Dahl Rats Research Articles

Multifractal approach to study of salt induced hypertension and baroreflex dysfunction in salt sensitive Dahl rats

This paper studies the multifractal properties of blood pressure (BP) time series of Salt Sensitive (SS) Dahl rats subject to low salt and high salt diet. The results are compared to those of the non hypertensive SSBN13 rats which are also subject to low salt and high salt diet. The time series exhibits multifractal properties in all cases. The BP time series is more complex in case of SS rats. The SSBN13 rats exhibit a higher degree of correlation compared to the SS rats. The results are interpreted and compared with results of previous investigation performed on the same samples The original time series was further decomposed into sign magnitude series of the increments and the analysis was repeated for the magnitude series. It was very interesting to observe that investigation of the original series as well as the magnitude series provide a better insight to the study. Some parameters which do not show significant variation for original series show considerable amount of change for magnitude series.

A10405 Influence of Gene Expression in Kidney of Dahl Rat under Sodium or Potassium Interventions

Objectives: Renal dysfunctional metabolism of sodium or potassium play a key role in formation of salt sensitivity. The aim was to investigate alteration of gene in kidney of Dahl rat and preliminaryly explore the protective mechanism of potassium on blood pressure, which would shed some new light in future. Methods: Male Dahl sensitive rats and 13BN-SS rats were randomly divided into nornal salt group, high salt group and high salt plus potassium supplement group respectively; Illumina RatRef-12 Expression BeadChip were used for screening the renal different genes between high salt group and high salt plus potassium supplement group, and the clusters, GO, Pathway analysis of functionally related genes were determined on the basis of their annotation term co-occurrence; qRT-PCR was performed to validate the gene expression data; Results: Microarray scanning had shown that 594 different gene were obtained between highsalt group and high salt plus potassium supplement group in Dahl salt sensitive rats; there were 429 upregulated genes and 479 downregulated genes between Dahl salt sensitive rats and13BN-SS rat in high salt group,; Dietary high saltcould increase the expression of SGK1 in Dahl salt sensitive rats, in contrast, potassium supplement could reverse this phenomenon; the expression of Mcoln3 was higher in Dahl salt sensitive ratsthan 13BN-SS rat, morever, potassium supplement could upregulate the expressionof Mcoln3 in Dahl salt sensitive rats and 13BN-SS rat. Conclusion: Dietary high salt could increase the expression of SGK1 in Dahl salt sensitive rats, in contrast, potassium supplement could reverse this phenomenon, which may be associated with the protective effect of potassium. Abnormality of the expression of Mcoln3 may be involved in salt-induced elevation of blood pressure in Dahl salt sensitive rat

Hydrogen gas improves left ventricular hypertrophy in Dahl rat of salt-sensitive hypertension

ABSTRACTPurpose: Hypertension is an important risk factor for death resulting from stroke, myocardial infarction, and end-stage renal failure. Hydrogen (H2) gas protects against many diseases, including ischemia-reperfusion injury and stroke. The effects of H2 on hypertension and its related left ventricular (LV) function have not been fully elucidated. The purpose of this study was to investigate the effects of H2 gas on hypertension and LV hypertrophy using echocardiography.Methods: Dahl salt-sensitive (DS) rats were randomly divided into three groups: those fed an 8% NaCl diet until 12 weeks of age (8% NaCl group), those additionally treated with 2% H2 gas (8% NaCl + 2% H2 group), and control rats maintained on a diet containing 0.3% NaCl until 12 weeks of age (0.3% NaCl group). H2 gas was supplied through a gas flowmeter and delivered by room air (2% hydrogenated room air, flow rate of 10 L/min) into a cage surrounded by an acrylic chamber. We evaluated interventricular septal wall thickness (IVST), LV posterior wall thickness (LVPWT), and LV mass using echocardiography.Results: IVST, LVPWT, and LV mass were significantly higher in the 8% NaCl group than the 0.3% NaCl group at 12 weeks of age, whereas they were significantly lower in the 8% NaCl + 2% H2 group than the 8% NaCl group. There was no significant difference in systolic blood pressure between the two groups.Conclusion: Our findings suggest that chronic H2 gas inhalation may help prevent LV hypertrophy in hypertensive DS rats.

Macrophage Depletion Lowered Blood Pressure and Attenuated Hypertensive Renal Injury and Fibrosis.

Monocyte/macrophage recruitment is closely associated with the degree of hypertensive renal injury. We investigated the direct role of macrophages using liposome-encapsulated clodronate (LEC) to deplete monocytes/macrophages in hypertensive renal injury. C57BL/6 mice were treated with a pressor dose of angiotensin (Ang, 1.4 mg/kg/day) II plus LEC or the PBS-liposome for 2 weeks. Ang II mice developed hypertension, albuminuria, glomerulosclerosis, and renal fibrosis. LEC treatment reduced systolic blood pressure (SBP), albuminuria, and protected against renal structural injury in Ang II mice. Ang II significantly increased renal macrophage infiltration (MOMA2+ cells) and the expression of renal tumor necrosis factor α and interleukin β1, which were significantly reduced in Ang II/LEC mice. Ang II increased renal oxidative stress and the expression of profibrotic factors transforming growth factor (TGF) β1 and fibronectin. Ang II also inhibited the phosphorylation of endothelial nitric oxide synthase [phospho-endothelial nitric oxide synthesis (eNOS), ser1177]. LEC treatment reduced renal oxidative stress and TGFβ1 and fibronectin expressions, and increased phospho-eNOS expression in the Ang II mice. In Dahl rats of salt-sensitive hypertension, LEC treatment for 4 weeks significantly attenuated the elevation of SBP induced by high salt intake and protected against renal injury and fibrosis. Our results demonstrate that renal macrophages play a critical role in the development of hypertension and hypertensive renal injury and fibrosis; the underlying mechanisms may be involved in the reduction in macrophage-driven renal inflammation and restoration of the balance between renal oxidative stress and eNOS. Therefore, macrophages should be considered as a potential therapeutic target to reduce the adverse consequences of hypertensive renal diseases.

Succinate decreases bladder function in a rat model associated with metabolic syndrome

Succinate and its receptor, GPR91, have been implicated in different aspects of metabolic syndrome. As GPR91 is expressed in the urinary bladder, the aim of this study is to show the effect of chronically increased succinate levels on bladder function. Healthy Sprague-Dawley (SD) rats and hypertensive Dahl rats received an intraperitoneal injection of either saline or succinate (50 mg/kg) daily for a period of 4 weeks. Conscious cystometry was performed at the end of this period. Bladders were collected and used for contractility studies and morphological assessment. Two-way ANOVA was performed to compare between the two strains and student t-tests to compare treatment groups within each strain. Compared to SD rats, Dahl rats showed signs of bladder dysfunction. Succinate treatment led to higher urinary succinate levels and lower bladder capacities compared to saline-treated animals. In SD rats, this was associated with higher collagen content, lower GPR91 expression and an altered bladder nerve profile in the bladder. In succinate-treated Dahl rats, detrusor contractility was reduced and associated with decreased cholinergic innervation and increased collagen content. It is suggested that succinate negatively affects bladder function via effects through its receptor, GPR91, and that its effects are enhanced in the presence of metabolic disturbance. These findings contribute to our understanding of the pathophysiology of bladder dysfunction, specifically in a metabolic syndrome setting.

Comparative studies of discrete cosine transform and lifting wavelet transform techniques for compression of blood pressure signal in salt sensitive Dahl rat

This paper introduces a study based on quality controlled discrete cosine transform (DCT) and lifting wavelet transform (LWT) based compression method for blood pressure signal compression in salt sensitive Dahl rat. The transformed coefficients are thresholded using the bisection algorithm to match the predefined user specified percentage root mean square difference (PRD) within the tolerance. Then, the binary lookup table is made to store the position map for zero and non-zero coefficients (NZC). The NZC are quantised by Max-Lloyd quantiser followed by arithmetic coding. Lookup table is encoded by Huffman coding. The results are presented on different blood pressure signals of varying characteristic. There is no significant difference in before quantisation PRD (BPRD) and after quantisation PRD (QPRD) in various signals in both transforms. Mean compression ratio increases with an increase in user define PRD (UPRD).

Fructose-Induced Cognitive Dysfunction is Associated with Increased Oxidative Stress in the Rat Brains

High fructose consumption is a risk factor for diabetes. Type 2 diabetes is associated with cognitive and memory impairment. To determine if fructose intake might affect memory function independently of diabetes development, we investigated the effects of monosaccharides on memory in prediabetic state. We examined whether 2.5% apple juice solution could influence cognitive function in salt-sensitive Dahl rats using passive avoidance methods. Furthermore, we examined the role of monosaccharides intake in cognitive function and oxidative stress in the brain. Four-week consumption of either apple juice or 2.5% fructose did not affect the blood glucose concentrations; however, apple juice, but not fructose, significantly decreased cognitive function compared with that of control rats given water. Second, Wistar rats aged 4 weeks were assigned to four groups given water, or 1.25% glucose, or fructose, or galactose solutions for 11 weeks. The fructose group had only slightly higher blood glucose concentrations than the control group. However, memory function engraved at age of 7 weeks and evaluated for 8 weeks in a passive avoidance test, was significantly decreased in the fructose and galactose groups compared with those in the glucose group. Oxidative stress in the brain, assessed by the tissue malondialdehyde (MDA) content, was significantly increased in the fructose group compared with that in the control group, and the decrease in cognitive function significantly correlated with the MDA content. These findings suggest that long-term apple juice consumption decreases memory function, possibly through an increase in oxidative stress in the brain, in turn induced by fructose overloading. Fructose-induced cognitive dysfunction is likely mediated by mechanisms other than insulin resistance.

Comparative studies of discrete cosine transform and lifting wavelet transform techniques for compression of blood pressure signal in salt sensitive Dahl rat

This paper introduces a study based on quality controlled discrete cosine transform (DCT) and lifting wavelet transform (LWT) based compression method for blood pressure signal compression in salt sensitive Dahl rat. The transformed coefficients are thresholded using the bisection algorithm to match the predefined user specified percentage root mean square difference (PRD) within the tolerance. Then, the binary lookup table is made to store the position map for zero and non-zero coefficients (NZC). The NZC are quantised by Max-Lloyd quantiser followed by arithmetic coding. Lookup table is encoded by Huffman coding. The results are presented on different blood pressure signals of varying characteristic. There is no significant difference in before quantisation PRD (BPRD) and after quantisation PRD (QPRD) in various signals in both transforms. Mean compression ratio increases with an increase in user define PRD (UPRD).

The effect of hypertension on adult hippocampal neurogenesis in young adult spontaneously hypertensive rats and Dahl rats.

The dentate gyrus of the hippocampus is one of the few places in the brain where neurogenesis occurs in adulthood. Nowadays, an increasing number of children and young adults are affected by hypertension, one of the factors in the development of cerebrovascular diseases and age-related cognitive deficits. Since these cognitive deficits are often hippocampus-dependent, it is possible that hypertension exerts this effect via decreasing adult neurogenesis which has been shown to be essential for a range of cognitive tasks. We used spontaneously hypertensive rats, which develop hypertension in the first weeks of life. Half of them were treated with the antihypertensive drug captopril. We found that the drug-induced lowering of blood pressure in this period did not affect the rate of adult neurogenesis. In a second experiment, we used another animal model of hypertension - salt-sensitive and salt-resistant strains of Dahl rats. A high-salt diet induces hypertension in the salt-sensitive strain, but not in the salt-resistant strain. The high-salt diet led to salt-induced hypertension, but did not affect the level of adult neurogenesis in the dentate gyrus of the hippocampus. We conclude that hypertension does not significantly affect the rate of hippocampal neurogenesis in young adult rats.

Physiology and pathophysiology of the plasminogen system in the kidney.

The plasminogen system is important for fibrinolysis in addition to tissue remodeling and inflammation with significance for kidney disease. The system consists of the circulating zymogen plasminogen (Plg) and the tissue- and urokinase-type plasminogen activators, tPAand uPA, expressed in the glomeruli, endothelium and tubular epithelium, respectively, and the inhibitors α2-antiplasmin and plasminogen activator inhibitor-type1, PAI-1. Plasminogen is activated by surface receptors, some with renal expression: urokinase-type plasminogen activator receptor (uPAR), plasminogen receptor KT (Plg-RKT), and tPA, most evident in the endothelium. Plasmin may exert effects through protease-activated receptors, PARs, expressed in the kidney. Deletion of plasminogen system component genes confers no major developmental or renal phenotypes in normal mice. In glomerular injury and renal interstitial fibrosis, deletion of various components, notably Plg, uPA, PAI, and uPAR is associated with protection suggesting a disease promoting effect of plasmin, in some cases exerted through PAR1 receptor activation. Plasminogen and uPA are aberrantly filtrated across the glomerular barrier in proteinuria, and plasminogen is activated in the tubular fluid. In the tubular fluid, plasmin may activate proteolytically the epithelial sodium channel (ENaC) and inhibit the apical calcium transporter transient receptor potential cation channel subfamily V member 5 (TRPV5), which could explain impaired sodium excretion and enhanced calcium excretion in proteinuria. Amiloride, a potassium-sparing diuretic, inhibits urokinase and plasmin activation in the tubular fluid and uPAR expression in vitro, which highlights new indications for an old drug. Protease inhibitors lowered blood pressure and antagonized fibrosis in salt-sensitive Dahl rats. Current knowledge indicates that the plasminogen system aggravates renal disease by direct and indirect hypertensive effects and is a promising target to antagonize disease progression.

Dietary salt blunts vasodilation by stimulating epithelial sodium channels in endothelial cells from salt-sensitive Dahl rats.

Our recent studies show that the reduced activity of epithelial sodium channels (ENaC) in endothelial cells accounts for the adaptation of vasculature to salt in Sprague-Dawley rats. The present study examines a hypothesis that enhanced ENaC activity mediates the loss of vasorelaxation in Dahl salt-sensitive (SS) rats. We used the cell-attached patch-clamp technique to record ENaC activity in split-open mesenteric arteries. Western blot and immunofluorescence staining were used to evaluate the levels of aldosterone, ENaC, eNOS and NO. Blood pressure was measured with the tail-cuff method and the artery relaxation was measured with the wire myograph assay. High-salt (HS) diet significantly increased plasma aldosterone and ENaC activity in the endothelial cells of Dahl SS rats. The endothelium-dependent artery relaxation was blunted by HS challenge in these rats. Amiloride, a potent blocker of ENaC, increased both phosphorylated eNOS and NO and therefore prevented the HS-induced loss of vasorelaxation. As, in SS rats, endogenous aldosterone was already elevated by HS challenge, exogenous aldosterone did not further elevate ENaC activity in the rats fed with HS. Eplerenone, a mineralocorticoid receptor antagonist, attenuated the effects of HS on both ENaC activity and artery relaxation. These data suggest that HS diet blunts artery relaxation and causes hypertension via a pathway associated with aldosterone-dependent activation of ENaC in endothelial cells. This pathway provides one of the mechanisms by which HS causes hypertension in Dahl SS rats. This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

Cytotoxic CD8+ interleukin (IL)-17+ T-cells play a role in hypertension-specific inflammatory responses associated with ovariectomy in Dahl rats

Abstract Background and Objective Oophorectomy is associated with increased body weight (BW) gain and incidence of hypertension (HT) compared with age-matched women. Increased BW gain and HT coincide with increased inflammatory biomarkers. To separate immune responses due to HT from those due to BW gain, we compared T-cell subpopulations in normotensive Dahl (DR) and hypertensive Dahl (DS) rats after ovariectomy. Methods Six week old DS and DR rats were ovariectomized (Ovx) or had sham surgery (Sham). Mean arterial pressure (MAP) was measured in anesthetized rats after 4 and 10 months (mo) acutely by indwelling vascular catheter. Splenic T-cells were assessed by flow cytometry at 10 mo. Results Ovariectomy increased the MAP in DS but not DR rats at 4 mo [MAP (mmHg): DS-Ovx, 143±1.0 vs DS-Sham, 129±2.9; p=0.0002 & DR-Ovx, 123±4.4 vs DR-Sham, 126±1.3; ns n=10–12/group]. At 10 mo, the MAP remained higher in the ovariectomized DS compared to DR rats [MAP (mmHg): DS-Ovx, 190±12 vs DR-Ovx, 114±1.2; n=5–8/group; p=0.002]. At 10 mo, ovariectomy increased BW to a similar extent in DS and DR rats [BW gain (g): DS, 179±13 vs DR, 202±14; ns]. The frequency of CD8+IL17a+ T-cells increased in the ovariectomized DS but not DR rats [Frequency (%) at 10 mo: DS-Ovx, 9.6±2 vs DR-Ovx, 1.3±0.4; n=5–8/group; p<0.0001]. Conclusion Cytotoxic CD8+ IL-17a+ T-cells may play a role in the HT-specific inflammatory response in ovariectomized DS rats.

