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(Hypertension. 2006;48:1066.)
© 2006 American Heart Association, Inc.

Original Articles

NO Synthase Uncoupling in the Kidney of Dahl S Rats

Role of Dihydrobiopterin

Norman E. Taylor; Kristopher G. Maier; Richard J. Roman; Allen W. Cowley, Jr

From the Department of Physiology, Medical College of Wisconsin, Milwaukee.

Correspondence to Norman E. Taylor, Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail ntaylor{at}mcw.edu

NO synthase (NOS) can paradoxically contribute to the production of reactive oxygen species when L-arginine or the cofactor R-tetrahydrobiopterin (BH₄) becomes limited. The present study examined whether NOS contributes to superoxide production in kidneys of hypertensive Dahl salt-sensitive (SS) rats compared with an inbred consomic control strain (SS-13^BN) and tested the hypothesis that elevated dihydrobiopterin (BH₂) levels are importantly involved in this process. This was assessed by determining the effects of L-nitroarginine methyl ester (L-NAME) inhibition of NOS on superoxide production and by comparing tissue concentrations of BH₄ and BH₂. A reverse-phase high-performance liquid chromatography method was applied for direct measurements of BH₄ and BH₂ using (S)-tetrahydrobiopterin as an internal standard. Superoxide concentrations were measured in vivo from medullary microdialysis fluid using dihydroethidine and in vitro using lucigenin. The results indicate the following: (1) that superoxide levels were elevated in the outer medulla of SS rats fed a 4% salt diet and could be inhibited by L-NAME. In contrast, L-NAME resulted in elevated superoxide production in consomic SS-13^BN rats because of higher NOS activity; (2) SS rats showed a reduced ratio of BH₄/BH₂ in the outer medulla that was driven by increased concentrations of BH₂; and (3) lower superoxide dismutase and catalase activities contributed to elevated reactive oxygen species in SS samples. Based on the shift of BH₄ to BH₂ and the observation of L-NAME inhibitable superoxide production, we conclude that NOS uncoupling occurs in the renal medulla of hypertensive SS rats fed a high-salt diet.

Key Words: free radicals • hypertension • renal • nitric oxide synthase • sodium

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