Abnormal neonatal sodium handling in skin precedes hypertension in the SAME rat

AbstractWe discovered high Na+ and water content in the skin of newborn Sprague–Dawley rats, which reduced ~ 2.5-fold by 7 days of age, indicating rapid changes in extracellular volume (ECV). Equivalent changes in ECV post birth were also observed in C57Bl/6 J mice, with a fourfold reduction over 7 days, to approximately adult levels. This established the generality of increased ECV at birth. We investigated early sodium and water handling in neonates from a second rat strain, Fischer, and an Hsd11b2-knockout rat modelling the syndrome of apparent mineralocorticoid excess (SAME). Despite Hsd11b2−/− animals exhibiting lower skin Na+ and water levels than controls at birth, they retained ~ 30% higher Na+ content in their pelts at the expense of K+ thereafter. Hsd11b2−/− neonates exhibited incipient hypokalaemia from 15 days of age and became increasingly polydipsic and polyuric from weaning. As with adults, they excreted a high proportion of ingested Na+ through the kidney, (56.15 ± 8.21% versus control 34.15 ± 8.23%; n = 4; P < 0.0001), suggesting that changes in nephron electrolyte transporters identified in adults, by RNA-seq analysis, occur by 4 weeks of age. Our data reveal that Na+ imbalance in the Hsd11b2−/− neonate leads to excess Na+ storage in skin and incipient hypokalaemia, which, together with increased, glucocorticoid-induced Na+ uptake in the kidney, then contribute to progressive, volume contracted, salt-sensitive hypertension. Skin Na+ plays an important role in the development of SAME but, equally, may play a key physiological role at birth, supporting post-natal growth, as an innate barrier to infection or as a rudimentary kidney.

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Abstract 41: Fructose Stimulates Na/H Exchanger 3 Activity and Enhances the Ability of Angiotensin II to Activate Na/H Exchanger 3 in the Proximal Tubule

Hypertension ◽

10.1161/hyp.62.suppl_1.a41 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Pablo Cabral ◽

Nancy Hong ◽

Jeffrey Garvin

Keyword(s):

Angiotensin Ii ◽

Proximal Tubule ◽

Physiological Saline ◽

Ang Ii ◽

Sprague Dawley ◽

Basal Rate ◽

Low Concentrations ◽

Sprague Dawley Rats ◽

High Fructose ◽

Salt Sensitive Hypertension

Consumption of high-fructose corn syrup as a sweetener has increased dramatically. Fructose has been implicated in the epidemic of diabetes, obesity and hypertension including salt-sensitive hypertension. However, the mechanisms are poorly understood. The proximal nephron reabsorbs 60-70% of the fluid and Na, and most of the filtered bicarbonate via Na/H exchanger 3. Enhanced proximal nephron transport has been implicated in several forms of hypertension. We hypothesized that fructose stimulates NHE3 activity and enhances the ability of angiotensin II (ANG II) to activate NHE3 in the proximal tubule. To test our hypothesis we isolated and perfused proximal tubules from Sprague Dawley rats. NHE3 activity was measured as the recovery of intracellular pH after an NH4Cl acid pulse using the pH sensitive dye BCECF. The rate of pH recovery was measured in Fluorescent Units per second (FU/sec). In the presence of a 5.5 mM glucose-containing physiological saline the basal rate of pH recovery was 3.1 ± 0.8 FU/sec. When the luminal solution was exchanged to a 0.6 mM glucose + 5 mM fructose-containing physiological saline in a second period, the rate of pH recovery increased to 5 ± 1 FU/sec (p<0.03, n=8).To study whether this effect was due to the addition of fructose or the removal of glucose to the lumen, we performed a separate set of experiments where 5 mM glucose was substituted for 5 mM fructose. In the presence of 0.6 mM glucose the basal rate of pH recovery was 3.6 ± 1.5 FU/sec. When 5 mM fructose was added the rate of pH recovery increased to 5.9 ± 2 FU/sec (p<0.02, n=5). Control experiments showed no differences between periods when 5 mm glucose was added back to the luminal perfusate. Finally, we tested the effect of low concentrations of ANG II in the presence or absence of luminal fructose. In the presence of 5.5 mM glucose, ANG II 10-12 M did not affect the rate of pH recovery (change: -1.1 ± 0.5 FU/sec, n=9). However, in the presence of 5 mM fructose, ANG II increased the rate of pH recovery (change: 4.0 ± 2.2 FU/sec, p< 0.03 n=6). We conclude that acute treatment with fructose stimulates NHE3 activity and enhances the ability of ANG II to activate NHE3 in the proximal tubule. These results may partially explain the mechanism by which a fructose diet induces hypertension.

