Salt-resistant Group Research Articles

Integrated analysis of the lncRNA-associated competing endogenous RNA network in salt sensitivity of blood pressure

Accumulating evidence showed that competing endogenous RNA (ceRNA) mechanism plays a pivotal role in salt sensitivity of blood pressure (SSBP). We constructed a ceRNA network based on SSBP-related differently expressed lncRNAs (2), mRNAs (73) and miRNAs (18). Bioinformatic analyses were utilized to analyze network and found network genes participate in biological pathways related to SSBP pathogenesis such as regulation of nitric oxide biosynthetic process (GO:0045,428) and cellular response to cytokine stimulus (GO:0071,345). Fourteen candidate ceRNA pathways were selected from network to perform qRT-PCR validation and found nine RNAs (KCNQ1OT1, SLC8A1-AS1, IL1B, BCL2L11, KCNJ15, CX3CR1, KLF2, hsa-miR-362–5p and hsa-miR-423–5p) differently expressed between salt-sensitive (SS) and salt-resistant (SR) groups (P < 0.05). Four ceRNA pathways were further validated by luciferase reporter assay and found KCNQ1OT1→hsa-miR-362–5p/hsa-miR-423–5p→IL1B pathways may influence the pathogenic mechanism of SS. Our findings suggested the ceRNA pathway and network may affect SS occurrence mainly through endothelial dysfunction and inflammatory activation.

Synthesis and performance evaluation of terpolymer high temperature retarder for oil well cement

With the increase of energy demand in the world, the exploration of deep and ultra-deep wells is increasing, which also puts forward higher requirements for cementing quality. Among them, retarder is a key material to ensure the safety of cementing operation. In view of the poor temperature resistance of conventional retarder, this paper introduces temperature-resistant and salt-resistant groups, optimizes the molecular structure design, and uses 2- acrylamido-2-methylpropanesulfonic acid (AMPS), maleic acid (MA) and polycyclic cycloolefin lactam (NX) as monomers to synthesize high temperature resistant retarder (AMN) by free radical aqueous solution polymerization and used as high temperature retarder in oil well cement. The results show that polymer retarder AMN has certain molecular weight and excellent temperature resistance. The performance evaluation results show that AMN has a good retarding effect at 140 °C and has no adverse effect on the development of mechanical strength of cement paste. AMN can solve the problem that conventional retarder is easy to fail at high temperature, and it has a good application prospect in deep and ultra-deep well cementing.

Abstract 11: Single Cell Eccite-seq Analysis Reveal An Important Role Of Monocyte-specific Nlrp3 Inflammasome For Salt-sensitivity Of Hypertension In Humans

Salt sensitivity of blood pressure is an independent predictor of death due to cardiovascular events. Diagnosis of salt-sensitivity is not feasible in the clinic, making it difficult to investigate therapeutic strategies. We hypothesized that NLRP3-inflammasome and IL-1β production in monocytes plays a role in salt-sensitive hypertension. We phenotyped salt-sensitivity of blood pressure using an acute inpatient Weinberger protocol of an isocaloric high salt diet and rapid intravenous salt-loading, followed by low salt diet and furosemide-induced salt-depletion. Ambulatory blood pressure was continuously monitored and averaged for the days of salt-loading and salt-depletion. Blood samples were obtained at baseline, salt-loading, and after salt-depletion. Median age was 54 years (44-55), 3 of the 5 subjects were female, screening systolic blood pressure was 140 mmHg (134-148), diastolic blood pressure was 88 mmHg (84-99), and BMI was 35 kg/m 2 (30-39). Using cell hashing and ECCITE-seq analysis, we profiled transcriptomes in multiple immune cell types using antibody-derived tags (ADTs). UMAP clustering of different cell types were identified by ADTs including monocyte markers CD14 and CD16. Interestingly, UMAP visualization of CD14+ and CD16+ clusters indicated a greater decrease in CD14+ clusters after salt-depletion in the salt-resistant subjects than the salt-sensitive; however the salt-sensitive subjects had a greater decrease in CD16+ clusters than the salt-resistant group after both salt-loading and salt-depletion. These data were confirmed using flow cytometry. Unlike in salt-resistant participants, we found that within monocyte clusters, salt-sensitivity was associated with down regulation of the inflammasome components NLRP3 (0.386 ± 1.18 vs. 0.197 ± 0.778) and IL-1β (0.858 ± 2.32 vs. 0.159 ± 0.925) following salt-depletion. Using flow cytometry, we found Δ% isoLG+ CD14+/CD16+ monocytes correlated with salt-sensitivity of blood pressure (r=0.88, 95% CI, p=0.05). These results suggest that the inflammasome and monocyte activation are dynamically regulated by dietary salt in vivo and can serve as a potential diagnostic biomarker for salt-sensitivity of blood pressure.

