β-blockade prevents coronary macro- and microvascular dysfunction induced by a high salt diet and insulin resistance in the Goto–Kakizaki rat

2021 ◽  
Vol 135 (2) ◽  
pp. 327-346
Author(s):  
James T. Pearson ◽  
Hamish P. Thambyah ◽  
Mark T. Waddingham ◽  
Tadakatsu Inagaki ◽  
Vijayakumar Sukumaran ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endothelial Dysfunction ◽  
Wistar Rats ◽  
Nitrosative Stress ◽  
Salt Intake ◽  
Microvascular Dysfunction ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
High Salt Intake

Abstract A high salt intake exacerbates insulin resistance, evoking hypertension due to systemic perivascular inflammation, oxidative-nitrosative stress and endothelial dysfunction. Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARBs) have been shown to abolish inflammation and redox stress but only partially restore endothelial function in mesenteric vessels. We investigated whether sympatho-adrenal overactivation evokes coronary vascular dysfunction when a high salt intake is combined with insulin resistance in male Goto–Kakizaki (GK) and Wistar rats treated with two different classes of β-blocker or vehicle, utilising synchrotron-based microangiography in vivo. Further, we examined if chronic carvedilol (CAR) treatment preserves nitric oxide (NO)-mediated coronary dilation more than metoprolol (MET). A high salt diet (6% NaCl w/w) exacerbated coronary microvessel endothelial dysfunction and NO-resistance in vehicle-treated GK rats while Wistar rats showed modest impairment. Microvascular dysfunction was associated with elevated expression of myocardial endothelin, inducible NO synthase (NOS) protein and 3-nitrotyrosine (3-NT). Both CAR and MET reduced basal coronary perfusion but restored microvessel endothelium-dependent and -independent dilation indicating a role for sympatho-adrenal overactivation in vehicle-treated rats. While MET treatment reduced myocardial nitrates, only MET treatment completely restored microvessel dilation to dobutamine (DOB) stimulation in the absence of NO and prostanoids (combined inhibition), indicating that MET restored the coronary flow reserve attributable to endothelium-derived hyperpolarisation (EDH). In conclusion, sympatho-adrenal overactivation caused by high salt intake and insulin resistance evoked coronary microvessel endothelial dysfunction and diminished NO sensitivity, which were restored by MET and CAR treatment in spite of ongoing inflammation and oxidative-nitrosative stress presumably caused by uninhibited renin–angiotensin–aldosterone system (RAAS) overactivation.

Stimulation of brain Na+ channels by FMRFamide in Dahl SS and SR rats

2003 ◽  
Vol 285 (5) ◽  
pp. H2013-H2018 ◽  
Author(s):  
Hao Wang ◽  
Roselyn White ◽  
Frans H. H. Leenen
Keyword(s):  
Wistar Rats ◽  
Sympathetic Nerve Activity ◽  
Salt Intake ◽  
High Salt ◽  
Nerve Activity ◽  
High Salt Diet ◽  
Salt Diet ◽  
Intracerebroventricular Infusion ◽  
High Salt Intake ◽  
Stimulation Of

Stimulation of brain Na+ channels by Phe-Met-Arg-Phe-NH2 (FMRFamide) increases sympathetic nerve activity and blood pressure (BP) in Wistar rats. Blockade of brain ouabain-like compounds (OLC) by specific antibody Fab fragments prevents these responses to intracerebroventricular FMRFamide. In the present study, we evaluated the effects of high-salt intake on brain FMRFamide levels and the responses of BP and brain OLC to intracerebroventricular infusion of FMRFamide in Dahl salt-sensitive (SS) and salt-resistant (SR) rats. FMRFamide and OLC content was measured with the use of RIA and ELISA, respectively. A high-salt diet (1,370 μmol Na+/g) for 2 wk significantly increased BP in Dahl SS but not in SR rats. On a regular salt diet, Dahl SS and SR rats showed similar FMRFamide levels in the whole hypothalamus, pons and medulla, and spinal cord. A high-salt diet for 2 wk did not affect FMRFamide levels in these tissues in both Dahl SS and SR rats. In Dahl SS but not in SR rats, chronic intracerebroventricular infusion of FMRFamide (200 nmol · kg–1 · day–1) for 2 wk significantly increased BP (mean arterial pressure: 116 ± 5 vs. 100 ± 2 mmHg; P < 0.01). Chronic intracerebroventricular infusion of FMRFamide significantly increased hypothalamic and pituitary OLC in Dahl SS but not SR rats. These results indicate that Dahl SS rats exhibit enhanced central responses to FMRFamide. In Dahl SS but not in SR rats on a high-salt diet, enhanced Na+ entry through FMRFamide-activated brain Na+ channels may increase brain OLC release, thereby leading to hypertension.

