may thus constitute a novel and useful marker for risk stratification in acute MI.

The administration of estrogens, combined with anti-androgens, has beneficial effects on the hormonal features and asymmetric dimethyl-arginine levels, in women with the polycystic ovary syndrome

The present study was designed in order to: (a) compare ET-1 and ADMA levels, between women with PCOS ( n = 106) and healthy controls ( n = 30); (b) determine the effects of treatment with estrogens and anti-androgens on the hormonal features of PCOS, insulin resistance, ET-1 and ADMA levels. Women with PCOS were randomized in five therapeutic protocols: (I) 17β-estradiol + cyproterone acetate 50 mg; (II) conjugated estrogen + CA 50 mg; (III) ethinyl estradiole + CA 2 mg; (IV) EE + CA 52 mg; (V) EE + desogestrel. In all women, gonadotropin, PRL, androgen, SHBG, insulin, glucose, ET-1 and ADMA levels were determined; in women with PCOS, testosterone, SHBG, ET-1 and ADMA levels were measured again after 3, 6, 12 months of treatment and insulin and glucose levels after 12 months. ET-1 and ADMA concentrations were higher in women with PCOS, and they were positively correlated with each other. ADMA levels were decreased and IR was increased with treatment. Treatment with synthetic estrogens (EE) resulted in a more pronounced increase in SHBG and a more pronounced decrease in FAI, compared to natural estrogens. Conclusively, PCOS is associated with endothelial dysfunction, which is ameliorated by the administration of estrogens and anti-androgens, independent of IR.

Asymmetric Dimethylarginine and Reduced Nitric Oxide Bioavailability in Young Black African Men

Black Africans have a higher incidence of cardiovascular disease than white Europeans. We explored potential mechanisms of this excess risk by assessing endothelium function, inflammatory status (C-reactive protein), oxidative stress (isoprostane-F2alpha), and plasma asymmetrical dimethyl arginine (ADMA; an endogenous competitive inhibitor of NO synthase) in each ethnic group. Thirty healthy black Africans and 28 well-matched white European male subjects were studied (mean age+/-SE: 32.2+/-0.9 and 29.2+/-1.2 years, respectively; P=0.07). High-resolution ultrasound was used to assess vascular function in the brachial artery by measuring flow mediated dilatation ([percentage of change]; endothelium-dependent function) and glyceryltrinitrate dilatation ([percentage of change]; endothelium-independent function). Blood pressure, fasting lipids, glucose, and estimated glomerular filtration rate levels were similar in both groups. There was no difference in C-reactive protein (black Africans: 0.8+/-0.1 mg/L; white Europeans: 0.6+/-0.1 mg/L; P=0.22), isoprostane-F2alpha (black Africans: 42.9+/-1.5 pg/mL; white Europeans: 39.2+/-1.5 pg/mL; P=0.23), and leptin (black Africans: 64.1+/-10.2 ng/mL; white Europeans: 47.8+/-9.8 ng/mL; P=0.37) levels between the 2 ethnic groups. However, compared with white Europeans, plasma ADMA levels were significantly higher in black Africans (0.34+/-0.02 micromol/L and 0.25+/-0.03 micromol/L; P=0.03). There was no difference in the percentage of glyceryltrinitrate dilatation (P=0.7), but the percentage of flow-mediated dilatation was significantly lower in black Africans (black Africans: 5.2+/-0.3; white Europeans: 6.3+/-0.4; P=0.02). In a stepwise multiple regression model, ADMA level was the only independent determinant of flow-mediated dilatation (P=0.02). In turn, race was the only independent determinant of ADMA levels (P=0.03). Our findings indicate that circulating ADMA levels are significantly higher in healthy black African males than in white European males. This may contribute to the lower NO bioavailability and higher incidence of cardiovascular disease seen in black Africans.

