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Sympathetic regulation of NCC in norepinephrine-evoked salt-sensitive hypertension in Sprague-Dawley rats.
Am J Physiol Renal Physiol. 2019 12 01; 317(6):F1623-F1636.AJ

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.

Authors+Show Affiliations

Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts.Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts.Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts.Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts.College of Arts and Sciences, Boston University, Boston, Massachusetts.Research Service, Atlanta Veterans Affairs Medical Center, Decatur, Georgia. Division of Nephrology, Department of Medicine, Emory University, Atlanta, Georgia.Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31608673

Citation

Frame, Alissa A., et al. "Sympathetic Regulation of NCC in Norepinephrine-evoked Salt-sensitive Hypertension in Sprague-Dawley Rats." American Journal of Physiology. Renal Physiology, vol. 317, no. 6, 2019, pp. F1623-F1636.
Frame AA, Puleo F, Kim K, et al. Sympathetic regulation of NCC in norepinephrine-evoked salt-sensitive hypertension in Sprague-Dawley rats. Am J Physiol Renal Physiol. 2019;317(6):F1623-F1636.
Frame, A. A., Puleo, F., Kim, K., Walsh, K. R., Faudoa, E., Hoover, R. S., & Wainford, R. D. (2019). Sympathetic regulation of NCC in norepinephrine-evoked salt-sensitive hypertension in Sprague-Dawley rats. American Journal of Physiology. Renal Physiology, 317(6), F1623-F1636. https://doi.org/10.1152/ajprenal.00264.2019
Frame AA, et al. Sympathetic Regulation of NCC in Norepinephrine-evoked Salt-sensitive Hypertension in Sprague-Dawley Rats. Am J Physiol Renal Physiol. 2019 12 1;317(6):F1623-F1636. PubMed PMID: 31608673.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sympathetic regulation of NCC in norepinephrine-evoked salt-sensitive hypertension in Sprague-Dawley rats. AU - Frame,Alissa A, AU - Puleo,Franco, AU - Kim,Kiyoung, AU - Walsh,Kathryn R, AU - Faudoa,Elizabeth, AU - Hoover,Robert S, AU - Wainford,Richard D, Y1 - 2019/10/14/ PY - 2020/12/01/pmc-release PY - 2019/10/15/pubmed PY - 2020/4/14/medline PY - 2019/10/15/entrez KW - adrenoceptors KW - blood pressure KW - norepinephrine KW - salt-sensitive hypertension KW - sodium-chloride cotransporter SP - F1623 EP - F1636 JF - American journal of physiology. Renal physiology JO - Am. J. Physiol. Renal Physiol. VL - 317 IS - 6 N2 - 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. SN - 1522-1466 UR - https://www.unboundmedicine.com/medline/citation/31608673/Sympathetic_regulation_of_NCC_in_norepinephrine_evoked_salt_sensitive_hypertension_in_Sprague_Dawley_rats_ L2 - http://journals.physiology.org/doi/full/10.1152/ajprenal.00264.2019?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -