Abstract P334: Sympathetically Mediated Alpha-1 Adrenoceptor Regulation of the NCC During High Salt Intake: A New Therapeutic Target for Resistant Hypertension

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Richard D Wainford ◽  
Kathryn R Walsh
Keyword(s):  
Salt Intake ◽  
Dietary Sodium ◽  
Primary Role ◽  
Sprague Dawley ◽  
Sd Rats ◽  
High Salt Intake ◽  
Adrenoceptor Regulation ◽  
Salt Sensitive Hypertension ◽  
Expression And Activity

Aim: We hypothesize that excess norepinephrine (NE) modulates NCC activity via an α1 adrenoceptor pathway to drive the development of salt-sensitive hypertension (HTN). Methods: Male Sprague-Dawley (SD) rats receiving a continuous s.c. saline or NE (600ng/min) infusion and naïve Dahl Salt-Sensitive (DSS) rats were fed a 0.6% (NS) or 8% NaCl (HS) diet for 14 or 21 days respectively (N=4/gp). On day 14 (SD) or 21 (DSS) MAP and NCC activity (peak natriuresis to iv hydrochlorothiazide (HCTZ; 2mg/kg) infusion) and expression (via immunoblotting) was assessed. Additional groups of NE infused SD and DSS rats received a propranolol (9.9mg/kg/day; s.c.) or prazosin (2.5mg/kg/day; oral) and a NS or HS diet for 14 or 21 days. Results: SD rats exhibit HS evoked suppression of NCC expression and activity. In contrast, NE infused SD rats and DSS 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 and DSS rats, but failed to decrease NCC activity or expression. In contrast α1-adreoceptor 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 and DSS rats. Conclusion: Our data suggests NE activates α, but not β, adrenoceptors to prevent dietary sodium evoked suppression of NCC activity and the development of salt-sensitive hypertension. The PATHWAY-2 Trial reported a primary role of sodium retention in resistant HTN suggesting α1-adreoceptor antagonism represents a new therapeutic approach for resistant and sympathetically mediated HTN.

Abstract 296: Norepinephrine Evoked Salt-Sensitive Hypertension Results in Impaired NCC Function, but Not Expression

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Kathryn Walsh ◽  
Sarah Mahne ◽  
Jill T Kuwabara ◽  
Richard D Wainford
Keyword(s):  
Salt Intake ◽  
Pcr Analysis ◽  
Kidney Cortex ◽  
Sprague Dawley ◽  
Sodium Homeostasis ◽  
Sd Rats ◽  
High Salt Intake ◽  
Induced Hypertension ◽  
Salt Sensitive Hypertension ◽  
The Impact

Aim: Recent controversial studies have proposed that excess norepinephrine (NE) evokes impaired NCC regulation to drive salt-sensitive hypertension. The following studies examine the impact of excess NE on salt-sensitivity and sodium homeostasis in conscious Sprague-Dawley (SD) rats. Methods: Naïve male SD rats, rats receiving a s.c. vehicle infusion (DMSO/Saline, 50:50), or rats receiving a s.c. NE infusion (600ng/min) were fed a 0.4% (NS) or 8% NaCl (HS) diet for 14 days. Additional rats received s.c. hydrochlorothiazide (HCTZ, 4mg/kg/d) in combination with NE (600ng/min) for 14 days on HS. On day 14, MAP, FENa, MAP response to i.v. hexamethonium (30mg/kg), and peak natriuresis to i.v. HCTZ (2mg/kg) infusion were assessed (N=4/gp). A PCR array examining NCC associated genes was performed on kidney cortex samples from each group. Results: NE increased MAP, FENa and vascular sympathetic tone (MAP [mmHg] NS 127±2, NE+NS 151±3, p<0.05). We observed no difference between the naïve and vehicle rats. A HS diet exacerbated NE induced hypertension (MAP [mmHg] HS 129±2, NE+HS 172±4, p<0.05), reduced FENa and prevented a salt stimulated reduction in HCTZ evoked natriuresis. Co-infusion of HCTZ with NE abolished the salt-sensitive component of NE-induced hypertension (MAP [mmHg] NE+HCTZ+HS: 152±3, p<0.05). PCR analysis revealed a significant increase in serine/threonine kinase 39 (0.83-fold increase vs. Naïve SD on NS) mRNA in NE+HS rats. We did not see NE or HS evoked changes in OSR-1, WNK4 or NCC mRNA in any group. Conclusion: The results support previous studies in mice and highlight an opposing interaction between excess NE and high salt intake on sodium homeostasis which exacerbated NE-induced hypertension via a mechanism independent of NE-mediated vascular constriction. Physiologically, our results show impaired NCC function, supporting previous data. In contrast, we failed to detect elevated NCC or WNK4 mRNA in response to NE infusion contradicting data generated in mice and suggesting a key role of altered NCC phosphorylation versus expression in NE treated rats.