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Adrenomedullin microinjection into the area postrema increases blood pressure

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1997.272.6.r1698 ◽

1997 ◽

Vol 272 (6) ◽

pp. R1698-R1703 ◽

Cited By ~ 9

Author(s):

M. A. Allen ◽

P. M. Smith ◽

A. V. Ferguson

Keyword(s):

Blood Pressure ◽

Area Postrema ◽

Area Under The Curve ◽

Physiological Role ◽

Cardiovascular Responses ◽

Hypotensive Effect ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Brain Site

Adrenomedullin (ADM) circulates in the blood at concentrations comparable to other vasoactive peptides with established roles in cardiovascular regulation. Intravenously administered ADM produces a clear hypotensive effect, whereas intracerebroventricular microinjections result in increases in blood pressure (BP). Recently, we demonstrated that ADM influences neurons of the area postrema (AP), a central nervous system site implicated in cardiovascular control. However, to address directly the physiological significance of the actions of ADM at the AP, an in vivo microinjection study was undertaken. ADM, at two concentrations (1 and 10 microM), in volumes of 50, 100, and 200 nl, was microinjected into the AP or NTS of 21 urethan-anesthetized male Sprague-Dawley rats. Microinjection of 10 microM ADM (100 nl) resulted in significant transient (2-5 min) increases in BP [120 s area under the curve (AUC): 684.3 +/- 268.6 mmHg/s (P < 0.05)], and heart rate (HR) [AUC: 12.5 +/- 4.5 beats/min (P < 0.05)]. The lower concentration of ADM (1 microM) had no effect on either BP (179.1 +/- 143.6 mmHg/s) or HR (0.8 +/- 2.6 beats/min). ADM was also microinjected into the immediately adjacent nucleus of the solitary tract, where it was found to be without effect on either BP or HR. This study demonstrates, for the first time, a physiological role for ADM acting at a specific brain site, the AP, to produce significant cardiovascular responses.

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Gut dysbiosis contributes to high fructose–induced salt-sensitive hypertension in Sprague-Dawley rats

Nutrition ◽

10.1016/j.nut.2020.110766 ◽

2020 ◽

Vol 75-76 ◽

pp. 110766 ◽

Cited By ~ 1

Author(s):

Yang Chen ◽

Yeyan Zhu ◽

Chunying Wu ◽

Aihua Lu ◽

Mokan Deng ◽

...

Keyword(s):

Sprague Dawley ◽

Gut Dysbiosis ◽

Sprague Dawley Rats ◽

High Fructose ◽

Salt Sensitive Hypertension

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Norepinephrine-evoked salt-sensitive hypertension requires impaired renal sodium chloride cotransporter activity in Sprague-Dawley rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00514.2014 ◽

2016 ◽

Vol 310 (2) ◽

pp. R115-R124 ◽

Cited By ~ 12

Author(s):

Kathryn R. Walsh ◽

Jill T. Kuwabara ◽

Joon W. Shim ◽

Richard D. Wainford

Keyword(s):

