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Hormone Molecular Biology and Clinical... Feb 2021Thyroid disorders are important risk factor for cardiovascular diseases. Levels of methylarginines such as asymmetric dimethyl arginine (ADMA), L-monomethyl arginine...
OBJECTIVES
Thyroid disorders are important risk factor for cardiovascular diseases. Levels of methylarginines such as asymmetric dimethyl arginine (ADMA), L-monomethyl arginine (L-NMMA), symmetric dimethyl arginine (SDMA) are increase in cardiovascular diseases. Multinodular goiter (MNG) is the most common type of goiter in adults. To date, no study has been conducted to determine the levels of methylarginine in euthyroid MNG patients. Our aim in this study is to compare levels of methylarginines and related metabolites in the preoperative, postoperative MNG patients and controls.
METHODS
Serum ADMA, SDMA, L-NMMA, homoarginine (hArg), arginine and citrulline concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS).
RESULTS
ADMA (p<0.001), L-NMMA (p=0.002), l-arginine (p=0.006) and citrulline (p<0.001) levels were statistically significantly higher in preop group than postop group. ADMA (p=0.003), L-NMMA (p=0.003) levels were statistically significantly higher and SDMA/ADMA (p<0.001), hArg/ADMA (p<0.001) levels were statistically significantly lower in preop group than control group.
CONCLUSIONS
The levels of methylarginines and related metabolites altered in the euthyroid MNG patients compared to the control group, and more importantly, there were significant differences between the preop and postop groups. Therefore, these metabolites can be useful in the diagnosis and prognosis of thyroid disorders, even if thyroid hormone levels are normal.
Topics: Adult; Arginine; Biomarkers; Case-Control Studies; Chromatography, High Pressure Liquid; Female; Goiter, Nodular; Humans; Male; Middle Aged; Postoperative Period; Sensitivity and Specificity; omega-N-Methylarginine
PubMed: 33607721
DOI: 10.1515/hmbci-2020-0093 -
Journal of Applied Physiology... Jul 2023Ninety-million Americans suffer metabolic syndrome (MetSyn), increasing the risk of diabetes and poor brain outcomes, including neuropathology linked to lower cerebral...
Ninety-million Americans suffer metabolic syndrome (MetSyn), increasing the risk of diabetes and poor brain outcomes, including neuropathology linked to lower cerebral blood flow (CBF), predominantly in anterior regions. We tested the hypothesis that total and regional CBF is lower in MetSyn more so in the anterior brain and explored three potential mechanisms. Thirty-four controls (25 ± 5 yr) and 19 MetSyn (30 ± 9 yr), with no history of cardiovascular disease/medications, underwent four-dimensional flow magnetic resonance imaging (MRI) to quantify macrovascular CBF, whereas arterial spin labeling quantified brain perfusion in a subset ( = 38/53). Contributions of cyclooxygenase (COX; = 14), nitric oxide synthase (NOS, = 17), or endothelin receptor A signaling ( = 13) were tested with indomethacin, -monomethyl-L-arginine (L-NMMA), and Ambrisentan, respectively. Total CBF was 20 ± 16% lower in MetSyn (725 ± 116 vs. 582 ± 119 mL/min, < 0.001). Anterior and posterior brain regions were 17 ± 18% and 30 ± 24% lower in MetSyn; reductions were not different between regions ( = 0.112). Global perfusion was 16 ± 14% lower in MetSyn (44 ± 7 vs. 36 ± 5 mL/100 g/min, = 0.002) and regionally in frontal, occipital, parietal, and temporal lobes (range 15-22%). The decrease in CBF with L-NMMA ( = 0.004) was not different between groups ( = 0.244, = 14, 3), and Ambrisentan had no effect on either group ( = 0.165, = 9, 4). Interestingly, indomethacin reduced CBF more in Controls in the anterior brain ( = 0.041), but CBF decrease in posterior was not different between groups ( = 0.151, = 8, 6). These data indicate that adults with MetSyn exhibit substantially reduced brain perfusion without regional differences. Moreover, this reduction is not due to loss of NOS or gain of ET-1 signaling but rather a loss of COX vasodilation. We tested the impact of insulin resistance (IR) on resting cerebral blood flow (CBF) in adults with metabolic syndrome (MetSyn). Using MRI and research pharmaceuticals to study the role of NOS, ET-1, or COX signaling, we found that adults with MetSyn exhibit substantially lower CBF that is not explained by changes in NOS or ET-1 signaling. Interestingly, adults with MetSyn show a loss of COX-mediated vasodilation in the anterior but not posterior circulation.
