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Recoupling of eNOS in hypertension: Effects of tetrahydrobiopterin and blockade of vascular NAD(P)H oxidases
Author(s) -
Cai Hua “Linda”,
Laude Karine,
Blair John,
McCann Louise,
Harrison David
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1453
Subject(s) - apocynin , enos , tetrahydrobiopterin , chemistry , superoxide , endocrinology , medicine , nitric oxide , nad+ kinase , nitric oxide synthase , nad(p)h oxidase , oxidase test , biopterin , nadph oxidase , oxidative stress , pharmacology , biochemistry , enzyme
The endothelial cell nitric oxide synthase (eNOS) requires tetrahydrobiopterin as a co‐factor, and in its absence, begins to produce superoxide rather than nitric oxide (NO), a condition referred to as eNOS uncoupling. In DOCA salt hypertension, activation of vascular NAD(P)H oxidase leads to oxidation of tetrahydrobiopterin and subsequent uncoupling of eNOS. The present study investigated whether acute administration of tetrahydrobiopterin and/or inhibition of the vascular NAD(P)H oxidase could restore NO production from uncoupled eNOS. NO detected by electron spin resonance (ESR) was markedly reduced in aortas of DOCA‐salt hypertensive mice. Incubation of vessels with H4B (10 æmol/L), at 37§C for 30 min markedly augmented NO production from control vessels and partially improved NO bioavailability from hypertensive aortas. Incubation with apocynin (100 æmol/L), an vascular NAD(P)H oxidase antagonist, also partially restored NO production from hypertensive vessels. Interestingly, co‐administration of H4B and apocynin normalized NO to control level while it completely attenuated superoxide production (measured quantitatively by monitoring the oxidation of dihydroethidium to oxyethidium) from hypertensive aortas. In summary, these data demonstrate that co‐administration of H4B and apocynin effectively recouples eNOS in hypertensive blood vessels. These observations provide insight into potentially new therapeutic approach to correction of oxidant stress in a variety of cardiovascular diseases in which eNOS uncoupling occurs. This work is supported by American Heart Association and American Diabetes Association Grants 0435189N, 7‐04‐RA‐16, NIH Grants HL077440 and HL081571 (all H Cai), and HL 39006 (DGH).