Abstract P118: Differential Effects of Renal α- and β-Adrenoreceptors in the Development of Sodium Chloride Cotransporter (NCC) Dysfunction and Salt-sensitive Hypertension
Aim: Determine the contribution of α vs. β-adrenoeceptors in NCC dysfunction & the development of salt-sensitive hypertension (HTN).
Methods: Sprague-Dawley rats receiving a sc saline, NE (600ng/min), NE with propranolol (Pro; 9.9mg/kg/day) or NE with prazosin (Praz; 2.5mg/kg/day, orally) infusion were fed a 0.4% (NS) or 8% NaCl (HS) diet for 14 days (N=6). On day 14, MAP & NCC activity (peak natriuresis to iv hydrochlorothiazide infusion; HCTZ; 2mg/kg) was assessed. Immunoblotting for NCC, STE-20 Alanine/Proline kinase (SPAK), & oxidative stress response-1 (OxSR1) was performed on kidney cortex tissue.
Results: NE infusion results in HTN that is exacerbated by HS (MAP [mmHg] NE+NS 151±3; NE+HS 171±4; p<0.05). Excess NE prevents HS-evoked suppression of NCC function and NCC & SPAK expression. NE:Pro co-infusion significantly decreased MAP (MAP NE:Pro+NS 136±4; NE:Pro+HS 136±4), regardless of Na+ intake, when compared to rats receiving the NE infusion, but failed to restore HS-evoked suppression of NCC activity (similar to results observed when AT1Rs are chronically antagonized during NE infusion; data not shown), or NCC, SPAK, or OxSR1 expression despite reduced baseline SPAK & OxSR1 compared to NE alone. NE:Praz co-administration abolished the salt-sensitive component of NE-induced HTN (MAP NE:Praz+NS 159±5; NE:Praz+HS 156±5) and restored HS-evoked suppression of NCC function and expression (Peak ΔUNaV [μeq/μl] NE:Praz+NS 10.7±1.2; NE:Praz+HS 6.14±1.2; p<0.05). NE+Praz co-administration resulted in HS-evoked suppression of SPAK, but not OxSR1 expression, in addition to decreased baseline expression of SPAK/OxSR1.
Discussion: Our data suggests that α, but not β, adrenoreceptors are predominantly responsible for NE-mediated NCC dysregulation and the development of salt-sensitive HTN. During a HS intake, α-adrenoreceptors mediate NE-evoked salt-sensitivity via a SPAK-NCC dependent pathway. Chronic antagonism of β-adrenoreceptors decreased MAP independent of direct effects on NCC possibly via actions on the RAS. Our data shows a synergistic relationship between α-/β-adrenoreceptors to upregulate SPAK/OxSR1 during chronic adrenergic stimulation with SPAK as the primary driver of NCC dysfunction & salt-sensitivity.
Author Disclosures: K.R. Walsh: None. R.D. Wainford: B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Significant; R01HL107330, K02HL112718.
- © 2015 by American Heart Association, Inc.