2006 Lewis K. Dahl Memorial Lecture—Nitric Oxide Deficiency in Renal Disease

Nitric oxide (NO) production is reduced in renal disease, in part because of decreased endothelial production. Evidence indicates that NO deficiency contributes to cardiovascular events and progression of kidney damage. Two possible causes of NO deficiency are substrate (L-arginine) limitation and increased levels of circulating endogenous inhibitors of NO synthase (particularly asymmetric dimethylarginine [ADMA]). Decreased L-arginine availability in chronic kidney disease (CKD) is due to perturbed renal biosynthesis of this amino acid. In addition, inhibition of transport of L-arginine into endothelial cells and shunting of L-arginine into other metabolic pathways (eg, involving arginase) might also decrease availability. Elevated plasma and tissue levels of ADMA in CKD are functions of both reduced renal excretion and reduced catabolism by dimethylarginine dimethylamino-hydrolase (DDAH). The latter might be associated with loss-of-function polymorphisms of a DDAH gene and/or functional inhibition of the enzyme by oxidative stress in CKD and end-stage renal disease. An increase in ADMA has emerged as a major independent risk factor in end-stage renal disease (and probably CKD). Raising endogenous L-arginine and/or lowering ADMA concentration is a major therapeutic goal to reduce endothelial dysfunction, cardiovascular risk, and possibly progression in renal disease.

Surgical Menopause, Salt Sensitivity, and NO Bioavailability in Women

HomeHypertensionVol. 48, No. 3Surgical Menopause, Salt Sensitivity, and NO Bioavailability in Women Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBSurgical Menopause, Salt Sensitivity, and NO Bioavailability in Women Kazushi Tsuda Kazushi TsudaKazushi Tsuda Division of Cardiology, Department of Medicine, Wakayama Medical University, Wakayama, Japan Search for more papers by this author Originally published7 Aug 2006https://doi.org/10.1161/01.HYP.0000237570.97050.57Hypertension. 2006;48:E12Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: August 7, 2006: Previous Version 1 To the Editor:We read with great interest the article by Schulman et al1 dealing with the association between the loss of ovarian hormones and the occurrence of salt sensitivity in healthy premenopausal women. The results of their study demonstrated that 38.7% of salt-resistant women developed salt sensitivity after surgical menopause. The authors indicated that the prevalence of salt sensitivity doubled as early as 4 months after surgical menopause. The authors proposed that the loss of ovarian function may unmask a population of women prone to salt sensitivity who would be at higher risk for the subsequent development of hypertension and cardiovascular disease.Numerous studies have shown that one of the mechanisms underlying the cardiovascular protective effect of estrogen may be the enhancement of NO production. There is evidence demonstrating that vascular endothelial function is markedly influenced by estrogen and is improved by hormone replacement therapy in postmenopausal women.2 Recently, Scuteri et al3 showed that inhibition of NO bioavailability by asymmetrical dimethylarginine ([ADMA] an endogenous NO synthase inhibitor) and a subsequent reduction in endothelial dysfunction might contribute to the increase in blood pressure during salt intake in normotensive postmenopausal women not receiving estrogen. It was also demonstrated that estrogen replacement therapy significantly reduced plasma concentration of ADMA in postmenopausal women.4 In a study that we presented earlier, it was shown that estrogen-induced improvement of membrane fluidity (the reciprocal value of microviscosity) of erythrocytes was counteracted by ADMA in postmenopausal women.5 In addition, we showed that amelioration in membrane fluidity of erythrocytes was associated with higher NO metabolite and lower ADMA levels in plasma.6 The findings might suggest that NO and ADMA might actively participate in the regulation of rheological behavior of cell membranes and microcirculation. In this context, it can be speculated that, in women with higher ADMA levels, the circulatory disorders are more pronounced. The precise role of ADMA in the development of hypertension and cardiovascular disease in women is still unclear. It is possible that estrogen deficiency after menopause might accelerate abnormalities in endothelial function by increasing ADMA levels. Therefore, we would like to know whether the plasma NO metabolite and ADMA concentrations might be associated with the changes in salt sensitivity after surgical menopause in the study by Schulman et al.1 It would be important to assess more precisely the relationship among estrogen status, salt sensitivity, and NO bioavailability in women after menopause.DisclosuresNone.1 Schulman IH, Aranda P, Raij L, Veronesi M, Aranda FJ, Martin R. Surgical menopause increases salt sensitivity of blood pressure. Hypertension. 2006; 47: 1168–1174.LinkGoogle Scholar2 Higashi Y, Sanada M, Sasaki S, Nakagawa K, Goto C, Matsuura H, Ohama K, Chyayama K, Oshima T. Effect of estrogen replacement therapy on endothelial function in peripheral resistance arteries in normotensive and hypertensive postmenopausal women. Hypertension. 2001; 37: 651–657.CrossrefMedlineGoogle Scholar3 Scuteri A, Stühlinger MC, Cooke JP, Wright JG, Lakatta EG, Anderson DE, Fleg JL. Nitric oxide inhibition as a mechanism for blood pressure increase during salt loading in normotensive postmenopausal women. J Hypertens. 2003; 21: 1339–1346.CrossrefMedlineGoogle Scholar4 Teerlink T, Neele SJ, de Jong S, Netelenbos JC, Stehouwer CD. Oestrogen replacement therapy lowers plasma levels of asymmetrical dimethylarginine in healthy postmenopausal women. Clin Sci(Lond). 2003; 105: 67–71.CrossrefGoogle Scholar5 Tsuda K, Kinoshita Y, Kimura K, Nishio I, Masuyama Y. Electron paramagnetic resonance investigation on modulatory effect of 17beta-estradiol on membrane fluidity of erythrocytes in postmenopausal women. Arterioscler Thromb Vasc Biol. 2001; 21: 1306–1312.CrossrefMedlineGoogle Scholar6 Tsuda K, Nishio I. An association between plasma asymmetric dimethylarginine and membrane fluidity of erythrocytes in hypertensive and normotensive men: an electron paramagnetic resonance investigation. Am J Hypertens. 2005; 18: 1243–1248.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Gohar E, Kasztan M, Becker B, Speed J and Pollock D (2017) Ovariectomy uncovers purinergic receptor activation of endothelin-dependent natriuresis, American Journal of Physiology-Renal Physiology, 10.1152/ajprenal.00098.2017, 313:2, (F361-F369), Online publication date: 1-Aug-2017. Schulman I, Aranda P, Raij L, Veronesi M, Aranda F and Martin R (2006) Response to Surgical Menopause, Salt Sensitivity, and NO Bioavailability in Women, Hypertension, 48:3, (E13-E13), Online publication date: 1-Sep-2006. September 2006Vol 48, Issue 3 Advertisement Article InformationMetrics https://doi.org/10.1161/01.HYP.0000237570.97050.57PMID: 16894052 Originally publishedAugust 7, 2006 PDF download Advertisement SubjectsEtiology