Topics: Humans; Young Adult; omega-N-Methylarginine; Metabolic Syndrome; Indomethacin; Cerebrovascular Circulation
PubMed: 37199780
DOI: 10.1152/japplphysiol.00688.2022 -
Biochemia Medica Feb 2023This study determines and compares the concentrations of arginine and methylated arginine products ((asymmetric dimethylarginine (ADMA), symmetric dimethylarginine...
INTRODUCTION
This study determines and compares the concentrations of arginine and methylated arginine products ((asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), n-monomethyl-1-arginine (L-NMMA) and homoarginine (HA)) for assessment of their association with disease severity in serum samples of COVID-19 patients.
MATERIALS AND METHODS
Serum arginine and methylated arginine products of 57 mild-moderate and 29 severe (N = 86) COVID-19 patients and 21 controls were determined by tandem mass spectrometry. Moreover, the concentrations of some of the routine clinical laboratory parameters -neutrophil lymphocyte ratio (NLR), C-reactive protein, ferritin, D-dimer, and fibrinogen measured during COVID-19 follow-up were also taken into consideration and compared with the concentrations of arginine and methylated arginine products.
RESULTS
Serum ADMA, SDMA and L-NMMA were found to be significantly higher in severe COVID-19 patients, than in both mild-moderate patients and the control group (P < 0.001 for each). In addition, multiple logistic regression analysis indicated L-NMMA (cut-off =120 nmol/L OR = 34, 95% confidence interval (CI) = 3.5-302.0, P= 0.002), CRP (cut-off = 32 mg/L, OR = 37, 95% CI = 4.8-287.0, P < 0.001), and NLR (cut-off = 7, OR = 22, 95% CI = 1.4-335.0, P = 0.020) as independent risk factors for identification of severe patients.
CONCLUSIONS
The concentration of methylated arginine metabolites are significantly altered in COVID-19 disease. The results of this study indicate a significant correlation between the severity of COVID-19 disease and concentrations of CRP, NLR and L-NMMA.
Topics: Humans; Arginine; COVID-19; Disease Progression; omega-N-Methylarginine
PubMed: 36627978
DOI: 10.11613/BM.2023.010701 -
PloS One 2022The endothelium maintains and regulates vascular homeostasis mainly by balancing interplay between vasorelaxation and vasoconstriction via regulating Nitric Oxide (NO)...
The endothelium maintains and regulates vascular homeostasis mainly by balancing interplay between vasorelaxation and vasoconstriction via regulating Nitric Oxide (NO) availability. Endothelial nitric oxide synthase (eNOS) is one of three NOS isoforms that catalyses the synthesis of NO to regulate endothelial function. However, eNOS's role in the regulation of endothelial function, such as cell proliferation and migration remain unclear. To gain a better understanding, we genetically knocked down eNOS in cultured endothelial cells using sieNOS and evaluated cell proliferation, migration and also tube forming potential in vitro. To our surprise, loss of eNOS significantly induced endothelial cell proliferation, which was associated with significant downregulation of both cell cycle inhibitor p21 and cell proliferation antigen Ki-67. Knockdown of eNOS induced cell migration but inhibited formation of tube-like structures in vitro. Mechanistically, loss of eNOS was associated with activation of MAPK/ERK and inhibition of PI3-K/AKT signaling pathway. On the contrary, pharmacologic inhibition of eNOS by inhibitors L-NAME or L-NMMA, inhibited cell proliferation. Genetic and pharmacologic inhibition of eNOS, both promoted endothelial cell migration but inhibited tube-forming potential. Our findings confirm that eNOS regulate endothelial function by inversely controlling endothelial cell proliferation and migration, and by directly regulating its tube-forming potential. Differential results obtained following pharmacologic versus genetic inhibition of eNOS indicates a more complex mechanism behind eNOS regulation and activity in endothelial cells, warranting further investigation.