scholarly journals Eplerenone inhibits aldosterone-induced renal expression of cyclooxygenase

2012 ◽  
Vol 13 (3) ◽  
pp. 353-359 ◽  
Author(s):  
MA Bayorh ◽  
A Rollins-Hairston ◽  
J Adiyiah ◽  
D Lyn ◽  
D Eatman
Keyword(s):  
Salt Intake ◽  
High Salt ◽  
Prostaglandin E ◽  
Renal Tubules ◽  
Protective Effects ◽  
High Salt Diet ◽  
Salt Diet ◽  
High Salt Intake ◽  
Low Salt ◽  
Cox 2

Introduction: The upregulation of cyclooxygenase (COX) expression by aldosterone (ALDO) or high salt diet intake is very interesting and complex in the light of what is known about the role of COX in renal function. Thus, in this study, we hypothesize that apocynin (APC) and/or eplerenone (EPL) inhibit ALDO/salt-induced kidney damage by preventing the production of prostaglandin E2 (PGE2). Methods: Dahl salt-sensitive rats on either a low-salt or high-salt diet were treated with ALDO (0.2 mg pellet) in the presence of EPL (100 mg/kg/day) or APC (1.5 mM). Indirect blood pressure, prostaglandins and ALDO levels and histological changes were measured. Results: Cyclooxygenase-2 (COX-2) levels were upregulated in the renal tubules and peritubular vessels after high-salt intake, and APC attenuated renal tubular COX-2 protein expression induced by ALDO. Plasma PGE2 levels were significantly reduced by ALDO in the rats fed a low-salt diet when compared to rats fed a high-salt diet. PGE2 was blocked by EPL but increased in the presence of APC. Conclusions: The beneficial effects of EPL may be associated with an inhibition of PGE2. The mechanism underlying the protective effects of EPL is clearly distinct from that of APC and suggests that these agents can have differential roles in cardiovascular disease.

scholarly journals Salt-sensitive splice variant of nNOS expressed in the macula densa cells

2010 ◽  
Vol 298 (6) ◽  
pp. F1465-F1471 ◽  
Author(s):  
Deyin Lu ◽  
Yiling Fu ◽  
Arnaldo Lopez-Ruiz ◽  
Rui Zhang ◽  
Ramiro Juncos ◽  
...  
Keyword(s):  
Salt Intake ◽  
Splice Variants ◽  
Macula Densa ◽  
High Salt ◽  
Tubuloglomerular Feedback ◽  
No Production ◽  
Thick Ascending Limb ◽  
High Salt Diet ◽  
Salt Diet ◽  
High Salt Intake

Neuronal nitric oxide synthase (nNOS), which is abundantly expressed in the macula densa cells, attenuates tubuloglomerular feedback (TGF). We hypothesize that splice variants of nNOS are expressed in the macula densa, and nNOS-β is a salt-sensitive isoform that modulates TGF. Sprague-Dawley rats received a low-, normal-, or high-salt diet for 10 days and levels of the nNOS-α, nNOS-β, and nNOS-γ were measured in the macula densa cells isolated with laser capture microdissection. Three splice variants of nNOS, α-, β-, and γ-mRNAs, were detected in the macula densa cells. After 10 days of high-salt intake, nNOS-α decreased markedly, whereas nNOS-β increased two- to threefold in the macula densa measured with real-time PCR and in the renal cortex measured with Western blot. NO production in the macula densa was measured in the perfused thick ascending limb with an intact macula densa plaque with a fluorescent dye DAF-FM. When the tubular perfusate was switched from 10 to 80 mM NaCl, a maneuver to induce TGF, NO production by the macula densa was increased by 38 ± 3% in normal-salt rats and 52 ± 6% ( P < 0.05) in the high-salt group. We found 1) macula densa cells express nNOS-α, nNOS-β, and nNOS-γ, 2) a high-salt diet enhances nNOS-β, and 3) TGF-induced NO generation from macula densa is enhanced in high-salt diet possibly from nNOS-β. In conclusion, we found that the splice variants of nNOS expressed in macula densa cells were α-, β-, and γ-isoforms and propose that enhanced level of nNOS-β during high-salt intake may contribute to macula densa NO production and help attenuate TGF.

