Sympathetic regulation of NCC in norepinephrine-evoked salt-sensitive hypertension in Sprague-Dawley rats

Author:

Frame Alissa A.1,Puleo Franco1,Kim Kiyoung1,Walsh Kathryn R.1,Faudoa Elizabeth2,Hoover Robert S.34,Wainford Richard D.1

Affiliation:

1. Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts

2. College of Arts and Sciences, Boston University, Boston, Massachusetts

3. Research Service, Atlanta Veterans Affairs Medical Center, Decatur, Georgia

4. Division of Nephrology, Department of Medicine, Emory University, Atlanta, Georgia

Abstract

Salt sensitivity of blood pressure is characterized by inappropriate sympathoexcitation and renal Na+ reabsorption during high salt intake. In salt-resistant animal models, exogenous norepinephrine (NE) infusion promotes salt-sensitive hypertension and prevents dietary Na+-evoked suppression of the Na+-Cl cotransporter (NCC). Studies of the adrenergic signaling pathways that modulate NCC activity during NE infusion have yielded conflicting results implicating α1- and/or β-adrenoceptors and a downstream kinase network that phosphorylates and activates NCC, including with no lysine kinases (WNKs), STE20/SPS1-related proline-alanine-rich kinase (SPAK), and oxidative stress response 1 (OxSR1). In the present study, we used selective adrenoceptor antagonism in NE-infused male Sprague-Dawley rats to investigate the differential roles of α1- and β-adrenoceptors in sympathetically mediated NCC regulation. NE infusion evoked salt-sensitive hypertension and prevented dietary Na+-evoked suppression of NCC mRNA, protein expression, phosphorylation, and in vivo activity. Impaired NCC suppression during high salt intake in NE-infused rats was paralleled by impaired suppression of WNK1 and OxSR1 expression and SPAK/OxSR1 phosphorylation and a failure to increase WNK4 expression. Antagonism of α1-adrenoceptors before high salt intake or after the establishment of salt-sensitive hypertension restored dietary Na+-evoked suppression of NCC, resulted in downregulation of WNK4, SPAK, and OxSR1, and abolished the salt-sensitive component of hypertension. In contrast, β-adrenoceptor antagonism attenuated NE-evoked hypertension independently of dietary Na+ intake and did not restore high salt-evoked suppression of NCC. These findings suggest that a selective, reversible, α1-adenoceptor-gated WNK/SPAK/OxSR1 NE-activated signaling pathway prevents dietary Na+-evoked NCC suppression, promoting the development and maintenance of salt-sensitive hypertension.

Funder

HHS | NIH | National Institute on Aging

HHS | NIH | National Heart, Lung, and Blood Institute

American Heart Association

HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases

Health Services Research and Development

American Society of Nephrology

American Physiological Society

Publisher

American Physiological Society

Subject

Physiology

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