Association study of fasting blood glucose and salt sensitivity of blood pressure in community population: The EpiSS study

Background and aimsTo evaluate the association between fasting blood glucose (FBG) and salt sensitivity of blood pressure (SSBP). Methods and resultsThis study is based on the baseline survey of systemic epidemiology of salt sensitivity study. Subjects were classified into salt sensitive (SS) and salt resistant groups according to blood pressure (BP) changes during the modified Sullivan's acute oral saline load and diuresis shrinkage test. Multivariate logistic and linear regression were used to evaluate associations between FBG with SS or BP changes. A total of 2051 participants were included in the analyses with 581 (28.33%) for SS. Multiple analysis showed that for every interquartile range increase in FBG, the OR (95%CI) for SS was 1.140 (1.069, 1.215), β (95%CI) for mean arterial pressure change (ΔMAP1), systolic and diastolic BP changes during saline load were 0.421 (0.221, 0.622), 0.589 (0.263, 0.914) and 0.340 (0.149, 0.531), respectively. Compared to the lowest FBG quartile (Q1), the OR (95%CI) for SS in Q3 and Q4 were 1.342 (1.014, 1.776) and 1.577 (1.194, 2.084), respectively. Compared to subjects with normal FBG, the β (95%CI) for ΔMAP1 was 0.973 (0.055, 1.891) in subjects with impaired FBG, and was 1.449 (0.602, 2.296) in patients with diabetes mellitus. Stratified analyses showed significant and stronger associations between FBG with SSBP in youngers, females, hypertensives, non-diabetics, non-current smokers and non-current drinkers. ConclusionOur findings suggest FBG is an independent, dose-dependent associated factor for SSBP, and prevention of SS focusing on controlling FBG elevation in the early stage is important.

CeRNA network analysis and functional enrichment of salt sensitivity of blood pressure by weighted-gene co-expression analysis.

BackgroundSalt sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular disease. The pathogenic mechanisms of SSBP are still uncertain. This study aimed to construct the co-regulatory network of SSBP and data mining strategy based on the competitive endogenous RNA (ceRNA) theory.MethodsLncRNA and mRNA microarray was performed to screen for candidate RNAs. Four criteria were used to select the potential differently expressed RNAs. The weighted correlation network analysis (WGCNA) package of R software and target miRNA and mRNA prediction online databases were used to construct the ceRNA co-regulatory network and discover the pathways related to SSBP. Gene ontology enrichment, gene set enrichment analysis (GSEA) and KEGG pathway analysis were performed to explore the functions of hub genes in networks.ResultsThere were 274 lncRNAs and 36 mRNAs that differently expressed between salt-sensitive and salt-resistant groups (P < 0.05). Using WGCNA analysis, two modules were identified (blue and turquoise). The blue module had a positive relationship with salt-sensitivity (R = 0.7, P < 0.01), high-density lipoprotein (HDL) (R = 0.53, P = 0.02), and total cholesterol (TC) (R = 0.55, P = 0.01). The turquoise module was positively related with triglyceride (TG) (R = 0.8, P < 0.01) and low-density lipoprotein (LDL) (R = 0.54, P = 0.01). Furthermore, 84 ceRNA loops were identified and one loop may be of great importance for involving in pathogenesis of SSBP. KEGG analysis showed that differently expressed mRNAs were mostly enriched in the SSBP-related pathways. However, the enrichment results of GSEA were mainly focused on basic physical metabolic processes.ConclusionThe microarray data mining process based on WGCNA co-expression analysis had identified 84 ceRNA loops that closely related with known SSBP pathogenesis. The results of our study provide implications for further understanding of the pathogenesis of SSBP and facilitate the precise diagnosis and therapeutics.

Effectiveness of Chrono-Pharmacotherapy Depending on the Salt Sensitivity of Patients with Arterial Hypertension and Diabetes Mellitus Type 2

Aim. To study the effect of two regimens of combined antihypertensive therapy during the day on daily monitoring of arterial pressure, central aortic pressure, and arterial stiffness, depending on the salt sensitivity of hypertensive patients with diabetes mellitus type 2. Material and methods. 130 hypertensive patients with type 2 diabetes mellitus were included into the study. They were divided into 2 subgroups: salt-sensitive (group 1) and salt-resistant (group 2), and then randomized to subgroups A and B of ongoing therapy: in the morning ramipril and indapamide retard, bedtime – amlodipine (subgroup 1A and 2A); or in the morning amlodipine and indapamide retard, bedtime – ramipril (subgroup 1B and 2B). Initially and after 24 weeks of antihypertensive therapy, 24-hour blood pressure monitoring was performed, the indices of central aortic pressure and arterial stiffness were determined. Results. After 24 weeks, in all subgroups, there was a significant positive dynamics of the parameters of 24-hour blood pressure monitoring, central aortic pressure and arterial stiffness indices. In the subgroup 1В, it was registered a significant improvement in the majority of parameters of 24-hour blood pressure monitoring (decrease in 24-hours systolic BP by 24.4%, 24-hours diastolic BP by 22.1%; p&lt;0.05), central aortic pressure (decrease in aortal systolic BP by 15.9%, aortal diastolic BP by 20.8%; p&lt;0.05) and vascular wall stiffness parameters (decrease in pulse wave velocity by 13.8%; p&lt;0.05) in comparison with group 1A (decrease in 24-hours systolic BP by 17.5%, 24-hours diastolic BP by 14.6%, aortal systolic BP by 12.7%, aortal diastolic BP by 9.7%, pulse wave velocity by 9.2%; p&lt;0.05 in comparison with the group 1B). In the case of salt-resistant patients, there were comparable positive changes in the parameters of 24-hour blood pressure monitoring, central aortic pressure and arterial stiffness indices against the background of both dosing regimens during the day. Conclusion. In the study, it was demonstrated the more pronounced antihypertensive and vasoprotective efficacy of the combination of thiazide-like diuretic with calcium channel blocker in the morning and ACE inhibitor in bedtime compared to the alternative regimen of prescribed pharmacotherapy in salt-sensitive patients, and comparable efficacy of both regimens in salt-resistant hypertensive patients with diabetes mellitus type 2.