scholarly journals High-salt intake enhances superoxide activity in eNOS knockout mice leading to the development of salt sensitivity

2010 ◽  
Vol 299 (3) ◽  
pp. F656-F663 ◽  
Author(s):  
Libor Kopkan ◽  
Arthur Hess ◽  
Zuzana Husková ◽  
Luděk Červenka ◽  
L. Gabriel Navar ◽  
...  
Keyword(s):  
Salt Intake ◽  
Salt Sensitivity ◽  
High Salt ◽  
No Production ◽  
Wild Type ◽  
Total N ◽  
High Salt Intake ◽  
Excretion Rates ◽  
Salt Sensitive Hypertension

A deficiency in nitric oxide (NO) generation leads to salt-sensitive hypertension, but the role of increased superoxide (O2−) in such salt sensitivity has not been delineated. We examined the hypothesis that an enhancement in O2− activity induced by high-salt (HS) intake under deficient NO production contributes to the development of salt-sensitive hypertension. Endothelial NO synthase knockout (eNOS KO; total n = 64) and wild-type (WT; total n = 58) mice were given diets containing either normal (NS; 0.4%) or high-salt (HS; 4%) for 2 wk. During this period, mice were chronically treated with a O2− scavenger, tempol (400 mg/l), or an inhibitor of NADPH oxidase, apocynin (1 g/l), in drinking water or left untreated ( n = 6–8 per group). Blood pressure was measured by radiotelemetry and 24-h urine samples were collected in metabolic cages. Basal mean arterial pressure (MAP) in eNOS KO was higher (125 ± 4 vs. 106 ± 3 mmHg) compared with WT. Feeding HS diet did not alter MAP in WT but increased it in eNOS KO to 166 ± 9 mmHg. Both tempol and apocynin treatment significantly attenuated the MAP response to HS in eNOS KO (134 ± 3 and 139 ± 4 mmHg, respectively). Basal urinary 8-isoprostane excretion rates (UIsoV), a marker for endogenous O2− activity, were similar (2.8 ± 0.2 and 2.4 ± 0.3 ng/day) in both eNOS KO and WT mice. However, HS increased UIsoV more in eNOS KO than in WT (4.6 ± 0.3 vs. 3.8 ± 0.2 ng/day); these were significantly attenuated by both tempol and apocynin treatment. These data indicate that an enhancement in O2− activity contributes substantially to the development of salt-sensitive hypertension under NO-deficient conditions.

scholarly journals Failure to upregulate the adenosine2A receptor-epoxyeicosatrienoic acid pathway contributes to the development of hypertension in Dahl salt-sensitive rats

2008 ◽  
Vol 295 (6) ◽  
pp. F1696-F1704 ◽  
Author(s):  
Elvira L. Liclican ◽  
John C. McGiff ◽  
John R. Falck ◽  
Mairéad A. Carroll
Keyword(s):  
Renal Perfusion ◽  
Epoxyeicosatrienoic Acid ◽  
Sprague Dawley ◽  
Salt Loading ◽  
Vasodilator Response ◽  
Sd Rats ◽  
Acid Pathway ◽  
Salt Sensitive Hypertension ◽  
Dose Dependent

