title: High-salt intake enhances superoxide activity in eNOS knockout mice leading to the development of salt sensitivity.
abstract: 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.
authors.affiliation: Department of Physiology, Tulane Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, Louisiana 70112, USA.
authors.forename: Libor
authors.initials: L
authors.lastname: Kopkan
authors.forename: Arthur
authors.initials: A
authors.lastname: Hess
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Husková
authors.forename: Ludek
authors.initials: L
authors.lastname: Cervenka
authors.forename: L Gabriel
authors.initials: LG
authors.lastname: Navar
authors.forename: Dewan S A
authors.initials: DS
authors.lastname: Majid
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology; D015237:Dinoprost / Q000031:analogs & derivatives / Q000652:urine; D004195:Disease Models, Animal; D006973:Hypertension / Q000209:etiology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D017673:Sodium Chloride, Dietary / Q000009:adverse effects / Q000494:pharmacology*; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism*
chemical_list: D000098:Acetophenones; D000975:Antioxidants; D003497:Cyclic N-Oxides; D017673:Sodium Chloride, Dietary; D013113:Spin Labels; D013481:Superoxides; C075750:8-epi-prostaglandin F2alpha; C056165:acetovanillone; D015237:Dinoprost; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C001803:tempol