Abstract P329: Sympathetically Alpha-1 Adrenoceptor Mediated Regulation of the NCC in Rat Models of Salt Sensitive and Neurogenic Hypertension

Abstract

Hypothesis: Excess SNS release of norepinephrine (NE) increases NCC activity, via an α1 adrenoceptor pathway, to drive the development and maintenance of salt-sensitive and neurogenic hypertension (HTN). Methods: Male Sprague-Dawley (SD) rats receiving a continuous s.c. saline or NE (600ng/min) infusion alone or in combination with terazosin (10mg/kg/day) were fed a 14-day 0.6% (NS) or 4% NaCl (HS) diet. Separate groups of male SD rats received a continuous s.c. NE infusion and 28-day NS or HS intake, on day 14 of HS a sub group of rats were switched to a co NE-terazosin s.c. infusion. Groups of male SHR rats received s.c. saline or terazosin for 14 days. Endpoint measurements (day 14 or 28) were basal MAP and NCC activity (peak natriuresis to iv hydrochlorothiazide (HCTZ; 2mg/kg) infusion and phosphoNCCT58 immunoblotting) and expression (via immunoblotting) was assessed (N=4/gp). Results: NE infused SD rats exhibit HTN and fail to suppress NCC expression and activity during HS-intake. α1-adreoceptor antagonism (confirmed pharmacologically) abolished the salt-sensitive component of NE HTN and restored dietary sodium evoked suppression of the NCC in NE infused SD rats. Critically, α 1 -adrenoceptor antagonism lowers BP and reduces NCC activity in established SHR HTN and restores sodium-evoked suppression of NCC activity and abolishes the salt sensitivity of BP in established NE-evoked SS HTN. Conclusion: SNS activation of the NCC by NE occurs in rat models of neurogenic and SS HTN. Our data demonstrates antagonism of α 1 -adrenoceptors lowers BP and NCC activity in established SS and neurogenic HTN and suggests α 1 -antagonists as a therapeutic option in sympathetically mediated HTN.