Adenosine-activated renovascular dilatation in Sprague-Dawley (SD) rats is mediated by stimulating adenosine2A receptors (A2AR), which is linked to epoxyeicosatrienoic acid (EET) synthesis. The A2AR-EET pathway is upregulated by high salt (HS) intake in normotensive SD rats. Because this pathway is antipressor, we examined the role of the A2AR-EET pathway in Dahl salt-sensitive (SS) rats. Male Dahl salt-resistant (SR) and SS rats were fed either HS (8.0% NaCl) or normal salt (NS; 0.4% NaCl) diet for 7 days. On day 8, isolated kidneys were perfused with Krebs-Henseleit buffer containing indomethacin and NG-nitro-l-arginine methyl ester and preconstricted with phenylephrine. Bolus injections of the stable adenosine analog 2-chloroadenosine (2-CA; 0.1–20 μg) elicited dose-dependent dilation in both Dahl SR and SS rats. Dahl SR rats fed a HS diet demonstrated a greater renal vasodilator response to 10 μg of 2-CA, as measured by the reduction in renal perfusion pressure, than that of Dahl SR rats fed a NS diet (−104 ± 6 vs. −77 ± 7 mmHg, respectively; P < 0.05). In contrast, Dahl SS rats did not exhibit a difference in the vasodilator response to 2-CA whether fed NS or HS diet (96 ± 6 vs. 104 ± 13 mmHg in NS- and HS-fed rats, respectively). In Dahl SR but not Dahl SS rats, HS intake significantly increased purine flux, augmented the protein expression of A2AR and the cytochrome P-450 2C23 and 2C11 epoxygenases, and elevated the renal efflux of EETs. Thus the Dahl SR rat is able to respond to HS intake by recruiting EET formation, whereas the Dahl SS rat appears to have exhausted its ability to increase EET synthesis above the levels observed on NS intake, and this inability of Dahl SS rats to upregulate the A2AR-EET pathway in response to salt loading may contribute to the development of salt-sensitive hypertension.

scholarly journals Epithelial Sodium Channel and Salt-Sensitive Hypertension

Hypertension ◽  
2021 ◽  
Vol 77 (3) ◽  
pp. 759-767
Author(s):  
Stephanie M. Mutchler ◽  
Annet Kirabo ◽  
Thomas R. Kleyman
Keyword(s):  
Blood Pressure ◽  
Sodium Channel ◽  
Salt Intake ◽  
Extracellular Fluid ◽  
Pressure Rise ◽  
Epithelial Sodium Channel ◽  
Sodium Reabsorption ◽  
High Salt Intake ◽  
Salt Sensitive Hypertension

The development of high blood pressure is influenced by genetic and environmental factors, with high salt intake being a known environmental contributor. Humans display a spectrum of sodium-sensitivity, with some individuals displaying a significant blood pressure rise in response to increased sodium intake while others experience almost no change. These differences are, in part, attributable to genetic variation in pathways involved in sodium handling and excretion. ENaC (epithelial sodium channel) is one of the key transporters responsible for the reabsorption of sodium in the distal nephron. This channel has an important role in the regulation of extracellular fluid volume and consequently blood pressure. Herein, we review the role of ENaC in the development of salt-sensitive hypertension, and present mechanistic insights into the regulation of ENaC activity and how it may accelerate sodium-induced damage and dysfunction. We discuss the traditional role of ENaC in renal sodium reabsorption and review work addressing ENaC expression and function in the brain, vasculature, and immune cells, and how this has expanded the implications for its role in the initiation and progression of salt-sensitive hypertension.

scholarly journals Amplification of Salt-Sensitive Hypertension and Kidney Damage by Immune Mechanisms