MP26-16 SUCCINATE IN VOIDING DYSFUNCTION ASSOCIATED WITH METABOLIC SYNDROME

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Basic Research & Pathophysiology I1 Apr 2017MP26-16 SUCCINATE IN VOIDING DYSFUNCTION ASSOCIATED WITH METABOLIC SYNDROME Monica Velasquez Flores, Abubakr Mossa, Philippe Cammisotto, and Lysanne Campeau Monica Velasquez FloresMonica Velasquez Flores More articles by this author , Abubakr MossaAbubakr Mossa More articles by this author , Philippe CammisottoPhilippe Cammisotto More articles by this author , and Lysanne CampeauLysanne Campeau More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.787AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Disruption in energy homeostasis, the main factor driving metabolic syndrome, may also be responsible for the development of its associated bladder dysfunction. Succinate, an intermediate of the citric acid cycle, along with its receptor, GPR91, have been implicated in different aspects of metabolic syndrome, and it is possible that their role could extend to the bladder. Our goal is to show that succinate can alter bladder function in a model of bladder overactivity associated with metabolic syndrome. METHODS Intraperitoneal injections of saline or succinate were administered daily for a period of 4 weeks to Sprague-Dawley (SD) rats and Dahl/SS rats, a model of metabolic syndrome with hypertension. Succinate levels were measured in the plasma and urine. Conscious cystometry was then performed. On the next day, bladders were collected for organ bath experiments and quantitative PCR for GPR91. Bladder detrusor strips were stimulated with potassium chloride (KCl), carbachol, and electrical field stimulation (EFS). One-way ANOVA with Bonferroni post-hoc test was used to measure differences between all groups. P<0.05 was considered significant. RESULTS Dahl rats have lower plasma succinate levels compared to SD rats. 24-hour urine levels of succinate were increased in succinate-treated rats in both SD and Dahl groups. SD succinate-treated rats had significantly lower levels of GPR91 in the bladder compared to SD control rats. This was not observed in Dahl rats. Dahl rats had shorter intercontraction intervals, smaller bladder capacities and lower micturition volumes than SD rats. Chronic administration of succinate lowered these parameters, albeit not significant. Organ bath data showed that the contractile responses to KCl, carbachol and EFS were significantly increased in detrusor strips from Dahl control rats compared to those from the other three groups. CONCLUSIONS Models of metabolic syndrome have obvious differences in bladder function compared with control rats. Chronic administration of succinate, as observed in vitro, alters detrusor contractility of Dahl rats. The absence of down-regulation of GPR91 in the Dahl bladder treated with succinate could explain the alterations in detrusor contractility observed only in this group. Increased urinary succinate levels may contribute to the development of bladder dysfunction. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e325-e326 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Monica Velasquez Flores More articles by this author Abubakr Mossa More articles by this author Philippe Cammisotto More articles by this author Lysanne Campeau More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Hydrogen Sulfide Inhibits High-Salt Diet-Induced Myocardial Oxidative Stress and Myocardial Hypertrophy in Dahl Rats.

