المؤلفون: Schwedhelm E; Clinical Pharmacology Unit, Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. schwedhelm@uke.uni-hamburg.de, Xanthakis V, Maas R, Sullivan LM, Schulze F, Riederer U, Benndorf RA, Böger RH, Vasan RS

المصدر: Clinical chemistry [Clin Chem] 2009 Aug; Vol. 55 (8), pp. 1539-45. Date of Electronic Publication: 2009 Jun 18.

نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: Oxford University Press Country of Publication: England NLM ID: 9421549 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1530-8561 (Electronic) Linking ISSN: 00099147 NLM ISO Abbreviation: Clin Chem Subsets: MEDLINE

مواضيع طبية MeSH: Reference Standards*, Arginine/*analogs & derivatives , Cardiovascular Diseases/*diagnosis , Chromatography, Liquid/*methods , Tandem Mass Spectrometry/*methods, Age Factors ; Aged ; Arginine/blood ; Chromatography, Liquid/standards ; Cohort Studies ; Female ; Homocysteine/blood ; Humans ; Male ; Middle Aged ; Multivariate Analysis ; Sensitivity and Specificity ; Sex Factors ; Tandem Mass Spectrometry/standards

مستخلص: Background: Accumulating evidence links higher circulating asymmetric dimethylarginine (ADMA) to greater risk of cardiovascular disease (CVD). Relatively small differences in ADMA concentrations between healthy individuals and those with disease underscore the need to formulate reference intervals that may aid risk stratification of individuals.
Methods: We formulated reference intervals for plasma ADMA concentrations using a community-based reference sample from the Framingham Offspring Study consisting of 1126 nonsmoking individuals [mean (SD) age 56 (9) years; 60% women] who were free of clinical CVD, hypertension, diabetes, and obesity and who attended a routine examination at which ADMA was assayed. ADMA concentrations were determined using a validated tandem mass spectrometry-liquid chromatography assay.
Results: In the study sample, the mean ADMA concentration was 0.52 (0.11) micromol/L, and the reference limits were 0.311 and 0.732 (2.5th and 97.5th percentile). The sex-specific reference limits were 0.310 and 0.745 in men and 0.313 and 0.721 micromol/L in women. In multivariable regression analysis, ADMA plasma concentrations were positively correlated with age and total plasma homocysteine (both P < 0.001).
Conclusions: Reference limits calculated for circulating ADMA in our large community-based healthy reference sample confirm the previous observation of a relatively narrow distribution of concentrations. This suggests a tight physiological control of ADMA plasma concentrations, presumably by dimethylarginine dimethylaminohydrolase (DDAH) metabolism of ADMA.

المؤلفون: Maas R; Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany. mass@uke.uni-hamburg.de, Schwedhelm E, Kahl L, Li H, Benndorf R, Lüneburg N, Förstermann U, Böger RH

المصدر: Clinical chemistry [Clin Chem] 2008 Feb; Vol. 54 (2), pp. 292-300. Date of Electronic Publication: 2007 Dec 10.

نوع المنشور: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: Oxford University Press Country of Publication: England NLM ID: 9421549 Publication Model: Print-Electronic Cited Medium: Print ISSN: 0009-9147 (Print) Linking ISSN: 00099147 NLM ISO Abbreviation: Clin Chem Subsets: MEDLINE

مواضيع طبية MeSH: Oxidative Stress*, Endothelium, Vascular/*physiopathology , Hypercholesterolemia/*metabolism , Hypercholesterolemia/*physiopathology , Nitric Oxide/*biosynthesis , Nitric Oxide Synthase/*metabolism, Adolescent ; Adult ; Aged ; Arginine/analogs & derivatives ; Arginine/blood ; Cyclic GMP/urine ; Dinoprost/analogs & derivatives ; Dinoprost/urine ; Female ; Humans ; Male ; Middle Aged ; Nitrates/urine ; Nitric Oxide Synthase/antagonists & inhibitors ; Nitric Oxide Synthase Type III/blood ; Sex Factors

مستخلص: Background: Endothelial function is impaired in hypercholesterolemia and atherosclerosis. Based on mostly indirect evidence, this impairment is attributed to reduced synthesis or impaired biological activity of endothelium-derived nitric oxide (NO). It was the aim of this study to directly estimate and compare whole-body NO production in normo- and hypercholesterolemia by applying a nonradioactive stable isotope dilution technique in vivo.
Methods: We enrolled 12 normocholesterolemic and 24 hypercholesterolemic volunteers who were all clinically healthy. To assess whole-body NO synthesis, we intravenously administered l-[guanidino-((15)N(2))]-arginine and determined the urinary excretion of (15)N-labeled nitrate, the specific end product of NO oxidation in humans, by use of gas chromatography-mass spectrometry. In addition, we measured flow-mediated vasodilation (FMD) of the brachial artery, expression of endothelial NOS (eNOS) in platelets, plasma concentration of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA), and urinary excretion of 8-isoprostaglandin F(2alpha) (8-iso-PGF(2alpha)).
Results: After infusion of l-[guanidino-((15)N(2))]-arginine, cumulative excretion of (15)N-labeled-nitrate during 48 h was 40% [95% CI 15%-66%] lower in hypercholesterolemic than normocholesterolemic volunteers [mean 9.2 (SE 0.8) micromol vs 15.4 (2.3) micromol/l, P = 0.003]. FMD was on average 36% [4%-67%] lower in hypercholesterolemic than normocholesterolemic volunteers [6.3 (4.0)% vs 9.4 (4.6)%, P = 0.027]. Normalized expression of NOS protein in platelets was also significantly lower in hypercholesterolemic volunteers, whereas there were no significant differences in plasma ADMA concentration or urinary excretion of 8-iso-PGF(2alpha) between the 2 groups.
Conclusions: This study provides direct evidence for a decreased whole body NO synthesis rate in healthy people with hypercholesterolemia.