title: Norepinephrine-evoked salt-sensitive hypertension requires impaired renal sodium chloride cotransporter activity in Sprague-Dawley rats.
abstract: Recent studies have implicated a role of norepinephrine (NE) in the activation of the sodium chloride cotransporter (NCC) to drive the development of salt-sensitive hypertension. However, the interaction between NE and increased salt intake on blood pressure remains to be fully elucidated. This study examined the impact of a continuous NE infusion on sodium homeostasis and blood pressure in conscious Sprague-Dawley rats challenged with a normal (NS; 0.6% NaCl) or high-salt (HS; 8% NaCl) diet for 14 days. Naïve and saline-infused Sprague-Dawley rats remained normotensive when placed on HS and exhibited dietary sodium-evoked suppression of peak natriuresis to hydrochlorothiazide. NE infusion resulted in the development of hypertension, which was exacerbated by HS, demonstrating the development of the salt sensitivity of blood pressure [MAP (mmHg) NE+NS: 151 ± 3 vs. NE+HS: 172 ± 4; P < 0.05]. In these salt-sensitive animals, increased NE prevented dietary sodium-evoked suppression of peak natriuresis to hydrochlorothiazide, suggesting impaired NCC activity contributes to the development of salt sensitivity [peak natriuresis to hydrochlorothiazide (μeq/min) Naïve+NS: 9.4 ± 0.2 vs. Naïve+HS: 7 ± 0.1; P < 0.05; NE+NS: 11.1 ± 1.1; NE+HS: 10.8 ± 0.4). NE infusion did not alter NCC expression in animals maintained on NS; however, dietary sodium-evoked suppression of NCC expression was prevented in animals challenged with NE. Chronic NCC antagonism abolished the salt-sensitive component of NE-mediated hypertension, while chronic ANG II type 1 receptor antagonism significantly attenuated NE-evoked hypertension without restoring NCC function. These data demonstrate that increased levels of NE prevent dietary sodium-evoked suppression of the NCC, via an ANG II-independent mechanism, to stimulate the development of salt-sensitive hypertension.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Walsh
authors.affiliation: Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Jill T
authors.initials: JT
authors.lastname: Kuwabara
authors.affiliation: Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Joon W
authors.initials: JW
authors.lastname: Shim
authors.affiliation: Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts rwainf@bu.edu.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Wainford
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure; D004195:Disease Models, Animal; D006852:Hydrochlorothiazide / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009318:Natriuresis; D009638:Norepinephrine; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology; D017673:Sodium Chloride, Dietary / Q000097:blood; D064486:Solute Carrier Family 12, Member 3 / Q000187:drug effects / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; C578876:Slc12a3 protein, rat; D049993:Sodium Chloride Symporter Inhibitors; D017673:Sodium Chloride, Dietary; D064486:Solute Carrier Family 12, Member 3; D006852:Hydrochlorothiazide; D019808:Losartan; D009638:Norepinephrine
keywords: NCC; norepinephrine; salt-sensitive hypertension; sodium homeostasis; sympathetic nervous system