Blood Pressure ◽

Sodium Chloride ◽

Salt Sensitivity ◽

Dietary Sodium ◽

Ang Ii ◽

Sprague Dawley ◽

Sodium Chloride Cotransporter ◽

Sprague Dawley Rats ◽

Salt Sensitive Hypertension ◽

The Impact

Recent studies have implicated a role of norepinephrine (NE) in the activation of the sodium chloride cotransporter (NCC) to drive the development of salt-sensitive hypertension. However, the interaction between NE and increased salt intake on blood pressure remains to be fully elucidated. This study examined the impact of a continuous NE infusion on sodium homeostasis and blood pressure in conscious Sprague-Dawley rats challenged with a normal (NS; 0.6% NaCl) or high-salt (HS; 8% NaCl) diet for 14 days. Naïve and saline-infused Sprague-Dawley rats remained normotensive when placed on HS and exhibited dietary sodium-evoked suppression of peak natriuresis to hydrochlorothiazide. NE infusion resulted in the development of hypertension, which was exacerbated by HS, demonstrating the development of the salt sensitivity of blood pressure [MAP (mmHg) NE+NS: 151 ± 3 vs. NE+HS: 172 ± 4; P < 0.05]. In these salt-sensitive animals, increased NE prevented dietary sodium-evoked suppression of peak natriuresis to hydrochlorothiazide, suggesting impaired NCC activity contributes to the development of salt sensitivity [peak natriuresis to hydrochlorothiazide (μeq/min) Naïve+NS: 9.4 ± 0.2 vs. Naïve+HS: 7 ± 0.1; P < 0.05; NE+NS: 11.1 ± 1.1; NE+HS: 10.8 ± 0.4). NE infusion did not alter NCC expression in animals maintained on NS; however, dietary sodium-evoked suppression of NCC expression was prevented in animals challenged with NE. Chronic NCC antagonism abolished the salt-sensitive component of NE-mediated hypertension, while chronic ANG II type 1 receptor antagonism significantly attenuated NE-evoked hypertension without restoring NCC function. These data demonstrate that increased levels of NE prevent dietary sodium-evoked suppression of the NCC, via an ANG II-independent mechanism, to stimulate the development of salt-sensitive hypertension.

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Functional genomics of the rat neuromedin U receptor 1 reveals a naturally occurring deleterious allele

Physiological Genomics ◽

10.1152/physiolgenomics.00070.2012 ◽

2013 ◽

Vol 45 (2) ◽

pp. 89-97 ◽

Cited By ~ 2

Author(s):

Rosemarie Panetta ◽

Luc Meury ◽

Chang Qing Cao ◽

Carole Puma ◽

Françoise Mennicken ◽

...

Keyword(s):

Functional Genomics ◽

Radioligand Binding ◽

Physiological Role ◽

Nociceptive Response ◽

Sprague Dawley ◽

Coding Region ◽

Binding Studies ◽

Naturally Occurring ◽

Sprague Dawley Rats ◽

Toxicological Studies

Neuromedin U (NMU) plays an important role in a number of physiological processes, but the relative contribution of its two known receptors, NMUR1 and NMUR2, is still poorly understood. Here we report the existence of a SNP T1022→A (Val341→Glu) in the third exon of the rat Nmur1 gene that leads to an inactive receptor. This SNP is present within the coding region of the highly conserved NPXXY motif found within all class A type G protein-coupled receptors and translates to an NMUR1 receptor that is not expressed on the cell surface. Genetic analysis of the Nmur1 gene in a population of Sprague-Dawley rats revealed that this strain is highly heterogeneous for the inactivating polymorphism. The loss of functional NMUR1 receptors in Sprague-Dawley rats homozygous for the inactive allele was confirmed by radioligand binding studies on native tissue expressing NMUR1. The physiological relevance of this functional genomics finding was examined in two nociceptive response models. The pronociceptive effects of NMU were abolished in rats lacking functional NMUR1 receptors. The existence of naturally occurring NMUR1-deficient rats provides a novel and powerful tool to investigate the physiological role of NMU and its receptors. Furthermore, it highlights the importance of verifying the NMUR1 single nucleotide polymorphism status for rats used in physiological, pharmacological or toxicological studies conducted with NMUR1 modulators.

