title: Simultaneous assessment of endothelial function, nitric oxide synthase activity, nitric oxide-mediated signaling, and oxidative stress in individuals with and without hypercholesterolemia.
abstract: 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.
authors: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany. mass@uke.uni-hamburg.de
authors: Renke
authors: R
authors: Maas
authors: Edzard
authors: E
authors: Schwedhelm
authors: Lydia
authors: L
authors: Kahl
authors: Huige
authors: H
authors: Li
authors: Ralf
authors: R
authors: Benndorf
authors: Nicole
authors: N
authors: Lüneburg
authors: Ulrich
authors: U
authors: Förstermann
authors: Rainer H
authors: RH
authors: Böger
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood; D006152:Cyclic GMP / Q000652:urine; D015237:Dinoprost / Q000031:analogs & derivatives / Q000652:urine; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000097:blood; D018384:Oxidative Stress; D012737:Sex Factors
chemical_list: D009566:Nitrates; C075750:8-epi-prostaglandin F2alpha; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D015237:Dinoprost; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D006152:Cyclic GMP