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Abstract: FR-PO325

Sympathetic Nervous System Regulation of the NCC Is Mediated by α1-Adrenoceptors and OxSR1 to Drive Hypertension

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Puleo, Franco J., Boston University, Boston, Massachusetts, United States
  • Frame, Alissa, Boston University, Boston, Massachusetts, United States
  • Wainford, Richard David, Boston University, Boston, Massachusetts, United States
Background

Recent studies suggest that Sympathetic nervous system (SNS) release of norepinephrine (NE) mediates acute sodium chloride cotransporter (NCC) upregulation via synergistic α1 and β adrenoceptor pathways and oxidative stress responsive 1 (OXSR1) signaling in NCC regulation.

Hypothesis: NE increases NCC activity via an α1-adrenoceptor and OxSR1 pathway to drive neurogenic or salt sensitive hypertension (HTN, SSH).

Methods

Male Sprague-Dawley (SD) rats receiving a continuous s.c. saline, NE (600ng/min), or NE + terazosin (α1 antagonist, 10mg/kg/day) infusion were fed a 0.6% (NS) or 4% NaCl (HS) diet for 14 days. Naïve or 14 day s.c. terazosin infused spontaneous hypertensive rats (SHR) and Wister Kyoto (WKY) rats were also assessed (N=4/gp). On day 14 basal MAP and NCC activity (peak natriuresis to hydrochlorothiazide [HCTZ]; 2mg/kg) were assessed. NCC, phosphoNCC, and OXSR1 protein levels were assayed via immunoblotting. Expression of adrenoceptor mRNA (α1A-D, β1, β2) was assessed via qPCR using kidney samples from separate groups of rats (N=6/gp).

Results

SD rats remain normotensive on a HS diet and NCC expression and activity is downregulated. NE infusion prevents HS-evoked NCC downregulation, leads to increased OXSR1 expression, and drives SSH. The SHR model of neurogenic HTN shows increased NCC activity and high BP. SHR and NE-infused SD rats show increased expression of α1-adrenoceptor-1D mRNA (SHR: 1.4±0.1 fold increase vs. WKY rats, NE-infused SD rats on NS: 2.2 ±0.5 fold increase, on HS: 2.2±0.4 fold increase vs. respective SD rat diet group). Antagonism of α1-adrenoceptors 1) abolishes SSH and restores HS evoked downregulation of NCC activity in NE-infused SD rats, 2) reduces NCC activity and BP in SHR.

Conclusion

SNS release of NE can modulate NCC activity via an α1-adrenoceptor pathway to evoke SSH and neurogenic HTN. Taken together, we propose a model whereby SNS release of NE activates a linear α1-adrenoceptor pathway that stimulates OxSR1-mediated NCC regulation. Thus, sympathetically driven increases in renal expression of α1-adrenoceptors may contribute to SSH and HTN by driving increases in NCC mediated sodium reabsorption and BP.

Funding

  • Other NIH Support