Increase In Urinary Sodium Excretion Research Articles

Acute over-additive natriuretic effects by a combination of finerenone and SGLT2 inhibition in rats with an activated renin-angiotensin-aldosterone system: a mechanistic basis for clinical outcomes?

Abstract Background Recent preclinical studies suggested an independent benefit of non-steroidal mineralocorticoid receptor (MR) antagonism by finerenone and SGLT2 inhibition in cardiorenal diseases, with a potential for combination therapy. Chronic low-dose combination of finerenone and empagliflozin in hypertensive rats revealed an early, sustained and over-additive reduction in proteinuria but the underlying mechanism(s) are not fully understood. Purpose To compare the acute glucosuric, natriuretic, kaliuretic and diuretic efficacy of individual dosages of finerenone and SGLT2 inhibitors (empagliflozin, canagliflozin or dapagliflozin) with the combined administration of both drug classes in conscious rats with an activated renin-angiotensin-aldosterone system (RAAS). Methods The RAAS was activated in male Wistar rats (body mass 250 to 500 g) by placing them on a low-salt diet containing 0.02% sodium chloride for 72 hours. In a series of three independent experiments, finerenone (1 mg/kg), SGLT2 inhibitor (3 mg/kg; either empagliflozin, canagliflozin or dapagliflozin) alone and the respective combinations were administered in 2-3 ml/kg of solvent (PEG400) by oral gavage and the animals (n=6-10 / group) were individually placed in metabolic cages on water ad libitum. The individual urine was collected for 24 hours and the concentration of glucose, sodium and potassium excreted in the urine was measured by a clinical-chemical analyzer system (ADVIA 2400). Results Administration of 1 mg/kg finerenone had no influence on urinary glucose, urinary volume and urinary potassium but caused an increase in urinary sodium excretion at least by trend. At a dose of 3 mg/kg, all SGLT2 inhibitors induced a strong increase in urinary glucose excretion but had no significant influence on urinary potassium and urinary sodium, while only dapagliflozin caused an increase in urinary volume at the tested dose. Administration of a combination of 1 mg/kg finerenone and 3 mg/kg SGLT2 inhibitor did not significantly modify urinary glucose and urinary potassium in comparison to the respective individual finerenone and SGLT2 inhibitor dosages and only the combination with empagliflozin increased urinary volume vs the respective monotherapies. Surprisingly, combination of finerenone with SGLT2 inhibition over-additively induced sodium excretion consistently in all three experiments (finerenone+empagliflozin: 171,4%; finerenone+canagliflozin: 139,6%; finerenone+dapagliflozin: 133,9%) in comparison to the calculated combination (set to 100%) of the respective individual finerenone and SGLT2 inhibitor groups. Conclusion Combination of MR antagonism by finerenone and SGLT2 inhibition revealed an acute over-additive natriuresis in a rat diuresis model. This might provide an additional mechanistic basis for near-term (e.g. hospitalization for heart failure) and long-term outcomes (e.g. blockade of the progression of kidney failure) in cardiorenal patient populations.

Urinary Sodium Excretion and Obesity Markers among Bangladeshi Adult Population: Pooled Data from Three Cohort Studies.

We evaluated the relationship of urinary sodium excretion with a conditional mean, 10th and 90th percentiles of body mass index (BMI), and waist circumference among 10,034 person-visits of Bangladeshi population. We fitted linear mixed models with participant-level random intercept and restricted maximum likelihood estimation for conditional mean models; and quantile mixed-effect models with participant-level random intercept and Laplace estimation for 10th and 90th percentiles models. For each 100 mmol/24 h increase in urinary sodium excretion, participants had a 0.10 kg/m2 (95% CI: 0.00, 0.10) increase in the mean; a 0.39 kg/m2 (95% CI: 0.23, 0.54) increase in the 10th percentile; and a 0.59 kg/m2 (95% CI: 0.39, 0.78) increase in the 90th percentile of BMI. For each 100 mmol/24 h increase in urinary sodium excretion, participants had a 0.20 cm (95% CI: 0.10, 0.30) increase in mean; a 0.18 cm (95% CI: −0.03, 0.40) change in the 10th percentile; and a 0.23 cm (95% CI: 0.03, 0.43) increase in the 90th percentile of waist circumference. We found a modest association between urine sodium and conditional mean of BMI and waist circumference. The magnitude of associations between urine sodium and the 10th and 90th percentile BMI distributions were higher compared to the conditional mean models, suggesting high sodium intake could be more detrimental to underweight and obese participants.

Pattern Recognition versus Pathogenesis: Electrolytes in a Patient with Adrenal Insufficiency.

Pattern Recognition versus Pathogenesis: Electrolytes in a Patient with Adrenal Insufficiency.

Roles of Sodium-Glucose Cotransporter 2 of Mesangial Cells in Diabetic Kidney Disease.