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

2009 ◽  
Vol 296 (4) ◽  
pp. R994-R1000 ◽  
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.

scholarly journals High-Salt Attenuates the Efficacy of Dapagliflozin in Tubular Protection by Impairing Fatty Acid Metabolism in Diabetic Kidney Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Meina Zou ◽  
Yanrong Chen ◽  
Zongji Zheng ◽  
Shuyue Sheng ◽  
Yijie Jia ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Salt Intake ◽  
High Salt ◽  
Renal Tubules ◽  
High Salt Diet ◽  
Salt Diet ◽  
High Salt Intake ◽  
Renal Tubular

High-salt intake leads to kidney damage and even limits the effectiveness of drugs. However, it is unclear whether excessive intake of salt affects renal tubular energy metabolism and the efficacy of dapagliflozin on renal function in diabetic kidney disease (DKD). In this study, we enrolled 350 DKD patients and examined the correlation between sodium level and renal function, and analyzed influencing factors. The results demonstrated that patients with macroalbuminuria have higher 24 h urinary sodium levels. After establishment of type 2 diabetes mellitus model, the animals received a high-salt diet or normal-salt diet. In the presence of high-salt diet, the renal fibrosis was aggravated with fatty acid metabolism dysregulation. Furthermore, Na+/K+-ATPase expression was up-regulated in the renal tubules of diabetic mice, while the fatty acid metabolism was improved by inhibiting Na+/K+-ATPase of renal tubular epithelial cells. Of note, the administration with dapagliflozin improved renal fibrosis and enhanced fatty acid metabolism. But high salt weakened the above-mentioned renal protective effects of dapagliflozin in DKD. Similar results were recapitulated in vitro after incubating proximal tubular epithelial cells in high-glucose and high-salt medium. In conclusion, our results indicate that high salt can lead to fatty acid metabolism disorders by increasing Na+/K+-ATPase expression in the renal tubules of DKD. High salt intake diminishes the reno-protective effect of dapagliflozin in DKD.

Blood pressure and fluid-electrolyte balance in mice with reduced or absent ANP

1996 ◽  
Vol 271 (1) ◽  
pp. R109-R114 ◽  
Author(s):  
S. W. John ◽  
A. T. Veress ◽  
U. Honrath ◽  
C. K. Chong ◽  
L. Peng ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Blood Volume ◽  
Volume Expansion ◽  
Salt Intake ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Blood Volume Expansion ◽  
High Salt Intake ◽  
Low Salt

Atrial natriuretic peptide (ANP)-gene knockout mice of three genotypes (+/+, +/-, and -/-) were maintained on a low-salt diet (0.008% NaCl). They were then fed either the same low-salt diet or a high-salt diet (8% NaCl) for 1 wk. No differences were found among genotypes in daily food and water intakes or in urinary volume and electrolyte excretions. Arterial blood pressures measured in anesthetized animals at the end of the dietary regimen were significantly and similarly increased in -/- compared with +/+ mice on each diet. Renal excretion of fluid and electrolytes was measured in anesthetized mice before and after acute blood volume expansion. No genotype differences were observed before volume expansion. After volume expansion the wild-type (+/+) mice had much greater saluretic responses than either the heterozygous (+/-) or the homozygous mutant (-/-) animals on the low-salt diet but not on the high-salt diet. We conclude that ANP lowers blood pressure in the absence of detected changes in renal function; ANP is not essential for normal salt balance, even on high-salt intake; and ANP is essential for the natriuretic response to acute blood volume expansion on a low-salt but not high-salt intake.