Expression of nitric oxide related enzymes in coronary heart disease

Enzymes involved in the metabolism nitric oxide (NO) and reactive oxygen species (ROS) may play a role for the decreased availability of NO in atherosclerosis. We, therefore, hypothesized that the pattern of gene expression of these enzymes is altered in atherosclerosis. Myocardial tissue from patients with coronary heart disease (CHD) or without CHD (control group) was investigated. The level of enzymes related to NO/ROS metabolism was determined both at mRNA level and protein level by rt-PCR, real-time PCR, and western blot. The expression of NOS1-3 (synthesis of NO), arginase1 (reduction of L-arginine), p22phox (active subunit of NADPH oxidase), GTPCH (rate limiting enzyme for tetrahydrobiopterin), SOD1-3 (scavengers of superoxide anions), PRTMT1-3, and DDAH2 (involved in the metabolism of ADMA) was determined. All enzymes were found to be expressed in human myocardium. NOS isoforms were decreased in CHD in protein level, but only the downregulation of NOS3 expression reached statistical significance. The expression of PRMT1 and PRMT3 was increased. In addition, the expression of DDAH2 was reduced, both theoretically leading to an increase of ADMA concentration. SOD3 was downregulated in tissue from patients with CHD. Taken together, in myocardial tissue from patients with atherosclerosis, the expression of genes increasing ADMA levels is enhanced in contrast to a reduced expression of genes promoting NO synthesis. These results may contribute to the explanation of increased oxidative stress in atherosclerosis on the level of gene expression.

Arginine, arginine analogs and nitric oxide production in chronic kidney disease

Nitric oxide (NO) production is reduced in renal disease, partially due to decreased endothelial NO production. Evidence indicates that NO deficiency contributes to cardiovascular events and progression of kidney damage. Two possible causes of NO deficiency are substrate (L-arginine) limitation and increased levels of circulating endogenous inhibitors of NO synthase (particularly asymmetric dimethylarginine [ADMA]). Decreased L-arginine availability in chronic kidney disease (CKD) is due to perturbed renal biosynthesis of this amino acid. In addition, inhibition of transport of L-arginine into endothelial cells and shunting of L-arginine into other metabolic pathways (e.g. those involving arginase) might also decrease availability. Elevated plasma and tissue levels of ADMA in CKD are functions of both reduced renal excretion and reduced catabolism by dimethylarginine dimethylaminohydrolase (DDAH). The latter might be associated with loss-of-function polymorphisms of a DDAH gene, functional inhibition of the enzyme by oxidative stress in CKD and end-stage renal disease, or both. These findings provide the rationale for novel therapies, including supplementation of dietary L-arginine or its precursor L-citrulline, inhibition of non-NO-producing pathways of L-arginine utilization, or both. Because an increase in ADMA has emerged as a major independent risk factor in end-stage renal disease (and probably also in CKD), lowering ADMA concentration is a major therapeutic goal; interventions that enhance the activity of the ADMA-hydrolyzing enzyme DDAH are under investigation.

