Altered tetrahydrobiopterin metabolism in atherosclerosis: implications for use of oxidized tetrahydrobiopterin analogues and thiol antioxidants.
OBJECTIVE
Tetrahydrobiopterin (BH4) is of fundamental importance for the normal function of endothelial NO synthase. The purpose of this study was to investigate the effects of hyperlipidemia on vascular BH4 levels and the effect of supplementation with sepiapterin in the presence and absence of N-acetylcysteine (NAC).


RESULTS
New Zealand White rabbits were fed normal chow (normocholesterolemic [NC] group) or hyperlipidemic chow (hyperlipidemic [HL] group) for 8 to 10 weeks. Mean cholesterol levels were 1465+/-333 and 53+/-17 mg/dL in the HL and NC group, respectively. Markedly diminished BH4 levels were found in the HL group compared with the NC group, but these levels could be restored after 6 hours of incubation with sepiapterin. Peak relaxations to acetylcholine and A23187 were impaired in the HL group. Supplementation with sepiapterin resulted in a further diminution of relaxation in the HL but not NC group. Incubation with NAC for 6 hours failed to raise BH4 levels, whereas NAC in conjunction with sepiapterin raised BH4 levels approximately 221-fold. However, this increase did not improve relaxations to A23187 and acetylcholine.


CONCLUSIONS
Prolonged exposure to sepiapterin impairs vasorelaxation in hyperlipidemia despite repletion of endogenous BH4. Antioxidant thiols do not correct this impairment. These studies have implications for the use of sepiapterin in the correction of vasomotor tone in atherosclerosis.
Vásquez-Vivar
Jeannette
J
Biophysics Research Institute, Medical College of Wisconsin, Milwaukee, USA.
Duquaine
Damon
D
Whitsett
Jennifer
J
Kalyanaraman
B
B
Rajagopalan
Sanjay
S
D000109:Acetylcholine / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001013:Aorta, Thoracic / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D001161:Arteriosclerosis / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D002784:Cholesterol / Q000097:blood; D004032:Diet; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006949:Hyperlipidemias / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism / Q000502:physiology; D052250:Nitric Oxide Synthase Type III; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D011621:Pteridines / Q000494:pharmacology; D011622:Pterins; D011817:Rabbits; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D014665:Vasodilator Agents / Q000494:pharmacology
D000975:Antioxidants; D016166:Free Radical Scavengers; D007476:Ionophores; D011621:Pteridines; D011622:Pterins; D013438:Sulfhydryl Compounds; D014665:Vasodilator Agents; D001708:Biopterins; D009569:Nitric Oxide; D000001:Calcimycin; D002784:Cholesterol; C016727:sepiapterin; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C003402:sapropterin; D000109:Acetylcholine; D010100:Oxygen; D000111:Acetylcysteine