Reactive oxygen species may contribute to reduced endothelium-dependent dilation in rats fed high salt

2000 ◽  
Vol 279 (1) ◽  
pp. H7-H14 ◽  
Author(s):  
Deborah M. Lenda ◽  
Bryan A. Sauls ◽  
Matthew A. Boegehold
Keyword(s):  
Reactive Oxygen Species ◽  
Salt Intake ◽  
Reactive Oxygen ◽  
High Salt ◽  
Oxygen Species ◽  
Dietary Salt ◽  
No Donor ◽  
High Salt Diet ◽  
Salt Diet ◽  
High Salt Intake

In normotensive rats, an increase in dietary salt leads to decreased arteriolar responsiveness to acetylcholine (ACh) because of suppressed local nitric oxide (NO) activity. We evaluated the possibility that generation of reactive oxygen species in the arteriolar wall is responsible for this loss of NO activity. Arteriolar responses to iontophoretically applied ACh were examined in the superfused spinotrapezius muscle of Sprague-Dawley rats fed a low-salt (LS; 0.45%) or high-salt diet (HS; 7%) for 4–5 wk. Responses to ACh were significantly depressed in HS rats but returned to normal in the presence of the oxidant scavengers superoxide dismutase + catalase or 2,2,6,6-tetamethylpiperidine- N-oxyl (TEMPO) + catalase. Arteriolar responses to the NO donor sodium nitroprusside were similar in HS and LS rats. Arteriolar and venular wall oxidant activity, as determined by reduction of tetranitroblue tetrazolium, was significantly greater in HS rats than in LS rats. Exposure to TEMPO + catalase reduced microvascular oxidant levels to normal in HS rats. These data suggest that a high-salt diet leads to increased generation of reactive oxygen species in striated muscle microvessels, and this increased oxidative state may be responsible for decreased endothelium-dependent responses associated with high salt intake.

scholarly journals Maternal high-salt diet alters redox state and mitochondrial function in newborn rat offspring’s brain

2018 ◽  
Vol 119 (9) ◽  
pp. 1003-1011 ◽  
Author(s):  
Daniela P. Stocher ◽  
Caroline P. Klein ◽  
André B. Saccomori ◽  
Pauline M. August ◽  
Nicolli C. Martins ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mitochondrial Function ◽  
Redox State ◽  
Salt Intake ◽  
High Salt ◽  
Health State ◽  
High Salt Diet ◽  
Salt Diet ◽  
High Salt Intake ◽  
Pregnancy And Lactation

AbstractExcessive salt intake is a common feature of Western dietary patterns, and has been associated with important metabolic changes including cerebral redox state imbalance. Considering that little is known about the effect on progeny of excessive salt intake during pregnancy, the present study investigated the effect of a high-salt diet during pregnancy and lactation on mitochondrial parameters and the redox state of the brains of resulting offspring. Adult female Wistar rats were divided into two dietary groups (n 20 rats/group): control standard chow (0·675 % NaCl) or high-salt chow (7·2 % NaCl), received throughout pregnancy and for 7 d after delivery. On postnatal day 7, the pups were euthanised and their cerebellum, hypothalamus, hippocampus, prefrontal and parietal cortices were dissected. Maternal high-salt diet reduced cerebellar mitochondrial mass and membrane potential, promoted an increase in reactive oxygen species allied to superoxide dismutase activation and decreased offspring cerebellar nitric oxide levels. A significant increase in hypothalamic nitric oxide levels and mitochondrial superoxide in the hippocampus and prefrontal cortex was observed in the maternal high-salt group. Antioxidant enzymes were differentially modulated by oxidant increases in each brain area studied. Taken together, our results suggest that a maternal high-salt diet during pregnancy and lactation programmes the brain metabolism of offspring, favouring impaired mitochondrial function and promoting an oxidative environment; this highlights the adverse effect of high-salt intake in the health state of the offspring.