Topics: Cells, Cultured; Endothelial Cells; Endothelium; Ki-67 Antigen; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type III; Protein Isoforms; Proto-Oncogene Proteins c-akt; omega-N-Methylarginine
PubMed: 36149900
DOI: 10.1371/journal.pone.0274487 -
Nitric Oxide : Biology and Chemistry Aug 2018Patients with chronic kidney disease have an increased cardiovascular morbidity and mortality. It has been recognized that the traditional cardiovascular risk factors... (Review)
Review
Patients with chronic kidney disease have an increased cardiovascular morbidity and mortality. It has been recognized that the traditional cardiovascular risk factors could only partially explain the increased cardiovascular morbidity and mortality in patients with chronic kidney disease. Asymmetric dimethylarginine (ADMA) and N-monomethy l-arginine (L-NMMA) are endogenous inhibitors of nitric oxide synthases that attenuate nitric oxide production and enhance reactive oxidative specie generation. Increased plasma ADMA and/or L-NMMA are strong and independent risk factor for chronic kidney disease, and various cardiovascular diseases such as hypertension, coronary artery disease, atherosclerosis, diabetes, and heart failure. Both ADMA and L-NMMA are also eliminated from the body through either degradation by dimethylarginine dimethylaminohydrolase-1 (DDAH1) or urine excretion. This short review will exam the literature of ADMA and L-NMMA degradation and urine excretion, and the role of chronic kidney diseases in ADMA and L-NMMA accumulation and the increased cardiovascular disease risk. Based on all available data, it appears that the increased cardiovascular morbidity in chronic kidney disease may relate to the dramatic increase of systemic ADMA and L-NMMA after kidney failure.
Topics: Amidohydrolases; Animals; Arginine; Endothelium, Vascular; Heart Failure; Humans; Nitric Oxide Synthase; Renal Insufficiency, Chronic; Risk Factors; Signal Transduction; omega-N-Methylarginine
PubMed: 29928990
DOI: 10.1016/j.niox.2018.06.004 -
European Journal of Pharmacology Dec 2023Myopia is one of the most prevalent eye diseases that seriously threaten the eyesight of children and adolescents worldwide. However, the pathogenesis is still unclear,...
Suppressive effect of nitric oxide synthase (NOS) inhibitor L-NMMA acetate on choroidal fibrosis in experimental myopic guinea pigs through the nitric oxide signaling pathway.
Myopia is one of the most prevalent eye diseases that seriously threaten the eyesight of children and adolescents worldwide. However, the pathogenesis is still unclear, and effective drugs are still scarce. In the present study, the guinea pigs were randomly divided into a normal control (NC) group, a lens-induced myopia (LIM) group, a NOS inhibitor (L-NMMA) injection group, and a NOS inhibitor solvent phosphate-buffered saline (PBS) group and the animals received relevant treatments. After 2- and 4-week different treatments, we noted that the refraction and choroidal thickness in the LIM group decreased compared with the NC group, whereas the ocular axial length increased significantly, and the choroid showed a fibrotic trend. The expression of NOS1, NOS3, TGF-β1, COLI, and α-SMA at gene and protein levels was increased significantly in the choroid (all P < 0.05). After intravitreal injection of NOS inhibitor L-NMMA, we found that compared with the LIM group, the refraction and the choroidal thickness significantly increased, whereas the axial length reduced significantly, accompanied by an increase of choroidal thickness and an improvement of choroidal fibrosis. The expression levels of choroidal NOS1, NOS3, TGF-β, COLI, and α-SMA were significantly reduced (all P < 0.05). In conclusion, the trend of choroidal fibrosis in LIM guinea pigs is positively correlated with the increase in axial length. The NOS inhibitor L-NMMA can alleviate the process of choroidal fibrosis in myopic guinea pigs by inhibiting NO signaling pathway.
Topics: Child; Guinea Pigs; Animals; Humans; Adolescent; omega-N-Methylarginine; Nitric Oxide; Myopia; Choroid; Enzyme Inhibitors; Signal Transduction; Nitric Oxide Synthase
PubMed: 37863413
DOI: 10.1016/j.ejphar.2023.176111 -
World Journal of Gastroenterology Aug 2022The mechanisms underlying gastrointestinal (GI) dysmotility with ulcerative colitis (UC) have not been fully elucidated. The enteric nervous system (ENS) plays an...
BACKGROUND
The mechanisms underlying gastrointestinal (GI) dysmotility with ulcerative colitis (UC) have not been fully elucidated. The enteric nervous system (ENS) plays an essential role in the GI motility. As a vital neurotransmitter in the ENS, the gas neurotransmitter nitric oxide (NO) may impact the colonic motility. In this study, dextran sulfate sodium (DSS)-induced UC rat model was used for investigating the effects of NO by examining the effects of rate-limiting enzyme nitric oxide synthase (NOS) changes on the colonic motility as well as the role of the ENS in the colonic motility during UC.
