α1‐Adrenoceptor Antagonism Attenuates the Development and Progression of Dahl Salt Sensitive Rat Hypertension by Modulating NCC Activity

Abstract

BackgroundDietary sodium intake plays a significant role in blood pressure (BP) regulation, as increased sodium retention is a well‐established precursor of hypertension risk. In particular, increased dietary sodium intake evokes increased BP in individuals that demonstrate the salt sensitivity of BP and promotes the development of salt sensitive hypertension (SSH). Recent studies suggest that excessive Sympathetic Nervous System (SNS) release of norepinephrine (NE) has the ability to stimulate the sodium chloride cotransporter (NCC) via synergistic α1 and β adrenergic receptor pathways to drive SSH.HypothesisEndogenous SNS release of NE activates an α1‐adrenoceptor pathway to mediate increases in NCC activity that drive the development and maintenance of Dahl rat SSH.MethodsGroups of naïve Dahl Salt Sensitive (DSS) rats, DSS rats receiving a continuous subcutaneous (s.c.) terazosin (10 mg/kg/day), or s.c. propranolol (10 mg/kg/day) infusion were fed a normal salt (NS, 0.6% NaCl) or high salt (HS, 4% NaCl) diet for 21 days respectively. On day 21 basal MAP and NCC activity (peak natriuresis to iv hydrochlorothiazide (HCTZ; 2mg/kg) infusion) were assessed. NCC expression and phosphoNCC levels were assayed via immunoblotting (N=6/gp). Additional groups of DSS rats were fed a 42 day HS diet. On day 21, rats were given s.c. saline/DMSO or s.c. terazosin/DMSO (10 mg/kg/day). On day 42, measurements were taken as described previously (N=4–6/gp).ResultsDSS rats develop SSH when fed a 21 day HS diet and show increased NCC activity compared to rats on a NS diet. NCC expression and phospho levels are similar in both the diets. Use of an α1‐adrenoceptor antagonist, terazosin (confirmed pharmacologically) attenuates SSH and reduces NCC activity and expression as well as phosphoNCC levels in rats on a HS diet. Use of a β‐adrenoceptor antagonist, propranolol fails to attenuate SSH or reduce NCC activity. Significantly, α1 antagonism has a trend to reduce BP and NCC activity in DSS rats with established HTN.ConclusionOur data reveals that SNS release of NE modulates NCC activity via an α1‐adrenoceptor pathway to evoke dietary evoked SSH. Significantly, α1‐adreoceptor antagonism can attenuate the development of SSH by evoking downregulation of NCC activity and expression. In a model of established HTN, α1‐adreoceptor antagonism reduces NCC activity and BP. Taken together, these findings suggest that SNS release of NE activates an α1‐adreoceptor pathway that stimulates NCC activity to drive the development and maintenance of SSH.Support or Funding InformationThis work was funded by NIH R56 AG057687, R01 HL139867, R01HL141406, AHA17GRNT33670023 to RDW, and F31DK116501 to AAF.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.