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

Am J Physiol Renal Physiol. 2019 Dec 1;317(6):F1623-F1636. doi: 10.1152/ajprenal.00264.2019. Epub 2019 Oct 14.

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.

Keywords: adrenoceptors; blood pressure; norepinephrine; salt-sensitive hypertension; sodium-chloride cotransporter.

Publication types

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

MeSH terms

  • Adrenergic alpha-1 Receptor Antagonists / pharmacology
  • Adrenergic beta-Antagonists / pharmacology
  • Animals
  • Hypertension / chemically induced
  • Hypertension / metabolism*
  • Hypertension / physiopathology
  • Kidney / drug effects
  • Kidney / metabolism
  • Male
  • Norepinephrine*
  • Protein Serine-Threonine Kinases / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, alpha-1 / metabolism
  • Receptors, Adrenergic, beta / metabolism
  • Sodium, Dietary / pharmacology
  • Solute Carrier Family 12, Member 3 / metabolism*
  • Sympathetic Nervous System / physiopathology*

Substances

  • Adrenergic alpha-1 Receptor Antagonists
  • Adrenergic beta-Antagonists
  • Receptors, Adrenergic, alpha-1
  • Receptors, Adrenergic, beta
  • Sodium, Dietary
  • Solute Carrier Family 12, Member 3
  • Wnk4 protein, rat
  • PAS domain kinases
  • Protein Serine-Threonine Kinases
  • Norepinephrine