Correlation of Salt Sensitivity, Plasma Renin Activity and Aldosterone in Hypertensive Patients

Abstract Plasma-renin values vary in normotensive and hypertensive populations. Some studies consider renin to be a key factor in the aetiology of hypertension, but other studies note that renin is an important factor in cardiovascular homeostasis and functions more as a growth factor than as a pressor hormone. The aim of this study was to assess the PRA and aldosterone values under different salt intake regimes in patients with essential hypertension. The study group consisted of 50 untreated patients (27 women and 23 men; average age 42±9,2 yrs.; average BMI 27,91±4,6 kg/m2) with essential hypertension. All patients were put on a high-sodium diet (200 mmol NaCl per day) for one week after a week on a low-sodium diet (20 mmol NaCl per day). Sodium sensitivity (SS) was defined as a 10-mmHg increase in the mean blood pressure at the end of the high- vs. the low-sodium diet. The SS group consisted of 26 patients, and the sodiuminsensitive group consisted of 24 patients. The PRA and aldosterone levels were determined in 12 patients. PRA values in the SS group during rest were significantly lower compared with the salt-resistant group during all regimes of salt intake (F=10,56, p=0,0012). Salt loading in SS patients causes a significant decrease in PRA (in rest and effort) values in comparison to values during a low salt intake regime (rest: t=4,49, p&lt;0,001; effort: t=3,45, p&lt;0,01). The PRA values in the salt-resistant group did not vary significantly under the different salt intake regimes. The aldosterone values followed the pattern of the PRA values. It is necessary to distinguish investigations on salt intake effects based on incidence and value of blood pressure and investigations on salt restriction’s effects on of blood pressure levels (i.e., non-pharmacological hypertension therapy).

GENDER DIFFERENCES IN ANTIHYPERTENSIVE EFFICIENCY OF COMBINATION PHARMACOTHERAPY IN PATIENTS WITH RESISTANT HYPERTENSION AND ABDOMINAL OBESITY IN RELATION TO SALT SENSITIVITY

Objective. To estimate the effectiveness of combination antihypertensive therapy, including the direct renin inhibitor aliskiren, in resistant hypertension (RHTN) and abdominal obesity (AO) according to gender and salt sensitivity. Design and methods. The study included 161 patients with RHTN and AO, 78 (48.4 %) men and 83 (51.6 %) women. All patients at baseline and after 48 weeks of therapy as well as clinical and anthropometric study, electrocardiography and ambulatory blood pressure monitoring (ABPM) («Petr Telegin» BPLab Vasotens, Russia). Based on the V. I. Kharchenko’s test, all patients were divided into 4 groups: group 1 m (n = 38) and 1 w (n = 42) — «salt sensitive» men and women, and group 2 m (n = 40) and 2 w (n = 41) — «salt resistant» men and women. All patients received combination therapy: enalapril (renitek 20 mg/day, MSD, Switzerland), amlodipine (normodipin 10 mg/day, Gedeon Richter, Hungary), hydrochlorothiazide (hydrochlorothiazide 12.5 mg/day, Gedeon Richter, Hungary) and direct renin inhibitor aliskiren (rasilez 150 mg/day, Novartis, Switzerland). After 3 weeks, aliskiren dose was increased up to 300 mg/day in case of low efficiency, followed by the repeated evaluation 3 weeks later. The data were processed using nonparametric statistics (Statistica 6.1, StatSoft Inc, USA). results. After 6 weeks of antihypertensive therapy including aliskiren (daily dose of 150/300 mg), target blood pressure (BP) < 140/90 mm Hg was detected in 31 (81.6 %) men and 32 (76 %) women in salt sensitive group, and in 31 (77.5 %) men and 39 (95.1 %) women in salt resistant group. Target BP < 140/90 mm Hg was registered more frequently among salt resistant women compared to salt resistant men (p = 0.02) and salt sensitive women (p = 0.01). All treatment groups showed a significant decrease in office systolic (SBP) and diastolic BP (DBP), and heart rate. Regardless of salt sensitivity and gender, there was a significant positive changes of ABPM indicators after 48 weeks of treatment. However, in salt sensitive men and women, the change in ABPM parameters was comparable, while salt resistant women showed more marked changes in comparison with salt resistant men positive, including changes in 24-mean and daily values of SBP and DBP, SBP and DBP time index and variability during the day, as well as the time and the speed of morning surge in SBP and DBP. After 48 weeks of therapy, «dipper» BP profile was found in 17 (54.8 %) of 31 men and 17 (53.1 %) of 32 women in the salt sensitive group. In salt resistance group, «dipper» type was more prevalent among women than among men (51.3 and 35.5 %, respectively, p = 0.048). conclusions. Results of the study demonstrated a significant efficiency of aliskiren as part of combination antihypertensive therapy in both men and women with RHTN and AO regardless of salt sensitivity. At the same time, in salt sensitive men and women antihypertensive effects of aliskiren were comparable regardless of gender, whereas among salt resistant patients women showed higher benefit compared to men.

