High-salt intake enhances superoxide activity in eNOS knockout mice leading to the development of salt sensitivity

• Published in: American Journal of Physiology - Renal Physiology 2010-09, Vol.299 (3), p.F656-F663
• Main Authors: Kopkan, Libor, Hess, Arthur, Husková, Zuzana, Cervenka, Ludek, Navar, L Gabriel, Majid, Dewan S A
• Format: Article
• Language: English
• Subjects: Acetophenones - pharmacology; Animals; Antioxidants - pharmacology; Blood Pressure - drug effects; Cyclic N-Oxides - pharmacology; Diet; Dinoprost - analogs & derivatives; Dinoprost - urine; Disease Models, Animal; Hypertension; Hypertension - etiology; Hypertension - metabolism; Kidneys; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric oxide; Nitric Oxide Synthase Type III - genetics; Nitric Oxide Synthase Type III - metabolism; Rodents; Salt; Sodium Chloride, Dietary - adverse effects; Sodium Chloride, Dietary - pharmacology; Spin Labels; Superoxides - metabolism
• ISSN: 1931-857X; 0363-6127; 1522-1466
• DOI: 10.1152/ajprenal.00047.2010

A deficiency in nitric oxide (NO) generation leads to salt-sensitive hypertension, but the role of increased superoxide (O(2)(-)) in such salt sensitivity has not been delineated. We examined the hypothesis that an enhancement in O(2)(-) activity induced by high-salt (HS) intake under deficient NO production contributes to the development of salt-sensitive hypertension. Endothelial NO synthase knockout (eNOS KO; total n = 64) and wild-type (WT; total n = 58) mice were given diets containing either normal (NS; 0.4%) or high-salt (HS; 4%) for 2 wk. During this period, mice were chronically treated with a O(2)(-) scavenger, tempol (400 mg/l), or an inhibitor of NADPH oxidase, apocynin (1 g/l), in drinking water or left untreated (n = 6-8 per group). Blood pressure was measured by radiotelemetry and 24-h urine samples were collected in metabolic cages. Basal mean arterial pressure (MAP) in eNOS KO was higher (125 +/- 4 vs. 106 +/- 3 mmHg) compared with WT. Feeding HS diet did not alter MAP in WT but increased it in eNOS KO to 166 +/- 9 mmHg. Both tempol and apocynin treatment significantly attenuated the MAP response to HS in eNOS KO (134 +/- 3 and 139 +/- 4 mmHg, respectively). Basal urinary 8-isoprostane excretion rates (U(Iso)V), a marker for endogenous O(2)(-) activity, were similar (2.8 +/- 0.2 and 2.4 +/- 0.3 ng/day) in both eNOS KO and WT mice. However, HS increased U(Iso)V more in eNOS KO than in WT (4.6 +/- 0.3 vs. 3.8 +/- 0.2 ng/day); these were significantly attenuated by both tempol and apocynin treatment. These data indicate that an enhancement in O(2)(-) activity contributes substantially to the development of salt-sensitive hypertension under NO-deficient conditions.