AIM
To reveal the relationship between the effects of NOS expression changes in NOS-containing nitrergic neurons and the colonic motility in a rat UC model.
METHODS
Male rats ( = 8/each group) were randomly divided into a control (CG), a UC group (EG1), a UC + thrombin derived polypeptide 508 trifluoroacetic acid (TP508TFA; an NOS agonist) group (EG2), and a UC + NG-monomethyl-L-arginine monoacetate (L-NMMA; an NOS inhibitor) group (EG3). UC was induced by administering 5.5% DSS in drinking water without any other treatment (EG1), while the EG2 and EG3 were gavaged with TP508 TFA and L-NMMA, respectively. The disease activity index (DAI) and histological assessment were recorded for each group, whereas the changes in the proportion of colonic nitrergic neurons were counted using immunofluorescence histochemical staining, Western blot, and enzyme linked immunosorbent assay, respectively. In addition, the contractile tension changes in the circular and longitudinal muscles of the rat colon were investigated using an organ bath system.
RESULTS
The proportion of NOS-positive neurons within the colonic myenteric plexus (MP), the relative expression of NOS, and the NOS concentration in serum and colonic tissues were significantly elevated in EG1, EG2, and EG3 compared with CG rats. In UC rats, stimulation with agonists and inhibitors led to variable degrees of increase or decrease for each indicator in the EG2 and EG3. When the rats in EGs developed UC, the mean contraction tension of the colonic smooth muscle detected was higher in the EG1, EG2, and EG3 than in the CG group. Compared with the EG1, the contraction amplitude and mean contraction tension of the circular and longitudinal muscles of the colon in the EG2 and EG3 were enhanced and attenuated, respectively. Thus, during UC, regulation of the expression of NOS within the MP improved the intestinal motility, thereby favoring the recovery of intestinal functions.
CONCLUSION
In UC rats, an increased number of nitrergic neurons in the colonic MP leads to the attenuation of colonic motor function. To intervene NOS activity might modulate the function of nitrergic neurons in the colonic MP and prevent colonic motor dysfunction. These results might provide clues for a novel approach to alleviate diarrhea symptoms of UC patients.
Topics: Animals; Male; Rats; Colitis, Ulcerative; Colon; Dextran Sulfate; Drinking Water; Gastrointestinal Motility; Nitrergic Neurons; Nitric Oxide; Nitric Oxide Synthase; omega-N-Methylarginine; Thrombin; Trifluoroacetic Acid
PubMed: 36157548
DOI: 10.3748/wjg.v28.i29.3854 -
Clinical Laboratory Jan 2022In this study, we aimed to show that methylated arginines are the predictors of non-clinical atherosclerotic cardiovascular complications in metal workers exposed to Cd.
BACKGROUND
In this study, we aimed to show that methylated arginines are the predictors of non-clinical atherosclerotic cardiovascular complications in metal workers exposed to Cd.
METHODS
The 80 Cd-exposed metal workers and 80 non-exposed workers (control) included in the study were available for measuring arginine, ADMA, SDMA, and L-NMMA levels.
RESULTS
The average urine Cd levels (CdU) found were 1.03 ± 0.8 µg/g creatinine (0.84 ± 0.65 µg/L) ranging from 0.01 to 3.00 µg/g creatinine in the control group and 5.41 ± 5.2 µg/g creatinine (4.29 ± 3.81 µg/L) ranged from 0.11 to 27.2 µg/g creatinine in metal workers. On the other hand, the median ratios of the different groups (exposed and control) were found to be 449.35 and 483.88 for arginine/ADMA and 1.28 and 1.33 SDMA/ADMA, respectively.
CONCLUSIONS
The present study was undertaken to investigate the relationship between cadmium exposure and methylated arginines such as ADMA/SDMA/L-NMMA parameters which is important for the early detection atherosclerotic cardiovascular diseases.
Topics: Arginine; Atherosclerosis; Cadmium; Creatinine; Humans; omega-N-Methylarginine
PubMed: 35023667
DOI: 10.7754/Clin.Lab.2021.210504 -
The Journal of Physiology Nov 2020Preclinical models have demonstrated that nitric oxide is a key component of neurovascular coupling; this has yet to be translated to humans. We conducted two separate...