Renal Urotensin II System Plays Roles in the Regulation of Blood Pressure in Dahl Salt-Resistant Rat.

Introduction. Dahl salt-resistant (SR) animal models are similar to peritoneal dialysis patients with fluid volumes overload with normal blood pressure in hemodynamic profiles. We will verify the roles of UII in the regulation of blood pressure in these animal models. Methodology. The Dahl salt-sensitive (SS) and SR rats and UII receptor gene knocked out (KO) mice were placed on a high-salt diet. Renal tissues were performed for the expression of UII in Dahl groups. Results. After high-salt diet for 6 weeks, the systolic blood pressure (SBP) in SR group was significantly lower, accompanied with higher urinary UII levels, higher 24-hour urinary sodium excretion, and higher urinary creatinine clearance in the SR rats in comparison to SS group. The expressions of UII and UT were both upregulated in the kidney tissues of SR group in comparison to SS group (P < 0.05). After high-salt diet for 8 weeks, the SBP of the KO group is significantly higher than that of the wild type group. Conclusion. We first demonstrate that renal UII system can play important roles in the regulation of blood pressure in Dahl SR rats which can be highly correlated to its effect on renal tubular sodium absorption.

ASSA14-03-31 CREG modulates Angiotensin II type 1 receptor to antagonise coronary oxidative stress and hypertension in salt-sensitive rats

Background This study examined whether CREG protected Sprague-Dawley (SD) rats against high salt-related hypertension and vascular endothelium oxidative stress, and explored the mechanisms and associated changes in components of the renin-angiotensin system and coronary artery injury. Methods In this study, SD rats received pure drinking water, or drinking water containing 1.5% NaCl for 16 weeks. Systolic blood pressure was measured before rats were divided into salt-sensitive and salt-resistant groups. After 16 weeks of treatment, NO, malondialdehyde (MDA), angiotensin II and IL-6 in plasma and angiotensin II in coronary arteries were detected, as was the expression of eNOS, AT1R, AT2R and CREG. Primary lung vascular endothelial cells were incubated in culture medium containing aldosterone (0.45 nmol/l). Salt-induced changes in eNOS and activation of NAD(P)H oxidase-gp91 were assessed. Supernatant ONOO- and NO, and the expression of AT1R, AT2R and CREG were measured. Losartan was used to block AT1R effects, and to investigate the biofunction of CREG on endothelial cells. Results The results showed that a long-term high salt intake significantly increased plasma IL-6 and MDA, angiotensin II in coronary arteries and AT1R expression, but decreased plasma NO, angiotensin II, AT2R and CREG expression in coronary arteries of salt-sensitive rats, which was prior to increase of blood pressure. Conversely, no obvious oxidative stress or vascular remodelling was observed in the salt-resistance group accompanying anti-hypertension. Mechanically, sodium concentrations significantly increased the expression of gp91 (a marker of oxidative stress) and AT1R, and reduced expression of eNOS and CREG in primary lung vascular endothelial cells from salt-sensitive rats. These effects were abrogated in cells with overexpression of CREG. Furthermore, Losartan blocking the biofunction of AT1R antagonised the NaCl-induced oxidative stress in CREG-silencing endothelial cells. Conclusions This is the first study to identify CREG-modulated AT1R activation as a novel target to block oxidative stress in blood vessels and prevent salt-related hypertension.

