High Salt Intake Delayed Angiotensin II-Induced Hypertension in Mice With a Genetic Variant of NADPH Oxidase

The sequential hemodynamics, fluid and electrolyte balances, and the hormonal responses to a 7-day high-salt (NaCl) intake were investigated in sodium-depleted conscious dogs (n = 6). Studies were carried out in metabolic cages mounted on sensitive load cells, which enabled continuous 24 h/day monitoring of total body weight (TBW) as an index of changes in body water. Beat-by-beat hemodynamics were determined 24 h/day. Water (700 ml/day iv) intake was maintained constant. Daily fluid and electrolyte balances and hormonal analyses were performed. An increase of daily salt intake from 8 to 120 meq increased TBW 251 +/- 44 g (P less than 0.05), which was sustained thereafter. Average 24-h mean arterial pressure (MAP) and heart rate (HR) remained unchanged. Average cardiac output (CO) increased 11% (P less than 0.05) above control values by day 2, while total peripheral resistance (TPR) decreased proportionally. CO and TPR returned to control values only when low salt was resumed. Blood volume (BV) was unchanged on day 2 as indicated by direct measurement of BV (51Cr-labeled red blood cells) or by analysis of plasma protein concentration. A 92-meq (P less than 0.05) sodium retention was observed initially, and plasma sodium concentration increased slightly. Plasma renin activity, angiotensin II, and aldosterone levels decreased significantly, whereas vasopressin and atrial natriuretic peptide levels remained unchanged. In summary, chronic high-salt intake resulted in a net retention of water and sodium with no changes in MAP, HR, or BV. The rise in CO was offset by a reduction in TPR, which appeared at least in part related to angiotensin II suppression.

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Central and peripheral slow-pressor mechanisms contributing to Angiotensin II-salt hypertension in rats

Cardiovascular Research ◽

10.1093/cvr/cvx214 ◽

2017 ◽

Vol 114 (2) ◽

pp. 233-246 ◽

Cited By ~ 11

Author(s):

Jiao Lu ◽

Hong-Wei Wang ◽

Monir Ahmad ◽

Marzieh Keshtkar-Jahromi ◽

Mordecai P Blaustein ◽

...

Keyword(s):

Angiotensin Ii ◽

Adrenal Cortex ◽

Salt Intake ◽

Plasma Corticosterone ◽

High Salt ◽

Ang Ii ◽

Intracerebroventricular Infusion ◽

High Salt Intake ◽

Endogenous Ouabain ◽

Salt Hypertension

AbstractAimsHigh salt intake markedly enhances hypertension induced by angiotensin II (Ang II). We explored central and peripheral slow-pressor mechanisms which may be activated by Ang II and salt.Methods and resultsIn protocol I, Wistar rats were infused subcutaneously with low-dose Ang II (150 ng/kg/min) and fed regular (0.4%) or high salt (2%) diet for 14 days. In protocol II, Ang II-high salt was combined with intracerebroventricular infusion of mineralocorticoid receptor (MR) blockers (eplerenone, spironolactone), epithelial sodium channel (ENaC) blocker (benzamil), angiotensin II type 1 receptor (AT1R) blocker (losartan) or vehicles. Ang II alone raised mean arterial pressure (MAP) ∼10 mmHg, but Ang II-high salt increased MAP ∼50 mmHg. Ang II-high salt elevated plasma corticosterone, aldosterone and endogenous ouabain but not Ang II alone. Both Ang II alone and Ang II-high salt increased mRNA and protein expression of CYP11B2 (aldosterone synthase gene) in the adrenal cortex but not of CYP11B1 (11-β-hydroxylase gene). In the aorta, Ang II-high salt increased sodium-calcium exchanger-1 (NCX1) protein. The Ang II-high salt induced increase in MAP was largely prevented by central infusion of MR blockers, benzamil or losartan. Central blockades significantly lowered plasma aldosterone and endogenous ouabain and markedly decreased Ang II-high salt induced CYP11B2 mRNA expression in the adrenal cortex and NCX1 protein in the aorta.ConclusionThese results suggest that in Ang II-high salt hypertension, MR-ENaC-AT1R signalling in the brain increases circulating aldosterone and endogenous ouabain, and arterial NCX1. These factors can amplify blood pressure responses to centrally-induced sympatho-excitation and thereby contribute to severe hypertension.