scholarly journals Activation of the Sympathetic Nervous System Promotes Blood Pressure Salt-Sensitivity in C57BL6/J Mice

Hypertension ◽  
2021 ◽  
Vol 77 (1) ◽  
pp. 158-168
Author(s):  
Ailsa F. Ralph ◽  
Celine Grenier ◽  
Hannah M. Costello ◽  
Kevin Stewart ◽  
Jessica R. Ivy ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Function ◽  
Salt Intake ◽  
Salt Sensitivity ◽  
High Salt ◽  
Sodium Balance ◽  
High Salt Diet ◽  
Salt Diet ◽  
High Salt Intake ◽  
Pressure Natriuresis

Global salt intake averages >8 g/person per day, over twice the limit advocated by the American Heart Association. Dietary salt excess leads to hypertension, and this partly mediates its poor health outcomes. In ≈30% of people, the hypertensive response to salt is exaggerated. This salt-sensitivity increases cardiovascular risk. Mechanistic cardiovascular research relies heavily on rodent models and the C57BL6/J mouse is the most widely used reference strain. We examined the effects of high salt intake on blood pressure, renal, and vascular function in the most commonly used and commercially available C57BL6/J mouse strain. Changing from control (0.3% Na + ) to high salt (3% Na + ) diet increased systolic blood pressure in male mice by ≈10 mm Hg within 4 days of dietary switch. This hypertensive response was maintained over the 3-week study period. Returning to control diet gradually reduced blood pressure back to baseline. High-salt diet caused a rapid and sustained downregulation in mRNA encoding renal NHE3 (sodium-hydrogen-exchanger 3) and EnaC (epithelial sodium channel), although we did not observe a suppression in aldosterone until ≈7 days. During the development of salt-sensitivity, the acute pressure natriuresis relationship was augmented and neutral sodium balance was maintained throughout. High-salt diet increased ex vivo sensitivity of the renal artery to phenylephrine and increased urinary excretion of adrenaline, but not noradrenaline. The acute blood pressure–depressor effect of hexamethonium, a ganglionic blocker, was enhanced by high salt. Salt-sensitivity in commercially sourced C57BL6/J mice is attributable to sympathetic overactivity, increased adrenaline, and enhanced vascular sensitivity to alpha-adrenoreceptor activation and not sodium retention or attenuation of the acute pressure natriuresis response.

Relationships between metabolic endocrine systems and voluntary feed intake in Merino sheep fed a high salt diet

2007 ◽  
Vol 47 (5) ◽  
pp. 544 ◽  
Author(s):  
Dominique Blache ◽  
Micaela J. Grandison ◽  
David G. Masters ◽  
Robyn A. Dynes ◽  
Margaret A. Blackberry ◽  
...  
Keyword(s):  
Feed Intake ◽  
Salt Intake ◽  
Control Diet ◽  
Plasma Concentrations ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Voluntary Feed Intake ◽  
High Salt Intake ◽  
Ad Libitum

Grazing saltbush reduces productivity in sheep mostly because the high salt intake decreases feed intake and challenges the metabolism of the animal. However, little is known of the effect of salt load on the endocrine control systems that regulate voluntary feed intake and metabolism. Plasma concentrations of leptin, insulin and cortisol and blood glucose were monitored in wethers fed for 2 weeks with either a control diet (adequate salt) fed ad libitum, a high salt diet (20% of dry matter) fed ad libitum or a group fed the control diet with an intake restricted to that of the high salt ad libitum group (control pair-fed). High salt intakes reduced voluntary feed intake within 1 day and circulating concentrations of insulin and glucose within 2 weeks. Liveweight and leptin concentrations were not specifically affected by the high intake of salt but decreased in response to the decrease in intake. Cortisol secretion was not affected. Although salt intake had a specific effect on insulin and glucose (over and above the effect of reduced feed intake alone), the reduction in insulin would be expected to increase rather than decrease appetite and feed intake. Therefore, insulin, leptin and cortisol do not appear to play major roles in the control of feed intake in sheep consuming high levels of salt.

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