Decreased arteriolar tetrahydrobiopterin is linked to superoxide generation from nitric oxide synthase in mice fed high salt.
OBJECTIVE
Impaired endothelium-dependent arteriolar dilation in mice fed high salt (HS) is due to local oxidation of nitric oxide (NO) by superoxide anion (O(2) (-)). We explored the possibility that "uncoupled" endothelial nitric oxide synthase (eNOS) is the source of this O(2) (-).


METHODS
Levels of L-arginine (L-Arg), tetrahydrobiopterin (BH(4)), and O(2) (-) (hydroethidine oxidation) were measured in spinotrapezius muscle arterioles of mice fed normal salt (0.45%, NS) or (4%, HS) diets for 4 weeks, with or without dietary L-Arg supplementation. The contribution of NO to endothelium-dependent dilation was determined from the effect of N(omega)-nitro-L-arginine methyl ester (L-NAME) on responses to acetylcholine (ACh).


RESULTS
Arterioles in HS mice had lower [BH(4)] and higher O(2) (-) levels than those in NS mice. ACh further increased arteriolar O(2) (-) in HS mice only. L-Arg supplementation prevented the reduction in [BH(4)] in arterioles of HS mice, and O(2) (-) was not elevated in these vessels. Compared to NS mice, arteriolar ACh responses were diminished and insensitive to L-NAME in HS mice, but not in HS mice supplemented with L-Arg.


CONCLUSIONS
These findings suggest that eNOS uncoupling due to low [BH(4)] is responsible for O(2) (-) generation and reduced NO-dependent dilation in arterioles of mice fed a HS diet.
Nurkiewicz
Timothy R
TR
Center for Cardiovascular and Respiratory Sciences, West Virginia University, School of Medicine, Morgantown, WV 26506-9105, USA.
Wu
Guoyao
G
Li
Peng
P
Boegehold
Matthew A
MA
D000818:Animals; D001120:Arginine / Q000378:metabolism; D001160:Arterioles / Q000378:metabolism* / Q000502:physiology; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D006136:GTP Cyclohydrolase / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage* / Q000009:adverse effects; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000502:physiology
D017673:Sodium Chloride, Dietary; D013481:Superoxides; D001708:Biopterins; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D006136:GTP Cyclohydrolase; C003402:sapropterin