The study aimed to examine the protective effect of hydrogen sulfide (H2S) on high-salt-induced oxidative stress and myocardial hypertrophy in salt-sensitive (Dahl) rats. Thirty male Dahl rats and 40 SD rats were included in the study. They were randomly divided into Dahl control (Dahl + NS), Dahl high salt (Dahl + HS), Dahl + HS + NaHS, SD + NS, SD + HS, SD + HS + NaHS, and SD + HS + hydroxylamine (HA). Rats in Dahl + NS and SD + NS groups were given chow with 0.5% NaCl and 0.9% normal saline intraperitoneally daily. Myocardial structure, α-myosin heavy chain (α-MHC) and β-myosin heavy chain (β-MHC) expressions were determined. Endogenous myocardial H2S pathway and oxidative stress in myocardial tissues were tested. Myocardial H2S pathway was downregulated with myocardial hypertrophy featured by increased heart weight/body weight and cardiomyocytes cross-sectional area, decreased α-MHC and increased β-MHC expressions in Dahl rats with high-salt diet (all P < 0.01), and oxidative stress in myocardial tissues was significantly activated, demonstrated by the increased contents of hydroxyl radical, malondialdehyde and oxidized glutathione and decreased total antioxidant capacity, carbon monoxide, catalase, glutathione, glutathione peroxidase, superoxide dismutase (SOD) activities and decreased SOD1 and SOD2 protein expressions (P < 0.05, P < 0.01). However, H2S reduced myocardial hypertrophy with decreased heart weight/body weight and cardiomyocytes cross-sectional area, increased α-MHC, decreased β-MHC expressions and inhibited oxidative stress in myocardial tissues of Dahl rats with high-salt diet. However, no significant difference was found in H2S pathway, myocardial structure, α-MHC and β-MHC protein and oxidative status in myocardial tissues among SD + NS, SD + HS, and SD + HS + NaHS groups. HA, an inhibitor of cystathionine β-synthase, inhibited myocardial H2S pathway (P < 0.01), and stimulated myocardial hypertrophy and oxidative stress in SD rats with high-salt diet. Hence, H2S inhibited myocardial hypertrophy in high salt-stimulated Dahl rats in association with the enhancement of antioxidant capacity, thereby inhibiting oxidative stress in myocardial tissues.

Hydrogen sulfide in paraventricular nucleus attenuates blood pressure by regulating oxidative stress and inflammatory cytokines in high salt-induced hypertension

Hydrogen sulfide (H2S) is an important gaseous signaling molecule in neuro-modulation, anti-inflammatory, anti-oxidant and anti-hypertensive effects. The paraventricular nucleus (PVN) is a major integrative nucleus in regulating BP and SNA. The aim of this study is to explore whether endogenous or exogenous H2S changed by hydroxylamine hydrochloride (HA) or GYY4137 infused in the PVN affects RSNA and MAP by regulating oxidative stress or the balance between pro-inflammatory cytokines (PICs) and anti-inflammatory cytokines in high salt-induced hypertensive rats. Male Dahl rats were fed by high-salt or normal-salt diet. At the end of the 4th week, GYY4137, HA or vehicle was microinjected into bilateral PVN for 6 weeks. The levels of MAP, HR, plasma norepinephrine (NE), reactive oxygen species (ROS), NOX2, NOX4 and IL-1β were increased significantly in high salt-induced hypertensive rats. Higher levels of these parameters were detected in the group treated by HA, but lower levels in the GYY4137 group. The trends of H2S, CBS, IL-10 and Cu/Zn SOD were opposite to the parameters described above. These findings suggest that endogenous or exogenous H2S in the PVN attenuates sympathetic activity and hypertensive response, which are partly due to decrease of ROS and PICs within the PVN in high salt-induced hypertension.

Basal and Activated Calcium Sensitization Mediated by RhoA/Rho Kinase Pathway in Rats with Genetic and Salt Hypertension

Calcium sensitization mediated by RhoA/Rho kinase pathway can be evaluated either in the absence (basal calcium sensitization) or in the presence of endogenous vasoconstrictor systems (activated calcium sensitization). Our aim was to compare basal and activated calcium sensitization in three forms of experimental hypertension with increased sympathetic tone and enhanced calcium entry—spontaneously hypertensive rats (SHR), heterozygous Ren-2 transgenic rats (TGR), and salt hypertensive Dahl rats. Activated calcium sensitization was determined as blood pressure reduction induced by acute administration of Rho kinase inhibitor fasudil in conscious rats with intact sympathetic nervous system (SNS) and renin-angiotensin system (RAS). Basal calcium sensitization was studied as fasudil-dependent difference in blood pressure response to calcium channel opener BAY K8644 in rats subjected to RAS and SNS blockade. Calcium sensitization was also estimated from reduced development of isolated artery contraction by Rho kinase inhibitor Y-27632. Activated calcium sensitization was enhanced in all three hypertensive models (due to the hyperactivity of vasoconstrictor systems). In contrast, basal calcium sensitization was reduced in SHR and TGR relative to their controls, whereas it was augmented in salt-sensitive Dahl rats relative to their salt-resistant controls. Similar differences in calcium sensitization were seen in femoral arteries of SHR and Dahl rats.

