Sympathetically mediated α1‐adrenoceptor regulation of the NCC during high salt intake to drive renal sodium retention: A new therapeutic anti‐hypertensive target?

Background It has been hypothesized that there is a direct role of increased sympathetic nervous system (SNS) release of norepinephrine (NE) in the up regulation of the sodium chloride cotransporter (NCC), via a β‐adrenoceptor pathway, to evoke the pathophysiology of salt sensitive hypertension (HTN). Recent data challenge this hypothesis and acute studies have suggested a potential role of α1 adrenoceptors in NCC regulation. Hypothesis Excess SNS release of norepinephrine (NE) increases NCC activity via an α1‐ adrenoceptor pathway to drive the development of salt‐sensitive HTN. Methods Male Sprague‐Dawley (SD) rats receiving a continuous s.c. saline or NE (600ng/min) infusion were fed a 0.6% (NS) or 4% NaCl (HS) diet for 14 days respectively (N=4/gp). Separate groups of NE infused SD and DSS rats received propranolol (9.9mg/kg/day; s.c.) or terazosin (10mg/kg/day; s.c.) and a NS or HS diet for 14‐days. On day 14 basal MAP and NCC activity (peak natriuresis to iv hydrochlorothiazide (HCTZ; 2mg/kg) infusion and phosphoNCCT58 (via immunoblotting) and expression (via immunoblotting) was assessed. Additional groups of rats received a continuous s.c. NE (600ng/min) infusion and 28‐day NS or HS intake. On day 14 of HS a sub group of rats were switched to a NE‐terazosin s.c. co‐infusion. On day‐28 basal MAP and NCC activity and expression were assessed as detailed above. Results SD rats exhibit HS evoked suppression of NCC expression and activity. In contrast, NE infused SD rats exhibit HTN and fail to suppress NCC expression and activity during HS‐intake. β‐adrenoceptor antagonism (confirmed pharmacologically) reduced MAP in NE infused SD rats but failed to decrease NCC activity or expression. In contrast α1‐adrenoceptor antagonism (confirmed pharmacologically) abolished the salt‐sensitive component of HTN and restored dietary sodium evoked suppression of NCC activity and expression in NE infused SD rats. Significantly, α 1 ‐adrenoceptor antagonism in established NE‐infusion evoked salt‐sensitive HTN in SD rats restored HS‐evoked suppression of NCC activity and abolished the salt‐sensitivity of BP. Conclusion Our data suggests SNS activation of the NCC by NE occurs via a reversible α1‐ adrenoceptor pathway to prevent dietary sodium evoked suppression of NCC activity to drive the development of salt‐sensitive HTN. The PATHWAY‐2 Trial reported a primary role of sodium retention in resistant HTN suggesting α1‐adrenoceptor antagonism represents a new therapeutic approach for resistant and sympathetically mediated HTN. Support or Funding Information This work was supported by NIH grants R01HL107330 and K02HL112718 and AHA 16MM32090001 to RDW and T32GM008541 to AAF. 1Dietary Salt Intake MAP (mmHg) Peak ΔUNaV to HCTZ (μeq/min) Total NCC Expression (ODU/mm 2 ) Total NCC Expression (ODU/mm 2 )SD rat 14‐day sc Saline NS 124±2 9.7±0.6 1.7±0.4 1.8±0.6 HS 124±1 6.2±0.4 * 0.7±0.3 * 0.6±0.2 * SD rat 14‐day sc NE (600ng/min) NS 149±4 10.1±1.3 1.8±0.4 1.9±0.4 HS 169±5 * # 10.8±0.4 # 2.4±0.9 # 2.1±0.4 # SD rat 14‐day sc NE + terazosin NS 152±4 10.7±1.2 1.8±0.3 1.7±0.4 HS 150±5 # 6.14±1.2 * 0.5±0.1 * 0.6±0.2 * SD rat 14‐day sc NE + propranolol NS 133±4 10.6±1 1.6±0.2 1.7±0.4 HS 134±4 9.8±1.8 # 1.7±0.4 # 1.9±0.3 # SD rat 28‐day sc Saline NS 122±3 10.6±1.2 N.D. N.D. HS 123±4 6.4±1.3 * N.D. N.D. SD rat 28‐day sc NE (600ng/min) NS 152±4 10.3±1 N.D. N.D. HS 174±6 * # 10.2±1.2 # N.D. N.D. SD rat 28‐day sc NE + 14‐day terazosin NS 148±3 10..5±0.8 N.D. N.D. HS 146±4 # 6.6±0.7 * N.D. N.D.* p<0.05 vs. respective NS group; # p<0.05 vs. respective SD sc saline HS group N.D. = not determined