Sympathetic Regulation of the NCC (Sodium Chloride Cotransporter) in Dahl Salt–Sensitive Hypertension

Abstract

Increased sympathoexcitation and renal sodium retention during high salt intake are hallmarks of the salt sensitivity of blood pressure. The mechanism(s) by which excessive sympathetic nervous system release of norepinephrine influences renal sodium reabsorption is unclear. However, studies demonstrate that norepinephrine can stimulate the activity of the NCC (sodium chloride cotransporter) and promote the development of SSH (salt-sensitive hypertension). The adrenergic signaling pathways governing NCC activity remain a significant source of controversy with opposing studies suggesting a central role of upstream α 1 - and β-adrenoceptors in the canonical regulatory pathway involving WNKs (with-no-lysine kinases), SPAK (STE20/SPS1-related proline alanine-rich kinase), and OxSR1 (oxidative stress response 1). In our previous study, α 1 -adrenoceptor antagonism in norepinephrine-infused male Sprague-Dawley rats prevented the development of norepinephrine–evoked SSH in part by suppressing NCC activity and expression. In these studies, we used selective adrenoceptor antagonism in male Dahl salt–sensitive rats to test the hypothesis that norepinephrine-mediated activation of the NCC in Dahl SSH occurs via an α 1 -adrenoceptor dependent pathway. A high-salt diet evoked significant increases in NCC activity, expression, and phosphorylation in Dahl salt–sensitive rats that developed SSH. Increases were associated with a dysfunctional WNK1/4 dynamic and a failure to suppress SPAK/OxSR1 activity. α 1 -adrenoceptor antagonism initiated before high–salt intake or following the establishment of SSH attenuated blood pressure in part by suppressing NCC activity, expression, and phosphorylation. Collectively, our findings support the existence of a norepinephrine-activated α 1 -adrenoceptor gated pathway that relies on WNK/SPAK/OxSR1 signaling to regulate NCC activity in SSH.

Activation of the kidney sodium chloride cotransporter by the β2-adrenergic receptor agonist salbutamol increases blood pressure

“…2 However, in norepinephrine-infused Sprague-Dawley rats and saltsensitive Dahl rats, a-AR antagonism attenuated hypertension in part by suppressing NCC activity and expression. 3,65 A simple explanation for these differences is not apparent, but it is plausible that there are different overall effects on BP and/or NCC if one type of AR receptor is stimulated/inhibited alone or in combination with another receptor, so-called receptor cross talk, which is well described for ARs. [66][67][68] Alternatively, there may be species-dependent differences in AR responses or distribution, which may be different under different dietary intakes or (patho)physiological settings, making a comprehensive study on the role of aand b-ARs in human saltsensitive hypertension of great importance.…”

Sensory Afferent Renal Nerve Activated Gαi2 Subunit Proteins Mediate the Natriuretic, Sympathoinhibitory and Normotensive Responses to Peripheral Sodium Challenges

“…Rats were instrumented with PE-50 catheters in the left femoral vein and left femoral artery and a PE-240 catheter in the bladder to allow I.V. administration of isotonic saline and experimental sodium challenges, measurement of mean arterial pressure (MAP) and heart rate (HR), and assessment of renal excretory function, respectively ( Walsh et al, 2016 ; Frame et al, 2019 ; Carmichael et al, 2020 ; Puleo et al, 2020 ). Rats were placed in a Plexiglas rat holder and an I.V.…”

Natriuresis During an Acute Intravenous Sodium Chloride Infusion in Conscious Sprague Dawley Rats Is Mediated by a Blood Pressure-Independent α1-Adrenoceptor-Mediated Mechanism

“…Rats were anesthetized using sodium brevital (20 mg/kg IP) and were randomly assigned to be surgically implanted with an osmotic minipump (2ML4, Alzet) subcutaneously in the subscapular region ( Walsh et al, 2016 ; Frame et al, 2019b ) delivering a continuous 21-day s.c. infusion (2.5 μL/h) of 50/50 isotonic saline/DMSO or terazosin hydrochloride [10mg/kg/day ( Maranon et al, 2015 ; Frame et al, 2019b ) Sigma] dissolved in 50/50 saline/DMSO ( Frame et al, 2019b ; Puleo et al, 2020 ).…”