Effect of salt intake on beat-to-beat blood pressure nonlinear dynamics and entropy in salt-sensitive versus salt-protected rats

Blood pressure exhibits substantial short‐ and long‐term variability (BPV). We assessed the hypothesis that the complexity of beat‐to‐beat BPV will be differentially altered in salt‐sensitive hypertensive Dahl rats (SS) versus rats protected from salt‐induced hypertension (SSBN13) maintained on high‐salt versus low‐salt diet. Beat‐to‐beat systolic and diastolic BP series from nine SS and six SSBN13 rats (http://www.physionet.org) were analyzed following 9 weeks on low salt and repeated after 2 weeks on high salt. BP complexity was quantified by detrended fluctuation analysis (DFA), short‐ and long‐range scaling exponents (α S and α L), sample entropy (SampEn), and traditional standard deviation (SD) and coefficient of variation (CV(%)). Mean systolic and diastolic BP increased on high‐salt diet (P < 0.01) particularly for SS rats. SD and CV(%) were similar across groups irrespective of diet. Salt‐sensitive and ‐protected rats exhibited similar complexity indices on low‐salt diet. On high salt, (1) SS rats showed increased scaling exponents or smoother, systolic (P = 0.007 [α L]) and diastolic (P = 0.008 [α L]) BP series; (2) salt‐protected rats showed lower SampEn (less complex) systolic and diastolic BP (P = 0.046); and (3) compared to protected SSBN13 rats, SS showed higher α L for systolic (P = 0.01) and diastolic (P = 0.005) BP. Hypertensive SS rats are more susceptible to high salt with a greater rise in mean BP and reduced complexity. Comparable mean pressures in sensitive and protective rats when on low‐salt diet coupled with similar BPV dynamics suggest a protective role of low‐salt intake in hypertensive rats. This effect likely reflects better coupling of biologic oscillators.

Cytotoxic CD8+ Interleukin (IL)‐17+ T‐cells Play a Role in Hypertension‐Specific Inflammatory Responses Associated with Ovariectomy in Dahl Rats

Background and ObjectiveOophorectomy is associated with increased body weight (BW) gain and incidence of hypertension (HT) compared with age‐matched women. Increased BW gain and HT coincide with increased inflammatory biomarkers. To separate immune responses due to HT from those due to BW gain, we compared T‐cell subpopulations in normotensive Dahl (DR) and hypertensive Dahl (DS) rats after ovariectomy.MethodsSix week old DS and DR rats were ovariectomized (Ovx) or had sham surgery (Sham). Mean arterial pressure (MAP) was measured in anesthetized rats after 4 and 10 months (mo) acutely by indwelling vascular catheter. Splenic T‐cells were assessed by flow cytometry at 10 mo.ResultsOvariectomy increased the MAP in DS but not DR rats at 4 mo [MAP (mmHg): DS‐Ovx, 143±1.0 vs DS‐Sham, 129±2.9; p=0.0002 &amp; DR‐Ovx, 123±4.4 vs DR‐Sham, 126±1.3; ns n=10–12/group]. At 10 mo, the MAP remained higher in the ovariectomized DS compared to DR rats [MAP (mmHg): DS‐Ovx, 190±12 vs DR‐Ovx, 114±1.2; n=5–8/group; p=0.002]. At 10 mo, ovariectomy increased BW to a similar extent in DS and DR rats [BW gain (g): DS, 179±13 vs DR, 202±14; ns]. The frequency of CD8+IL17a+ T‐cells increased in the ovariectomized DS but not DR rats [Frequency (%) at 10 mo: DS‐Ovx, 9.6±2 vs DR‐Ovx, 1.3±0.4; n=5–8/group; p&lt;0.0001].ConclusionCytotoxic CD8+ IL‐17a+ T‐cells may play a role in the HT‐specific inflammatory response in ovariectomized DS rats.Support or Funding InformationGeorgetown University Medical Center, and Translational Biomedical Science Predoctoral Training Program Georgetown‐Howard Universities Center for Clinical and Translational Science

The influence of erythrocyte maturity on ion transport and membrane lipid composition in the rat.