Novel mechanism for the radiation-induced bystander effect: Nitric oxide and ethylene determine the response in sponge cells

Until now the bystander effect had only been described in vertebrates. In the present study the existence of this effect has been demonstrated for the phylogenetically oldest metazoan phylum, the Porifera. We used the demosponge Suberites domuncula for the experiments in the two-chamber-system. The lower dish contained irradiated “donor” cells (single cells) and the upper dish the primmorphs (“recipient” primmorphs). The “donor” cells were treated with UV-B light (40 mJ/cm 2) and 100 μM hydrogen peroxide (H 2O 2), factors that exist also in the natural marine aquatic environment of sponges; these factors caused a high level of DNA strand breaks followed by a reduced viability of the cells. If these cells were added to the “recipient” primmorphs these 3D-cell cultures started to undergo apoptosis. This effect could be abolished by the NO-specific scavenger PTIO and ethylene. The conclusion that NO is synthesized by the UV-B/H 2O 2-treated cells was supported analytically. The cDNA encoding the enzyme dimethylarginine dimethylaminohydrolase (DDAH) was isolated from the “donor” cells. High levels of DDAH transcripts were measured in UV-B/H 2O 2-treated “donor” cells while after ethylene treatment the steady-state level of expression drops drastically. We conclude that in the absence of ethylene the concentration of the physiological inhibitor for the NO synthase ADMA is low, due to the high level of DDAH. In consequence, high amounts of NO are released from “donor” cells which cause apoptosis in “recipient” primmorphs. In contrast, ethylene reduces the DDAH expression with the consequence of higher levels of ADMA which prevent the formation of larger amounts of NO. This study describes the radiation-induced bystander effect also for the most basal metazoans and demonstrates that this effect is controlled by the two gasses NO and ethylene.

Selective Substrate-Based Inhibitors of Mammalian Dimethylarginine Dimethylaminohydrolase

The enzyme DDAH metabolizes methylarginines that are inhibitors of nitric oxide synthase (NOS). Substrate-based inhibitors of mammalian DDAH have been synthesized, with optimization to give selective inhibition of DDAH with no significant direct effect on NOSs. These are the first examples of reversible DDAH inhibitors with significant activity and selectivity. In vivo administration increases plasma ADMA levels, giving proof of concept that these inhibitors can be used to probe the physiological effects of DDAH inhibition, with potential for pharmaceutical use of DDAH inhibitors in diseases where excess NO production is implicated.

Determination of asymmetric and symmetric dimethylarginines in plasma of hyperhomocysteinemic subjects

The aim of this study was to investigate the possible relationship among dimethylarginines (asymmetric, ADMA; symmetric, SDMA) and homocysteine (Hcy) levels in subjects affected by chronic, mild to intermediate, hyperhomocysteinemia. ADMA and SDMA were assayed by an optimised HPLC method in 75 patients (Hcy = 20.8 micromol/L, 17.1-30.2; median and percentile range) and, for comparison, in 85 healthy subjects (Hcy = 8.0 micromol/L, 7.0-9.1). In controls, the cut-off values were set at 0.61 micromol/L for ADMA and 0.56 or 0.48 micromol/L for male and female SDMA, respectively. In patients, ADMA and SDMA levels were increased (p < 0.001) with respect to controls, but no correlation with Hcy was observed. Hyperhomocysteinemic subjects showed a different behaviour in respect to ADMA and SDMA levels and this allowed their stratification in 3 subgroups characterized by ADMA and SDMA in the normal range, only SDMA, or both ADMA and SDMA over the cut-off values. A lack of correlation with Hcy was again observed, thus minimizing the direct role of Hcy on ADMA and SDMA metabolism and suggesting the need for further studies on this issue.