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.

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.

scholarly journals Chronic clofibrate administration prevents salineinduced endothelial dysfunction and oxidative stress in young Sprague-Dawley rats

2008 ◽  
Vol 31 (2) ◽  
pp. 62 ◽  
Author(s):  
Sowndramalingam Sankaralingam ◽  
Kaushik M Desai ◽  
Thomas W Wilson
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Salt Intake ◽  
High Salt ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
High Salt Intake ◽  
Induced Hypertension ◽  
And Oxidative Stress ◽  
Hypotensive Response

Purpose: High salt intake causes hypertension and endothelial dysfunction in young Sprague-Dawley rats. Clofibrate (clof) prevents this salt induced hypertension. We asked whether clof can prevent salt-induced endothelial dysfunction, and if so, its mechanism. We also questioned whether high salt intake can induce endothelial dysfunction without hypertension in older animals. Methods: Young (Y, 5 weeks) and old (O, 53 weeks) male Sprague-Dawley rats were given either vehicle (Con, 20 mM Na2CO3) or 0.9% NaCl (Sal) to drink for three weeks. Some young rats received clof (80 mg/d) in their drinking fluid. After three weeks, we measured mean arterial pressure (MAP), endothelial function, by comparing hypotensive responses to acetylcholine (ACh, endothelium dependent) and sodium nitroprusside (SNP, endothelium independent), plasma total nitrite+nitrate levels (PNOx), by the Griess reaction, and aortic superoxide production by lucigenin chemiluminescence. Results: Carotid artery MAP did not change in O. Sal-Y developed hypertension: 133±3 vs. 114±2 mmHg, P < 0.001, which was prevented by clof: 105±2 mmHg. ACh induced a similar dose dependent hypotensive response in Con-O and Sal-O that was inhibited by L-NAME (100mg/kg i.v.). Responses to ACh were blunted in Sal-Y but not in Con-Y. Further, L-NAME inhibited ACh responses only in Con-Y. The response to SNP was similar in all animals. Importantly, the ACh-induced hypotensive response was potentiated in clof+Sal-Y, an effect which was attenuated by blocking calcium-activated potassium channels (KCa) with a combination of apamin (50 ug/kg i.v.) + charybdotoxin (50 ug/kg i.v.), but not by L-NAME. PNOx was reduced in Sal-Y compared to Con-Y (2.09±0.26 vs. 4.8±0.35 µM, P < 0.001), but not in Sal-O. Aortic superoxide production was higher (P < 0.001) in Sal-Y (2388±40 milliunits/mg/min) than Sal-O (1107±159 milliunits/mg/min), but was reduced by clof (1378±64 milliunits/mg/min; P < 0.001). Conclusions: High salt intake increases oxidative stress in young animals, leading to impaired nitric oxide activity and endothelial dysfunction. Clofibrate prevents endothelial dysfunction partly through reduced O2?- formation but mainly via selective activation of KCa channels. Older animals are resistant to both salt induced hypertension and oxidative stress.

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.

scholarly journals Salt Intake in Nigeria: a nationwide population survey

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A.N Odili ◽  
B.S Chori ◽  
B Danladi ◽  
P.C Nwakile ◽  
J.O Ogedengbe ◽  
...  
Keyword(s):  
Salt Intake ◽  
Sodium Intake ◽  
Population Analysis ◽  
Cost Effective ◽  
Rural Site ◽  
Urban Site ◽  
Funding Source ◽  
Salt Reduction ◽  
High Salt Intake ◽  
The Impact

Abstract Background Population wide salt reduction programmes are cost effective strategies for control of cardiovascular diseases (CVDs). Obtaining a nationwide salt consumption data in a multi-cultural setting as Nigeria's is key for proper implementation and monitoring of such strategy. Methods We measured sodium in 24-hour urine of free-living adult Nigerians selected from an urban and a rural site each from the 6 geopolitical zones of Nigeria to evaluate patterns of salt intake and its associations with blood pressures (BP). Results Across the 12 sites, sodium intake ranged from 97.9 in the rural South-South to 210 mmol/day in the urban site of the same zone. Overall, the median (IQR) daily sodium intake was 143.5 (97.8) mmol; with higher (p=0.0028) levels among the urban 149.7 (113.8) compared to the rural 133.1 (105.2) dwellers. Overall, 20% of the subjects consumed less than the recommended 2g (86mmol) of sodium daily. After adjustment for age, sex and BMI; sodium intake and BP (systolic and diastolic) were positively associated in 8 out of the 12 sites; significantly so in 2 (p&lt;0.05) for systolic. Within population analysis; which included 973 individuals, increasing sodium intake tended (not significantly) to increase SBP but decrease DBP. However, among subjects whose sodium intake was in excess of 257mmol/day, a 100 mmol/day increase in sodium intake was significantly (p=0.04) associated with a 3.3 mmHg increase in SBP. Conclusion Salt intake among Nigerians is higher than the recommended. The impact of sodium intake on BP appears to be evident only among individuals with high salt intake. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Wellcome Trust

Abstract 131: Anti-inflammatory and Mitochondrial Effects of Butyrate in Shr Astrocytes in vitro