2020 ◽  
Author(s):  
David L Mattson ◽  
John Henry Dasinger ◽  
Justine M Abais-Battad
Keyword(s):  
Renal Damage ◽  
Salt Intake ◽  
Disease Process ◽  
Organ Damage ◽  
Immune Mechanisms ◽  
Adaptive Immune ◽  
High Salt Intake ◽  
Normotensive Subjects ◽  
Salt Sensitive Hypertension

Abstract Humans with salt-sensitive (SS) hypertension demonstrate increased morbidity, increased mortality, and renal end-organ damage when compared with normotensive subjects or those with salt-resistant hypertension. Increasing evidence indicates that immune mechanisms play an important role in the full development of SS hypertension and associated renal damage. Recent experimental advances and studies in animal models have permitted a greater understanding of the mechanisms of activation and action of immunity in this disease process. Evidence favors a role of both innate and adaptive immune mechanisms that are triggered by initial, immune-independent alterations in blood pressure, sympathetic activity, or tissue damage. Activation of immunity, which can be enhanced by a high-salt intake or by alterations in other components of the diet, leads to the release of cytokines, free radicals, or other factors that amplify renal damage and hypertension and mediate malignant disease.

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

Hypertension ◽  
2020 ◽  
Vol 76 (5) ◽  
pp. 1461-1469
Author(s):  
Franco Puleo ◽  
Kiyoung Kim ◽  
Alissa A. Frame ◽  
Kathryn R. Walsh ◽  
Mohammed Z. Ferdaus ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Sodium Chloride ◽  
Salt Intake ◽  
High Salt ◽  
Sodium Reabsorption ◽  
Sprague Dawley ◽  
Sodium Chloride Cotransporter ◽  
High Salt Intake ◽  
Sympathetic Regulation ◽  
Salt Sensitive Hypertension

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.

scholarly journals Sympathetic regulation of NCC in norepinephrine-evoked salt-sensitive hypertension in Sprague-Dawley rats

2019 ◽  
Vol 317 (6) ◽  
pp. F1623-F1636 ◽  
Author(s):  
Alissa A. Frame ◽  
Franco Puleo ◽  
Kiyoung Kim ◽  
Kathryn R. Walsh ◽  
Elizabeth Faudoa ◽  
...  
Keyword(s):  
Salt Intake ◽  
High Salt ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
High Salt Intake ◽  
Sympathetic Regulation ◽  
Salt Sensitive Hypertension ◽  
And Oxidative Stress ◽  
Resistant Animal

Salt sensitivity of blood pressure is characterized by inappropriate sympathoexcitation and renal Na+ reabsorption during high salt intake. In salt-resistant animal models, exogenous norepinephrine (NE) infusion promotes salt-sensitive hypertension and prevents dietary Na+-evoked suppression of the Na+-Cl− cotransporter (NCC). Studies of the adrenergic signaling pathways that modulate NCC activity during NE infusion have yielded conflicting results implicating α1- and/or β-adrenoceptors and a downstream kinase network that phosphorylates and activates NCC, including with no lysine kinases (WNKs), STE20/SPS1-related proline-alanine-rich kinase (SPAK), and oxidative stress response 1 (OxSR1). In the present study, we used selective adrenoceptor antagonism in NE-infused male Sprague-Dawley rats to investigate the differential roles of α1- and β-adrenoceptors in sympathetically mediated NCC regulation. NE infusion evoked salt-sensitive hypertension and prevented dietary Na+-evoked suppression of NCC mRNA, protein expression, phosphorylation, and in vivo activity. Impaired NCC suppression during high salt intake in NE-infused rats was paralleled by impaired suppression of WNK1 and OxSR1 expression and SPAK/OxSR1 phosphorylation and a failure to increase WNK4 expression. Antagonism of α1-adrenoceptors before high salt intake or after the establishment of salt-sensitive hypertension restored dietary Na+-evoked suppression of NCC, resulted in downregulation of WNK4, SPAK, and OxSR1, and abolished the salt-sensitive component of hypertension. In contrast, β-adrenoceptor antagonism attenuated NE-evoked hypertension independently of dietary Na+ intake and did not restore high salt-evoked suppression of NCC. These findings suggest that a selective, reversible, α1-adenoceptor-gated WNK/SPAK/OxSR1 NE-activated signaling pathway prevents dietary Na+-evoked NCC suppression, promoting the development and maintenance of salt-sensitive hypertension.