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Role of central nervous system aldosterone synthase and mineralocorticoid receptors in salt-induced hypertension in Dahl salt-sensitive rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90903.2008 ◽

2009 ◽

Vol 296 (4) ◽

pp. R994-R1000 ◽

Cited By ~ 66

Author(s):

Bing S. Huang ◽

Roselyn A. White ◽

Arco Y. Jeng ◽

Frans H. H. Leenen

Keyword(s):

Salt Intake ◽

High Salt ◽

High Salt Diet ◽

Salt Diet ◽

Aldosterone Synthase ◽

High Salt Intake ◽

Induced Hypertension ◽

Synthase Inhibitor ◽

The Brain

In Dahl salt-sensitive (S) rats, high salt intake increases cerebrospinal fluid (CSF) Na+ concentration ([Na+]) and blood pressure (BP). Intracerebroventricular (ICV) infusion of a mineralocorticoid receptor (MR) blocker prevents the hypertension. To assess the role of aldosterone locally produced in the brain, we evaluated the effects of chronic central blockade with the aldosterone synthase inhibitor FAD286 and the MR blocker spironolactone on changes in aldosterone and corticosterone content in the hypothalamus and the increase in CSF [Na+] and hypertension induced by high salt intake in Dahl S rats. After 4 wk of high salt intake, plasma aldosterone and corticosterone were not changed, but hypothalamic aldosterone increased by ∼35% and corticosterone tended to increase in Dahl S rats, whereas both steroids decreased by ∼65% in Dahl salt-resistant rats. In Dahl S rats fed the high-salt diet, ICV infusion of FAD286 or spironolactone did not affect the increase in CSF [Na+]. ICV infusion of FAD286 prevented the increase in hypothalamic aldosterone and 30 mmHg of the 50-mmHg BP increase induced by high salt intake. ICV infusion of spironolactone fully prevented the salt-induced hypertension. These results suggest that, in Dahl S rats, high salt intake increases aldosterone synthesis in the hypothalamus and aldosterone acts as the main MR agonist activating central pathways contributing to salt-induced hypertension.

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High-Salt Intake Induces Cardiomyocyte Hypertrophy in Rats in Response to Local Angiotensin II Type 1 Receptor Activation

Journal of Nutrition ◽

10.3945/jn.114.192054 ◽

2014 ◽

Vol 144 (10) ◽

pp. 1571-1578 ◽

Cited By ~ 17

Author(s):

Isis A. Katayama ◽

Rafael C. Pereira ◽

Ellen P. B. Dopona ◽

Maria H. M. Shimizu ◽

Luzia N. S. Furukawa ◽

...

Keyword(s):

Angiotensin Ii ◽

Salt Intake ◽

Receptor Activation ◽

High Salt ◽

Cardiomyocyte Hypertrophy ◽

High Salt Intake

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ROS Production Is Increased in the Kidney but Not in the Brain of Dahl Rats With Salt Hypertension Elicited in Adulthood

Physiological Research ◽

10.33549/physiolres.933054 ◽

2015 ◽

pp. 303-312 ◽

Cited By ~ 5

Author(s):

