Chronic treatment with tetrahydrobiopterin reverses endothelial dysfunction and oxidative stress in hypercholesterolaemia.
BACKGROUND
Reduced availability of tetrahydrobiopterin (BH(4)), an essential cofactor of nitric oxide (NO) synthase (NOS), decreases NO production and increases reactive oxygen species. Both mechanisms contribute to atherosclerotic vascular disease. Although acute supplementation of BH(4) improves endothelial dysfunction, the effect of chronic BH(4) in humans is unknown.


OBJECTIVE
To investigate the effect of chronic BH(4) supplementation on endothelial function and oxidative stress in hypercholesterolaemia.


METHODS
Randomised double-blind, placebo-controlled trial.


METHODS
University Hospital.


METHODS
22 hypercholesterolaemic patients (low-density lipoprotein (LDL) >4.5 mmol/l) were randomised to 4 weeks of oral BH(4) (400 mg twice daily) or placebo. Age-matched healthy volunteers served as controls.


METHODS
Endothelium-dependent and -independent vasodilatation was assessed by venous occlusion plethysmography. To elucidate the mechanisms of BH(4) effect, NO release and superoxide anion (O(2)(-)) production were measured in human aortic endothelial cells exposed to native LDL (2.6 mmol cholesterol/l).


RESULTS
BH(4) plasma levels were significantly increased by oral supplementation. NO-mediated vasodilatation to acetylcholine was reduced in patients compared with controls and restored by BH(4). No effect of BH(4) on endothelium-independent vasodilatation was seen. Furthermore, 8-F(2 )isoprostane plasma levels, a marker of vascular oxidative stress, were reduced by BH(4). In LDL-treated endothelial cells, BH(4) levels and NO release were reduced and O(2)(-) production increased compared with control cells. Exogenous BH(4) normalised NO and O(2)(-) production.


CONCLUSIONS
In hypercholesterolaemia, endothelial dysfunction and oxidative stress can be reversed by chronic oral treatment with BH(4). Thus, BH(4) availability is essential for maintaining NO synthesis and low O(2)(-) production by endothelial NOS in vivo, and may provide a rational therapeutic approach to prevent cardiovascular disease.
Cosentino
F
F
Cardiovascular Centre, University Hospital, Rämistrasse 100, CH-8091 Zurich, Switzerland.
Hürlimann
D
D
Delli Gatti
C
C
Chenevard
R
R
Blau
N
N
Alp
N J
NJ
Channon
K M
KM
Eto
M
M
Lerch
P
P
Enseleit
F
F
Ruschitzka
F
F
Volpe
M
M
Lüscher
T F
TF
Noll
G
G
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D008078:Cholesterol, LDL / Q000097:blood; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D005260:Female; D005542:Forearm / Q000098:blood supply; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010991:Plethysmography / Q000379:methods; D012039:Regional Blood Flow / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
D008078:Cholesterol, LDL; D013481:Superoxides; D001708:Biopterins; D009569:Nitric Oxide; C003402:sapropterin