Microvascular function is reduced in normotensive salt‐sensitive individuals independent of dietary sodium intake

Impairments in microvascular (MV) function are thought to occur early in cardiovascular disease development. We sought to determine if MV function is altered in salt‐sensitive (SS) adults compared to salt‐resistant (SR) adults during low (LS) and high (HS) sodium diets. Seven healthy SS adults and 7 healthy SR adults were studied (SS: 2M, 5F; 48±4 yrs; SR: 2M, 5F; 45±3 yrs). After a run‐in diet, subjects were randomized to a 7 day LS (20 mmol/d) and 7 day HS (300–350 mmol/d) diet (controlled feeding study). Salt sensitivity was defined as a &gt;; 5 mmHg change in 24‐hour mean arterial BP (MAP) from the LS to HS diet. MV function was assessed using laser Doppler flowmetry during local heating (42°C). Cutaneous vascular conductance (CVC) was calculated as red blood cell flux/MAP and all data were expressed as a percentage of the maximum CVC (28 mM SNP, 43°C). 24 hour MAP (mmHg) increased in the SS group between diets, but was unchanged in the SR group (SS: LS: 85±2, HS: 92±3, p&lt;0.05; SR: LS:83±3, HS: 83±2, p&gt;;0.05). Plateau %CVCmax was impaired in the SR group on the HS diet compared to the LS diet (80±2 vs. 90±2%; p&lt;0.05). There were no differences in plateau %CVCmax in the SS group between LS and HS diets (80±4 vs. 82±3%; p&gt;;0.05) but both were impaired (p&lt;0.05) compared to the SR group on the LS diet. These data suggest that MV function is impaired in SS adults independent of dietary sodium intake. Supported by 2 P20 RR016472‐11 &amp; R01 HL 104106.

High Dietary Sodium Reduces Flow Mediated Dilation Similarly in Humans with Salt Sensitive &amp; Salt Resistant Blood Pressure

Recent studies demonstrate that high dietary sodium (HS) impairs endothelial function in those with salt‐resistant (SR) blood pressure (BP), suggesting that the effect of dietary sodium on endothelial function may be independent of BP. We hypothesized that HS would impair flow mediated dilation (FMD) more in those with salt sensitive (SS) BP compared to those with SR BP. Five SS (2M 3W, 43±5yrs) &amp; 7 SR (3M 4W, 45±2.4yrs) subjects were enrolled in a controlled feeding study consisting of a run‐in diet followed by a two phase randomized crossover 7‐day diet perturbation: low dietary sodium (LS) (20 mmol/d) &amp; HS (300 or 350 mmol/d). Brachial artery FMD and 24‐hr BP were assessed on the last day of each diet. SS BP was defined as a change in 24‐hr mean arterial pressure of &gt;; 5 mmHg between LS &amp; HS diets. HS attenuated FMD in both the SS (LS: 12.8±2.4%, HS: 8.2±1.4%, p&lt;0.05) &amp; SR (LS: 10.5±1.8%, HS: 6.9±1.1%, p&lt;0.05) groups. The decline in FMD was not different between groups for the change in FMD (SS: Δ‐4.6±1.2%, SR: Δ‐3.6±1.2%, p&gt;;0.05). These data indicate a HS diet impairs FMD to a similar extent in SS &amp; SR individuals, providing additional evidence suggesting a BP independent effect of dietary sodium on endothelial function.Research funded by NIH grants 2 P20 RR016472–11 &amp; R01 HL104106.

Differential Predictors of Insulin Resistance in Nondiabetic Salt-Resistant and Salt-Sensitive Subjects

We studied the characteristics of insulin resistance in 19 normotensive and 25 hypertensive subjects who underwent an acute protocol for determination of salt-sensitivity of blood pressure. Hypertensive subjects were older and more obese, with higher creatinine, lipids, and aldosterone than normotensive volunteers. They also had higher glucose and insulin levels with a marked decrease in insulin sensitivity (HOMA2-S index). Once all participants were classified into salt-sensitive (SS) and salt-resistant (SR) groups, most of these differences were no longer present. In contrast, SS had classical characteristics of this phenotype (higher percentage of blacks, suppressed plasma renin, increased aldosterone-to-renin ratio, and blunted renin and aldosterone responses to changes in salt balance). Despite similar insulin levels, HOMA2-S was significantly lower in SS than SR. Salt-loading did not change HOMA2-S in SS or SR. In contrast, salt-depletion, by significantly increasing glucose and insulin of SR, decreased their HOMA2-S to the levels observed in SS. Correlates of insulin resistance in SR included age, triglycerides, body mass index, mean arterial pressure, aldosterone, and epinephrine. However, only body mass index and aldosterone remained as significant predictors in multivariate analyses. Correlates of insulin resistance in SS were mean arterial pressure, epinephrine, and norepinephrine, all remaining as significant predictors in multivariate modeling. Our data confirm that salt-sensitivity of blood pressure is associated with insulin resistance, suggest that salt restriction may be beneficial in SS but perhaps detrimental in SR subjects, and uncover possible differences in mechanisms of insulin resistance between SS and SR, with implications for pharmacological therapy.