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RNA-seq-based transcriptome profiling reveals differential gene expression in the lungs of Sprague–Dawley rats during early-phase acute hypobaric hypoxia

Molecular Genetics and Genomics ◽

10.1007/s00438-015-1064-0 ◽

2015 ◽

Vol 290 (6) ◽

pp. 2225-2240 ◽

Cited By ~ 4

Author(s):

Priyanka Sharma ◽

Anju Bansal ◽

Prakash Chand Sharma

Keyword(s):

Gene Expression ◽

Differential Gene Expression ◽

Early Phase ◽

Hypobaric Hypoxia ◽

Transcriptome Profiling ◽

Rna Seq ◽

Sprague Dawley ◽

Acute Hypobaric Hypoxia ◽

Sprague Dawley Rats ◽

Differential Gene

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OXIDATIVE STRESS INDUCED RENAL D1 RECEPTOR DYSFUNCTION CAUSES SALT SENSITIVE HYPERTENSION IN SPRAGUE DAWLEY RATS

The FASEB Journal ◽

10.1096/fasebj.20.5.a1184 ◽

2006 ◽

Vol 20 (5) ◽

Author(s):

ANEES AHMAD BANDAY ◽

MUSTAFA F. LOKHANDWALA

Keyword(s):

Oxidative Stress ◽

D1 Receptor ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Salt Sensitive Hypertension

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Corrigendum to

Nutrition ◽

10.1016/j.nut.2020.110845 ◽

2020 ◽

Vol 77 ◽

pp. 110845

Author(s):

Yang Chen ◽

Yeyan Zhu ◽

Chunying Wu ◽

Aihua Lu ◽

Mokan Deng ◽

...

Keyword(s):

Sprague Dawley ◽

Gut Dysbiosis ◽

Sprague Dawley Rats ◽

High Fructose ◽

Salt Sensitive Hypertension

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Antihypertensive effect of dietary calcium loading in angiotensin II-salt rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1991.261.5.r1070 ◽

1991 ◽

Vol 261 (5) ◽

pp. R1070-R1074 ◽

Cited By ~ 1

Author(s):

K. Ando ◽

Y. Sato ◽

A. Ono ◽

K. Takahashi ◽

T. Shimosawa ◽

...

Keyword(s):

Angiotensin Ii ◽

Antihypertensive Effect ◽

Hypotensive Effect ◽

Plasma Catecholamine ◽

Ang Ii ◽

Sprague Dawley ◽

Calcium Loading ◽

Sprague Dawley Rats ◽

Salt Sensitive Hypertension ◽

Do So

To clarify the hypotensive effect of high dietary Ca intake on salt-sensitive hypertension, 7-wk-old Sprague-Dawley rats, 3.15% Na and/or 4.07% Ca diet loaded, were administered 125 ng/ml of angiotensin II (ANG II) intraperitoneally for 12 days. Compared with control rats (mean blood pressure 108 +/- 2 mmHg), ANG II administration caused hypertension (131 +/- 4 mmHg, P less than 0.05). Na loading enhanced the hypertensive effect of ANG II (161 +/- 4 mmHg, P less than 0.01). Dietary Ca loading did not significantly inhibit the pressor effect of ANG II alone (119 +/- 4 mmHg). However, Ca loading suppressed hypertension in ANG II-salt rats (126 +/- 4 mmHg, P less than 0.01). Plasma total catecholamine (norepinephrine + epinephrine) was increased in ANG II-salt rats (176 +/- 14 vs. 290 +/- 23 pg/ml, P less than 0.05), but Ca loading decreased plasma catecholamine (182 +/- 13 pg/ml, P less than 0.05). In contrast, plasma catecholamine was not significantly different between ANG II-treated rats with and without Ca loading. Ca loading increased serum Ca in ANG II rats (10.9 +/- 0.1 vs. 11.7 +/- 0.1 mg/dl, P less than 0.05) but did not do so significantly in ANG II-salt rats (10.8 +/- 0.2 vs. 10.9 +/- 0.1 mg/dl). Thus Ca loading exclusively ameliorated salt-sensitive hypertension, which was induced with ANG II administration and Na loading in rats, probably through suppression of the increased sympathetic activity. In addition, these effects of Ca loading were not mediated through an increased blood level of Ca.

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