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Tao Yang ◽  
Ty Redler ◽  
Carla G Bueno Silva ◽  
Rebeca Arocha ◽  
Jordan Schmidt ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Rna Isolation ◽  
Inflammatory Factors ◽  
Pcr Analysis ◽  
Sprague Dawley ◽  
Beneficial Effects ◽  
Sd Rats ◽  
Anti Inflammatory

Emerging evidence demonstrates a significant link between gut dysbiosis and hypertension (HTN). Butyrate is one of the major fermented end-products of gut microbiota that reportedly produces beneficial effects on the immune system and metabolism. A contraction in butyrate-producing bacteria in the gut of spontaneously hypertensive rats (SHR) suggests that reduced butyrate may be associated with HTN. Considering its role in mitochondrial metabolism, we proposed that the positive anti-inflammatory effects of butyrate may be mediated via improvement in mitochondrial function in astrocytes. Methods: Sprague Dawley (SD) and SHR primary astrocytes from two-day old pups were cultured in DMEM, supplemented with 10% FBS and 1% pen/strep, for 14 days, prior to treatment with butyrate (0-1mM) for 4 hours. Cells were then subjected to the Seahorse XFe24 Extracellular Flux Analyzer to evaluate mitochondrial function following butyrate treatment. Additional samples were collected for total RNA isolation for real time PCR analysis of inflammatory factors and transcripts related to mitochondrial function and stress. Results: Butyrate significantly increased both basal and maximal mitochondrial respiration (by 3-4 fold, P<0.001) and elevated proton leak (by 4 fold, P<0.01) in astrocytes from SD rats but not SHR. Furthermore, we observed a trend for an increase in both ATP-linked and non-mitochondrial respiration in SD astrocytes compared to SHR (by 2-3 fold, P=0.07). This was associated with a significant reduction in relative expression levels in catalase (by 50%, P<0.05) and a trend in reduction in Sod1 and Sod2 (by 25%-50%, P=0.1) in astrocytes harvested from SD rats but not the SHR. Conversely, butyrate significantly lowered expression of pro-inflammatory Ccl2 (by 33%, P<0.05) and Tlr4 (by 48%, P <0.05) in astrocytes of SHR, but not SD rats. Conclusion: Butyrate modulated mitochondrial bioenergetics in SD but not the SHR, suggesting that the mitochondria of astrocytes may be less sensitive to the effects of butyrate in HTN. In addition, butyrate reduced inflammatory mediators in the SHR, but had no effect in the SD rat astrocytes. Thus, central anti-inflammatory effects of butyrate may be mediated via a mitochondria-independent mechanism.

Abstract 142: A Fructose-but Not a Glucose-enriched Diet, Induces a Salt-dependent Increase in Blood Pressure and Enhances NKCC2 Phosphorylation in Normal Rats

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Keyona N King-Medina ◽  
Emily Henson ◽  
Pablo Ortiz
Keyword(s):  
Blood Pressure ◽  
Drinking Water ◽  
Salt Intake ◽  
Caloric Intake ◽  
High Salt ◽  
Human Consumption ◽  
Thick Ascending Limb ◽  
Sprague Dawley ◽  
High Fructose ◽  
High Salt Intake

Human consumption of fructose as a sweetener has increased in the past 30 years. High fructose intake has been implicated in the development of hypertension, diabetes, and obesity. In the US, the upper 10th percentile of the population consumes up to 40% of their caloric intake from added sugars, in which fructose represents half of these. Fructose metabolism is strikingly different from that of glucose. Yet, the effect of a fructose or glucose-enriched diet in salt handling by the kidney, affecting blood pressure, and its interaction with high salt intake has been poorly studied. In genetic models of salt-sensitive hypertension, the activity of the Na + /K + /2Cl - cotransporter (NKCC2) in the thick ascending limb (TAL) is abnormally enhanced. We hypothesized that chronic fructose in drinking water induces a salt-dependent increase in blood pressure and stimulates NKCC2 during high salt intake in normal rats. Sprague-Dawley rats were given 20% fructose or 20% glucose in drinking water for 1 week after which a high salt (HS) diet (4% Na + in chow) was started for 3 weeks. When we measured systolic blood pressure (SBP) by tail cuff plethysmography in fructose-fed and glucose-fed rats on a HS diet, only the fructose-fed rats had an increased SBP from 120±10 to 132±6 mmHg on day 7 of HS (p<0.01). SBP continued to increase up to 144±18 mmHg after 3 weeks (p<0.01 vs glucose). Fructose or glucose alone did not increase SBP after 4 weeks. We then repeated the protocol using radiotelemetry to monitor the blood pressure (BP). In rats fed fructose, by day 5 of HS the SBP increased by 12±3 mmHg (p<0.02) and SBP remained elevated for 3 weeks (delta: 10±2.5 mmHg, n=3). In rats fed glucose, a HS diet did not significantly change SBP for 3 weeks (n=5). Moreover, NKCC2 activity in the TAL is enhanced by phosphorylation at Thr96, 101. We found that NKCC2 phosphorylation was higher in rats fed fructose plus HS (p<0.02) but not in rats fed glucose plus HS for 3 weeks (HS: 100, fructose+HS: 250±40%, glucose+HS: 95±10%). Therefore, we conclude that a high fructose (but not a glucose) diet in normal rats induces a salt-dependent increase in BP independently from caloric intake. Thus, the increase in BP may in part be due to the stimulation of NKCC2 phosphorylation in the TAL by fructose.

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