Significant relationships between ion transport and membrane lipid composition (cholesterol, total phospholipids and sphingomyelins) were found in erythrocytes of salt hypertensive Dahl rats. In these animals mean cellular hemoglobin content correlated negatively with Na(+)-K(+) pump activity and Na(+) leak but positively with Na(+)-K(+) cotransport activity. Immature erythrocytes exhibit lower mean cellular hemoglobin content (MCHC) than mature ones. The aim of the present study was to find a relationship between erythrocyte maturity, membrane lipid composition and ion transport activity in Wistar rats aged three months which were subjected to repeated hemorrhage (blood loss 2 ml/day for 6 days) to enrich circulating erythrocytes with immature forms. Immature and mature erythrocyte fractions in control and hemorrhaged rats were separated by repeated centrifugation. Hemorrhaged rats had increased number of reticulocytes but reduced hematocrit and MCHC compared to control rats. Immature erythrocytes of hemorrhaged rats differed from mature ones of control animals by elevated Na(+)-K(+) pump activity, reduced Na(+)-K(+) cotransport activity and increased Rb(+) leak. These ion transport changes in immature erythrocytes were accompanied by higher concentration of total phospholipids in their cell membranes. Membrane phospholipid content correlated positively with Na(+)-K(+) pump activity and cation leaks but negatively with Na(+)-K(+) cotransport activity. Moreover, they were also negatively related with MCHC which correlated negatively with Na(+)-K(+) pump activity and Rb(+) leak but positively with Na(+)-K(+) cotransport activity. Thus certain abnormalities of erythrocyte ion transport and membrane lipid composition detected in hypertensive animals might be caused by higher incidence of immature cells.

Sex-specific genetic determinants for arterial stiffness in Dahl salt-sensitive hypertensive rats.

BackgroundArterial stiffness is an independent predictor of cardiovascular outcomes in hypertensive patients including myocardial infarction, fatal stroke, cerebral micro-bleeds which predicts cerebral hemorrhage in hypertensive patients, as well as progression to hypertension in non-hypertensive subjects. The association between arterial stiffness and various cardiovascular outcomes (coronary heart disease, stroke) remains after adjusting for age, sex, blood pressure, body mass index and other known predictors of cardiovascular disease, suggesting that arterial stiffness, measured via carotid-femoral pulse wave velocity, has a better predictive value than each of these factors. Recent evidence shows that arterial stiffening precedes the onset of high blood pressure; however their molecular genetic relationship (s) and sex-specific determinants remain uncertain. We investigated whether distinct or shared genetic determinants might underlie susceptibility to arterial stiffening in male and female Dahl salt-sensitive rats. Thus, we performed a genome-wide scan for quantitative trait loci (QTLs) affecting arterial stiffness in six-week old F2 (Dahl S x R)-intercross male and female rats characterized for abdominal aortic pulse wave velocity and aortic strain by high-resolution ultrasonography.ResultsWe detected five highly significant QTLs affecting aortic stiffness: two interacting QTLs (AS-m1 on chromosome 4 and AS-m2 on chromosome16, LOD 8.8) in males and two distinct interacting QTLs (AS-f1 on chromosome 9 and AS-f2 on chromosome11, LOD 8.9) in females affecting pulse wave velocity. One QTL (AS-1 on chromosome 3, LOD 4.3) was found to influence aortic strain in a sex-independent manner. None of these arterial stiffness QTLs co-localized with previously reported blood pressure QTLs detected in equivalent genetic intercrosses.ConclusionsThese data reveal sex-specific genetic determinants for aortic pulse wave velocity and suggest distinct polygenic susceptibility for arterial stiffness and salt-sensitive hypertension in Dahl rats based upon reported blood pressure QTLs in equivalent (Dahl S x R)-intercrosses.