Simultaneous assessment of endothelial function, nitric oxide synthase activity, nitric oxide-mediated signaling, and oxidative stress in individuals with and without hypercholesterolemia.

TY - JOUR

T1 - Simultaneous assessment of endothelial function, nitric oxide synthase activity, nitric oxide-mediated signaling, and oxidative stress in individuals with and without hypercholesterolemia.

AU - Maas, Renke

AU - Schwedhelm, Edzard

AU - Kahl, Lydia

AU - Li, Huige

AU - Benndorf, Ralf

AU - Lüneburg, Nicole

AU - Förstermann, Ulrich

AU - Böger, Rainer

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

M3 - SCORING: Zeitschriftenaufsatz

VL - 54

SP - 292

EP - 300

JO - CLIN CHEM

JF - CLIN CHEM

SN - 0009-9147

IS - 2

M1 - 2

ER -