534 HEMODYNAMIC CHANGES DURING ACUTE SALT LOADING IN PATIENTS WITH RESISTANT HYPERTENSION

Objective: To assess the changes of hemodynamic parameters during acute salt-loading (SL) in patients with resistant hypertension (RHTN) and its associations with salt-sensitivity of blood pressure (BP). Design and Methods: We studied 34 patients (17 males, 17 females; 56 ± 6 yrs) with RHTN (taking combination antihypertensive therapy (lisnopril 20 mg + amlodipine 10 mg + hydrochlorothiazide 25 mg per day and BP over 140/90 mm Hg) and 6 healthy normotensive subjects (3 males, 3 females; 54 ± 2 yrs). SL was performed via i.v. infusion of 1000 mL saline for 1 hour. Beat-to-beat BP was registered using Finometer Pro device (Amstredam). Results: Within 1 hour of SL patients with RHTN exhibited elevation of systolic (SBP) and diastolic BP (DBP) (from 188 ± 6 to 161 ± 4 mm Hg for SBP and from 104 ± 2 to 89 ± 2 mm Hg for DBP, both p < 0.01 vs baseline). In one hour after SL BP returned close to baseline level (158 ± 4 and 86 ± 2 mm Hg, respectively). At baseline total peripheral vascular resistance in RHTN was significantly higher compared to controls (1767 ± 24 vs 1212 ± 28 dyn × s × sm−5; P < 0.05). Moreover, at peak of saline infusion BRS was also higher in patients with RHTN than in controls (2212 ± 35 vs 1573 ± 44 dyn × s × sm−5; P < 0.01). In hypertensive patients total peripheral vascular resistance changes positively correlated with the magnitude of NaCl-induced elevation of SBP (r = 0.61; P = 0.01) and DBP (r = 0.52; P = 0.02) BP. Hypertensive patients were subdivided on two groups: salt-resistant (SL-induced BP elevation <20 mm Hg for both SBP and DBP (n = 15)) and salt-sensitive (SL-induced BP elevation ≥ 20 mm Hg for SBP and/or DBP (n = 19)). Total peripheral vascular resistance at baseline was similar in both groups. In salt-sensitive patients a significant correlation of total peripheral vascular resistance delta with peak SBP delta was observed (r = 0,88, P < 0.01), while in slat-resistant no relation was documented. The final BRS was higher in salt-sensitive that in salt-resistant group (2560 ± 28 vs 2030 ± 24 dyn × s × sm−5; P < 0.001). Conclusion: In patients with RHTN total peripheral vascular resistance is increased and is positively associated with the level of pressor response to SL. The increase of total peripheral vascular resistance during SL is observed only in salt-sensitive RHTN.

Abstract 500: Differential Predictors of Insulin Resistance in Non-Diabetic, Salt-Resistant and Salt-Sensitive Subjects

Normotensive (NT=16) and untreated hypertensive (HT=23) subjects, without diabetes, underwent an inpatient study of salt-sensitivity of blood pressure (24 hr salt loading [HI] with 2L saline and 160 mMol Na diet, and 24 hr salt depletion [LO] with 10 mMol Na diet and furosemide 40 mg x3); and of insulin sensitivity (homeostatic index, SI HOMA ). A fall of ≥10 mmHg in average systolic BP (noon to 10 pm) from HI to LO, was the cutoff for defining salt-sensitive (SS) vs salt-resistant (SR) subjects. Laboratory data were obtained before HI, and after HI and LO. NT were younger (40±2 vs 46±2 years, p&lt;0.05) and had lower aldosterone (Aldo; 10±1 vs 22±2 ng/dl, p&lt;0.01) than HT. Despite similar BMIs (30±2 vs 34±1 Kg/m 2 ), plasma insulin was lower (10±1 vs 28±3 μU/ml, p&lt;0.01) and SI HOMA higher (0.61±0.09 vs 0.18±0.02 ml*L/[μU*mmol], p&lt;0.01) in NT than HT. SS prevalence was 37% in NT and 43% in HT. BP fall was not different between NT and HT, within the SS (-13±2 vs -16±2 mmHg) or SR (-1±1 vs -3±1) groups. Differences between SS and SR included greater percentage of Blacks (63 vs 26%), lower PRA (1.0±0.3 vs 1.9±0.4 ngA I /ml/hr), higher Aldo-renin ratio (32±6 vs 17±3 ng*dl -1 /ngAI*ml -1 *hr -1 ) and lower SI HOMA (0.25±0.03 vs 0.43±0.09) in SS (p&lt;0.05 for all). HI suppressed PRA and Aldo, whereas LO stimulated PRA, Aldo and catecholamines (CAT) in both SR and SS. SI HOMA of SR was diminished by LO to the level of SS. Univariate correlates of SI HOMA in SR were: age (r=-0.31, p&lt;0.02), MAP (r=-0.48, p&lt;0.001), BMI (r=-0.54, p&lt;0.001), triglycerides (r=-0.43, p&lt;0.001), and Aldo (r=-0.42, p&lt;0.001). Those in SS were: age (r=-0.31, p&lt;0.05), MAP (r=-0.38, p&lt;0.01) and CAT (r=-0.32, p&lt;0.03). Multivariate regressions showed that independent predictors of SI HOMA in SR were BMI and Aldo (SI HOMA =1.35 - 0.025BMI - 0.013Aldo, r 2 =0.50, F=33.5, p&lt;0.0001); whereas those in SS were MAP and CAT (SI HOMA =0.80 - 0.0055MAP - 0.0003CAT, r 2 =0.31, F=10.1, p&lt;0.0003). We conclude: 1. SS are more insulin resistant; 2. acute salt-depletion worsens insulin sensitivity of SR; and most importantly, 3. the hormonal predictors of insulin resistance are different in SR vs SS. Our data suggest that insulin sensitivity could be improved by mineralocorticoid blockers in SR, whereas adrenergic antagonists may be more effective in SS.