scholarly journals Salt-Sensitive Hypertension in GR+/− Rats Is Accompanied with Dysregulation in Adrenal Soluble Epoxide Hydrolase and Polyunsaturated Fatty Acid Pathways

2021 ◽  
Vol 22 (24) ◽  
pp. 13218
Author(s):  
Paul-Emmanuel Vanderriele ◽  
Qing Wang ◽  
Anne-Marie Mérillat ◽  
Frédérique Ino ◽  
Gilles Aeschlimann ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Epoxide Hydrolase ◽  
Salt Intake ◽  
Soluble Epoxide Hydrolase ◽  
High Salt ◽  
Standard Diet ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
High Salt Intake ◽  
Salt Sensitive Hypertension

Mutations within the glucocorticoid receptor (GR) gene locus lead to glucocorticoid resistance which is characterized by several clinical symptoms such as adrenal gland hyperplasia and salt-sensitive hypertension, although the underlying mechanisms are still unknown. We studied GR haploinsufficient (GR+/−) Sprague Dawley rats which, on a standard diet, showed significantly increased plasma aldosterone and corticosterone levels and an adrenocortex hyperplasia accompanied by a normal systolic blood pressure. Following a high salt diet, these rats developed salt-sensitive hypertension and maintained elevated enzyme-soluble epoxide hydrolase (sEH) in adrenal glands, while sEH was significantly decreased in wild-type rats. Furthermore, GR+/− rats showed dysregulation of the equilibrated linoleic and arachidonic acid pathways, with a significant increase of less active metabolites such as 8,9-DiHETrE. In Sprague Dawley rats, GR haploinsufficiency induced steroid disturbances, which provoked hypertension only in combination with high salt intake, which was accompanied by disturbances in sEH and fatty acid metabolism. Our results suggest that sEH inhibition could be a potential target to treat hypertension in patients with GR haploinsufficiency.

Blood pressure in conscious and anesthetized adrenal-enucleated Sprague–Dawley and Wistar–Furth rats

1978 ◽  
Vol 56 (6) ◽  
pp. 1036-1040 ◽  
Author(s):  
C. E. Hall ◽  
D. Nasseth
Keyword(s):  
Blood Pressure ◽  
Salt Intake ◽  
Sprague Dawley ◽  
Sd Rats ◽  
High Salt Intake ◽  
Crucial Problem ◽  
Single Exception ◽  
Blood Pressures ◽  
Depressor Effect ◽  
Conscious Animals

Systolic blood pressure was measured weekly in conscious and in anesthetized female Sprague–Dawley (SD) and Wistar–Furth (W/Fu) rats following adrenal enucleation, unilateral nephrectomy, and the imposition of a high salt intake. SD rats quickly developed adrenal-regeneration hypertension (ARH) which progressed rapidly, and was identifiable in both the conscious and the anesthetized state. W/Fu rats slowly developed mild ARH, which, with a single exception, was identifiable only in conscious animals; the arterial pressures were within the normotensive range under anesthesia. The depressor effect of ether was also greater in adrenal-enucleated W/Fu than in similarly prepared SD rats, and in hypertensives than in normotensives. It is concluded that blood pressure measurements taken under anesthesia may not be representative of the true resting blood pressures: this is likely to be a particularly crucial problem in identifying early hypertension under circumstances and in rat strains highly susceptible to the depressor effects of ether.

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