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

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: Alissa A Frame, Franco Puleo, Kiyoung Kim, Kathryn R Walsh, Elizabeth Faudoa, Robert S Hoover, Richard D Wainford
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 317 Issue 6 Pg. F1623-F1636 (12 01 2019) ISSN: 1522-1466 [Electronic] United States
• PMID: 31608673 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Adrenergic alpha-1 Receptor Antagonists (pharmacology)
• Adrenergic beta-Antagonists (pharmacology)
• Animals
• Hypertension (chemically induced, metabolism, physiopathology)
• Kidney (drug effects, 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)