Effect of acute salt ingestion upon core temperature in healthy men.

Salt intake may cause conflict for the cardiovascular system as it attempts to simultaneously maintain blood pressure (BP) and temperature homeostasis. Our objective was to determine the effect of a salt and water load vs. a water load upon rectal temperature (Tre) in healthy volunteers. Twenty-two healthy, non-hypertensive Caucasian men enrolled in two trials in which they ingested either salt and body temperature water (SALT), or body temperature water (WATER). BP, Tre, cardiac index, peripheral resistance and urine output were monitored one, 2 and 3 h post-baseline. Changes in the dependent variables were compared between those subjects who were salt sensitive (SS) and those who were salt resistant (SR) at the same time intervals. The percentage change reduction in Tre was greater following SALT compared with WATER at +120 min (-1.1±0.7 vs. -0.6±0.5%, P=0.009) and at +180 min (-1.3±0.8 vs. -0.7±0.6%, P=0.003). The percentage change reduction in Tre was greater in the SR group compared with the SS group at +180 min (-1.6±0.9 vs. -0.9±0.5%, P=0.043). SALT decreased Tre more than WATER. SS individuals maintained temperature homeostasis more effectively than SR individuals following SALT. These results may explain why some individuals are SS while others are SR. If these results are generalizable, it would be possible to account for the role of sodium chloride in the development of SS hypertension.

Novel genetic variations associated with salt sensitivity in the Korean population

Salt sensitivity is a risk factor for cardiovascular morbidity and mortality. To date, only a few genetic variations have been identified as being associated with salt sensitivity. This study aimed to estimate the prevalence of salt sensitivity in the Korean population and to identify genetic variants affecting its development. A total of 101 Korean participants consumed a low-salt diet for 7 days followed by a high-salt diet for 7 additional days. Salt sensitivity was determined by noting any significant elevation in the 24-h mean arterial blood pressure. To determine genetic variants affecting salt sensitivity, 36 single-nucleotide polymorphisms (SNPs) that were previously reported to be associated with hypertension were tested for any associations with salt sensitivity. Of the 101 subjects, 28 (27.7%) were determined to have salt sensitivity. Out of the 36 SNPs tested, four were significantly associated with salt sensitivity after adjusting for confounding factors: rs2681472 in ATPase, Ca(++) transporting, plasma membrane 1 (ATP2B1), rs7961152 in branched chain aminotransferase 1 (BCAT1), rs16998073 in fibroblast growth factor 5 (FGF5) and rs2398162 in LOC100132798. For rs3754777 in serine threonine kinase 39 (STK39) and rs1937506, associations with salt sensitivity were observed before adjusting for confounding factors. Haplotype analysis revealed that the A-C haplotype of rs3754777-rs6749447 in STK39 was more frequent in the salt-sensitive group compared with the salt-resistant group, and was associated with salt sensitivity. This study estimates the prevalence of salt sensitivity in the Korean population and demonstrates a novel association between salt sensitivity and the ATP2B1, BCAT1, FGF5, LOC100132798 and STK39 genetic variations.