KEY POINTS
Preclinical models have demonstrated that nitric oxide is a key component of neurovascular coupling; this has yet to be translated to humans. We conducted two separate protocols utilizing intravenous infusion of a nitric oxide synthase inhibitor and isovolumic haemodilution to assess the influence of nitric oxide on neurovascular coupling in humans. Isovolumic haemodilution did not alter neurovascular coupling. Intravenous infusion of a nitric oxide synthase inhibitor reduced the neurovascular coupling response by ∼30%, indicating that nitric oxide is integral to neurovascular coupling in humans.
ABSTRACT
Nitric oxide is a vital neurovascular signalling molecule in preclinical models, yet the mechanisms underlying neurovascular coupling (NVC) in humans have yet to be elucidated. To investigate the contribution of nitric oxide to NVC in humans, we utilized a visual stimulus paradigm to elicit an NVC response in the posterior cerebral circulation. Two distinct mechanistic interventions were conducted on young healthy males: (1) NVC was assessed during intravenous infusion of saline (placebo) and the non-selective competitive nitric oxide synthase inhibitor N -monomethyl-l-arginine (l-NMMA, 5 mg kg bolus & subsequent 50 μg kg min maintenance dose; n = 10). The order of infusion was randomized, counterbalanced and single blinded. A subset of participants in this study (n = 4) underwent a separate intervention with phenylephrine infusion to independently consider the influence of blood pressure changes on NVC (0.1-0.6 μg kg min constant infusion). (2) NVC was assessed prior to and following isovolumic haemodilution, whereby 20% of whole blood was removed and replaced with 5% human serum albumin to reduce haemoglobin concentration (n = 8). For both protocols, arterial and internal jugular venous blood samples were collected at rest and coupled with volumetric measures of cerebral blood flow (duplex ultrasound) to quantify resting cerebral metabolic parameters. l-NMMA elicited a 30% reduction in the peak (P = 0.01), but not average (P = 0.11), NVC response. Neither phenylephrine nor haemodilution influenced NVC. Nitric oxide signalling is integral to NVC in humans, providing a new direction for research into pharmacological treatment of humans with dementia.
Topics: Cerebrovascular Circulation; Enzyme Inhibitors; Humans; Male; Neurovascular Coupling; Nitric Oxide; omega-N-Methylarginine
PubMed: 32785972
DOI: 10.1113/JP280162 -
Clinical and Experimental Hypertension... 2020Asymmetric dimethylarginine, symmetric dimethylarginine, and L-monomethylarginine are originated from the subsequent proteolytic catalysis of methylated arginine...
Asymmetric dimethylarginine, symmetric dimethylarginine, and L-monomethylarginine are originated from the subsequent proteolytic catalysis of methylated arginine residues on different proteins and inhibit the endogenous nitric oxide generation. The changes in total methylarginine load (Asymmetric dimethylarginine plus symmetric dimethylarginine plus L-monomethylarginine) may contribute to hypertension. The aim of this study was to determine serum methylarginine concentrations in patients with masked hypertension and determine the association between these biomarkers and blood pressure measurements. Control group, masked hypertension and hypertension groups consisted of 40 subjects (11 males, 28 females, mean age 48.6 ± 13.1), 28 subjects (14 males, 14 females, mean age 50.9 ± 11.0) and 36 subjects (15 males, 21 females, mean age 54.4 ± 12.3 years), respectively (= 0.149). Serum total methylarginine load was significantly higher in hypertension group (0.63 ± 0.23) compared to masked hypertension (0.49 ± 0.16) and control groups (0.38 ± 0.13) (= 0.008 and < 0.001). While there was no statistically significant difference between healthy control groups [0.147 (0.03-0.29)] and masked hypertension patients [0.144 (0.05-0.42)] for serum symmetric dimethylarginine levels (= 0.970), it was markedly elevated in hypertension group [0.25 (0.07-0.54)] compared to masked hypertension group [0.14 (0.05-0.42)] (= 0.001). Serum total methylarginine load was positively correlated with night-time SBP (r = 0.214, = 0.029). Serum methylarginine levels might be a useful marker for determining the courses of clinical hypertension.
Topics: Arginine; Biomarkers; Blood Pressure Determination; Female; Humans; Hypertension; Male; Masked Hypertension; Middle Aged; Nitric Oxide; Risk Factors; omega-N-Methylarginine
PubMed: 30795691
DOI: 10.1080/10641963.2019.1583246