M. VOKURKOVÁ ◽

H. RAUCHOVÁ ◽

L. ŘEZÁČOVÁ ◽

I. VANĚČKOVÁ ◽

J. ZICHA

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Nadph Oxidase ◽

Salt Intake ◽

Renal Medulla ◽

High Salt ◽

Ros Production ◽

High Salt Intake ◽

Salt Hypertension ◽

The Brain

Enhanced production of superoxide radicals by nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase in the brain and/or kidney of salt hypertensive Dahl rats has been proposed to participate in the pathogenesis of this form of experimental hypertension. Most information was obtained in young Dahl salt-sensitive (DS) rats subjected to high salt intake prior to sexual maturation. Therefore, the aim of our study was to investigate whether salt hypertension induced in adult DS rats is also accompanied with a more pronounced oxidative stress in the brain or kidney as compared to Dahl salt-resistant (DR) controls. NADPH oxidase activity as well as the content of thiobarbituric acid-reactive substances (TBARS) and conjugated dienes (oxidative index), which indicate a degree of lipid peroxidation, were evaluated in two brain regions (containing either hypothalamic paraventricular nucleus or rostral ventrolateral medulla) as well as in renal medulla and cortex. High salt intake induced hypertension in DS rats but did not modify blood pressure in DR rats. DS and DR rats did not differ in NADPH oxidase-dependent production of ROS, TBARS content or oxidative index in either part of the brain. In addition, high-salt diet did not change significantly any of these brain parameters. In contrast, the enhanced NADPH oxidase-mediated ROS production (without significant signs of increased lipid peroxidation) was detected in the renal medulla of salt hypertensive DS rats. Our findings suggest that there are no signs of enhanced oxidative stress in the brain of adult Dahl rats with salt hypertension induced in adulthood.

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

Clinical & Investigative Medicine ◽

10.25011/cim.v31i2.3365 ◽

2008 ◽

Vol 31 (2) ◽

pp. 62 ◽

Cited By ~ 3

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.

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Febuxostat ameliorates high salt intake-induced hypertension and renal damage in Dahl salt-sensitive rats

Journal of Hypertension ◽

10.1097/hjh.0000000000003012 ◽

2021 ◽

Vol Publish Ahead of Print ◽

Author(s):

Takahiro Miura ◽

Akihiro Sakuyama ◽

Lusi Xu ◽

Jiahe Qiu ◽

Asako Namai-Takahashi ◽

...

Keyword(s):

Renal Damage ◽

Salt Intake ◽

High Salt ◽

High Salt Intake ◽

Induced Hypertension

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Evidence for Prohypertensive, Proinflammatory Effect of Interleukin-10 During Chronic High Salt Intake in the Condition of Elevated Angiotensin II Level

Hypertension ◽

10.1161/hypertensionaha.117.09401 ◽

2017 ◽

Vol 70 (4) ◽

pp. 839-845 ◽

Cited By ~ 8

Author(s):

Purnima Singh ◽

Alexander Castillo ◽

M. Toriqul Islam ◽

Dewan S.A. Majid

Keyword(s):

Angiotensin Ii ◽

Salt Intake ◽

Interleukin 10 ◽

High Salt ◽

High Salt Intake ◽

Proinflammatory Effect

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Renal angiotensin II concentration and interstitial infiltration of immune cells are correlated with blood pressure levels in salt-sensitive hypertension

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00645.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. R251-R256 ◽

Cited By ~ 72

Author(s):

Martha Franco ◽

Flavio Martínez ◽

Yasmir Quiroz ◽

Othir Galicia ◽

Rocio Bautista ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Immune Cell ◽

Salt Intake ◽

Experimental Models ◽

High Salt ◽

Salt Diet ◽

High Salt Intake ◽

Plasma Angiotensin ◽

Salt Sensitive Hypertension

Renal immune cell infiltration and cells expressing angiotensin II (AII) in tubulointerstitial areas of the kidney are features of experimental models of salt-sensitive hypertension (SSHTN). A high-salt intake tends to suppress circulating AII levels, but intrarenal concentrations of AII have not been investigated in SSHTN. This study explored the relationship between these features to gain insight into the pathophysiology of SSHTN. Plasma angiotensin II (AII) and renal interstitial AII (microdialysis technique) and the infiltration of macrophages, lymphocytes, and AII-positive cells were determined in SSHTN induced by 5 wk of a high-salt diet (HSD) after short-term infusion of AII in rats with ( n = 10) and without ( n = 11) treatment with mycophenolate mofetil (MMF) and in control rats fed a high- ( n = 7) and normal ( n = 11) salt diet. As in previous studies, MMF did not affect AII-associated hypertension but reduced the interstitial inflammation and the SSHTN in the post-AII-period. During the HSD period, the AII group untreated with MMF had mean ± SD) low plasma (2.4 ± 1.4 pg/ml) and high interstitial AII concentration (1,310 ± 208 pg/ml); MMF treatment resulted in a significantly lower interstitial AII (454 ± 128 pg/ml). Renal AII concentration and the number of tubulointerstitial AII-positive cells were correlated. Blood pressure correlated positively with interstitial AII and negatively with plasma AII, thus giving compelling evidence of the paramount role of the AII within the kidney in the AII-induced model of salt-driven hypertension.

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