ASSOCIATION OF THE PLASMA ARG/ADMA RATIO WITH THE SALT-SENSITIVITY: PP.9.370

Objectives: Asymmetric dimethylarginine (ADMA) is the unique endogenous inhibitor of the NO synthases. As NO plays important roles both in the regulation of the systemic vascular tone and of salt excretion in the kidney, ADMA may be a key player in the regulation of salt-sensitivity. In this communication, we explored the relation of ADMA with the salt-sensitivity in Africans by a salt-loading experiment on volunteers. Design and Method: Thirthy-one Tanzanian male healthy volunteers without hypertension (25–35 years old) were recruited for the experiment. A salt-loading experiment was performed following the protocol designed previously (Hypertens Res 2002;25:809). Briefly, the participants ingested 140mEq/day NaCl additional to their normal diet (containing about 85mEq/day NaCl) in the first week and then took 25 mg/day hydrochlorthiazide (without the salt-loading) in the second week. Blood sampling and blood pressure (BP) measurement was performed at the entry, on the 4th and 7th days of the each week. L-arginine (Arg), ADMA and symmetric dimethylarginine (SDMA) were measured in plasma with HPLC. All the participants gave an informed consent. Results: The change in the mean BP (δMBP) between the salt-loading and the diuretic phase showed a biphasic distribution; the participants with a larger δMBP were defined as a salt-sensitive group (SS, δMBP = -7.3 ± 2.7mmHg, n = 8) while the others were as a salt-resistant group (SR, δMBP = 3.4 ± 4.2mmHg, n = 23). The basal level of ADMA was significantly greater in SS than in SR (SS:0.57 ± 0.09mmol/L, SR: 0.49 ± 0.06mmol/L, p = 0.006) although it was quite stable either in the salt-loading or in the diuretic phase. The increase in the Arg/ADMA ratio from the salt-loading to the diuretic phase (δArg/ADMA_diuret-salt) was significantly greater in SS than in SR (p = 0.04). δArg/ADMA_diuret-salt showed an clear inverse correlation with δMBP (r = -0.53, p = 0.002). The multiple regression analysis confirmed the independent effect of δArg/ADMA_diuret-salt with other factors of the basal ADMA level and the change in the serum Chloride level. Conclusions: The plasma Arg/ADMA ratio was found to be related to the salt-sensitivity in healthy African males.

Salt sensitivity and insulin resistance in normotensives.

Among hypertensive patients salt sensitivity and insulin resistance are commonly observed together. We investigated if a causal relationship already exists in young normotensive adults. With a standardized dietary regimen we determined salt sensitivity in 35 male volunteers by measuring diastolic blood pressure (24-hours-RR-recording). Insulin resistance was tested using hyperinsulinaemic-euglycaemic-clamp-technique by de Fronzo after a freely chosen diet, after 7 days of salt loading (260 mmol/d) and after 7 days of salt restriction (60 mmol/d). Data from euglycaemic-clamp technique were available from 27 subjects. 18 of them (67%) could be characterized as salt resistant; 9 persons (33%) were salt sensitive. Glucose infusion rate, mean glucose and insulin concentrations were measured in plasma, metabolic clearance rate (MCR) and indices of insulin sensitivity (ISI) were calculated. The results of MCR and ISI show large interindividual variances. There were no differences between the salt sensitive and salt resistant group regarding the mean insulin concentrations and also the mean glucose uptake in the steady state clamp period and also the calculated MCR and ISI. Comparing the periods of different salt intake, there were no differences between salt loading and salt restriction. Whereas salt sensitivity can already be shown in the normotensive state, with this experimental design a changed insulin sensitivity is not detectable. This supports the idea, that insulin resistance is not causally linked with salt sensitivity. It may be a secondary phenomenon of salt induced hypertension.

Greater attenuation of blood pressure levels in salt sensitive hypertensive patients after short-term administration of simvastatin

Statins have been reported to improve blood pressure control in essential hypertensive subjects via diverse pathophysiological mechanisms, while salt sensitivity is an emerging cardiovascular risk factor. In this study, we sought to investigate the possible effects of short-term administration of simvastatin on blood pressure levels in salt sensitive and salt resistant essential hypertensive subjects. Eighteen untreated mild essential hypertensive patients (9 men, age 51.2±10.9 years) were screened for salt sensitivity by means of an established protocol. All subjects underwent 24h ambulatory BP monitoring before and after 1 month of treatment with simvastatin (40mg/day). Venous blood samples were drawn before and after statin administration period for determination of lipid, lipoprotein-a, apolipoprotein A1 and apolipoprotein B levels. For the pooled population BMI was 27.2±3.6 kg/m2, left ventricular mass index was 106±35.1 g/m2 and relative wall thickness was 0.45±0.07. Four patients were classified as salt sensitive (SS) (2 men, 60±9 years), while 14 were salt resistant (SR) (7 men, 60±10 years). After 1 month on simvastatin, only SS patients, presented significant reductions in office systolic BP (155±12.9 vs 130±18.2 mmHg, p<0.05), 24-h diastolic BP (85.9±5.7 vs 76.3±4.3 mm Hg, p<0.05), 24-h mean BP (104.4±5.1 vs 93.3±7.5 mm Hg, p<0.05), daytime diastolic BP (89.1±7.6 vs 78.9±6 mm Hg, p<0.05), daytime mean BP (107.5±8.5 vs 95.1±8.3 mm Hg, p<0.05), while patients in the SR group did not exhibit any significant reduction in 24h BP levels (p=NS). Moreover, there was no correlation between the reductions of 24h BP in the SS group and the reductions of the lipid parameters (p=NS). In newly diagnosed essential hypertensive subjects, short-term administration of simvastatin resulted in a significant attenuation of BP values in salt sensitive hypertensives, independently of lipid lowering, suggesting a possible link between salt sensitivity and the pleiotropic mechanisms of statins action. These findings suggest that salt sensitive patients may benefit more from the pleiotropic effects of statins, in the same setting.