We have been studying the presence of sodium-glucose cotransporter 2 (SGLT2) in mesangial cells and pericytes since 1992. Recent large placebo-controlled studies of SGLT2 inhibitors in patients with type 2 diabetes mellitus have reported desirable effects of the inhibitors on the diabetic kidney and the diabetic heart. Most studies have indicated that these effects of SGLT2 inhibitors could be mediated by the tubuloglomerular feedback system. However, a recent study about urine sodium excretion in the presence of an SGLT2 inhibitor did not show any increases in urine sodium excretion. A very small dose of an SGLT2 inhibitor did not inhibit SGLT2 at the S1 segment of proximal tubules. Moreover, SGLT2 inhibition protects against progression in chronic kidney disease with and without type 2 diabetes. In these circumstances, the tubuloglomerular feedback hypothesis involves several theoretical concerns that must be clarified. The presence of SGLT2 in mesangial cells seems to be very important for diabetic nephropathy. We now propose a novel mechanism by which the desirable effects of SGLT2 inhibitors on diabetic nephropathy are derived from the direct effect on SGLT2 expressed in mesangial cells.

BLOOD PRESSURE IN RELATION TO INTERACTION BETWEEN DIETARY SODIUM INTAKE AND SERUM URIC ACID IN CHILDREN AND ADOLESCENTS WITH PRIMARY HYPERTENSION

Abstract Objective: We investigated ambulatory blood pressure in relation to interaction between dietary sodium intake and serum uric acid in children and adolescents with primary hypertension. Design and method: The study subjects were in the age range from 10 to 24 years, admitted in Ruijin Hospital because of hypertension. Ambulatory blood pressure monitoring was performed during hospitalization using SpaceLabs 90217 monitors. We collected 24-hour urine for measurements of sodium excretion. We measured serum uric acid concentration with a blood chemistry autoanalyzer, and defined hyperuricemia as a serum uric acid concentration of at least 5.5 mg/dl. Our analysis was restricted to those with primary hypertension (n = 580). Results: The prevalence of hyperuricemia was 48.7%, being higher in male (n = 252) than female (n = 31, 54.9% vs 25.4%) and in untreated (n = 84) than treated patients (n = 199, 56.4% vs 46.1%). Ambulatory blood pressure did not differ across the quartile distributions of urinary sodium excretion (P > = 0.05), but was significantly (P < = 0.04) higher in patients with hyperuricemia than those without for all components, except 24-hour and daytime systolic blood pressure (P > = 0.15). In multivariable regression analysis adjusted for age, sex, body mass index, current smoking and alcohol intake, there was a significant (P < = 0.03) interaction between urinary sodium excretion and serum uric acid in relation to 24-hour systolic and diastolic blood pressure. Indeed, in the presence of hyperuricemia, 24-hour systolic/diastolic blood pressure was 2.2/1.1 mm Hg higher with 100 mmol increase in urinary sodium excretion. Conclusions: Dietary sodium intake interacts with serum uric acid to be associated with ambulatory blood pressure.

Longitudinal Changes in Prorenin and Renin in the Chronic Renal Insufficiency Cohort

Introduction: Prorenin, a precursor of renin, and renin play an important role in regulation of the renin-angiotensin system. More recently, receptor-bound prorenin has been shown to activate intracellular signaling pathways that mediate fibrosis, independent of angiotensin II. Prorenin and renin may thus be of physiologic significance in CKD, but their plasma concentrations have not been well characterized in CKD. Methods: We evaluated distribution and longitudinal changes of prorenin and renin concentrations in the plasma samples collected at follow-up years 1, 2, 3, and 5 of the Chronic Renal Insufficiency Cohort (CRIC) study, an ongoing longitudinal observational study of 3,939 adults with CKD. Descriptive statistics and multivariable regression of log-transformed values were used to describe cross-sectional and longitudinal variation and associations with participant characteristics. Results: A total of 3,361 CRIC participants had plasma available for analysis at year 1. The mean age (±standard deviation, SD) was 59 ± 11 years, and the mean estimated glomerular filtration rate (eGFR, ± SD) was 43 ± 17 mL/min per 1.73 m². Median (interquartile range) values of plasma prorenin and renin at study entry were 4.4 (2.1, 8.8) ng/mL and 2.0 (0.8, 5.9) ng/dL, respectively. Prorenin and renin were positively correlated (Spearman correlation 0.51, p < 0.001) with each other. Women and non-Hispanic blacks had lower prorenin and renin values at year 1. Diabetes, lower eGFR, and use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins, and diuretics were associated with higher levels. Prorenin and renin decreased by a mean of 2 and 5% per year, respectively. Non-Hispanic black race and eGFR <30 mL/min/1.73 m² at year 1 predicted a steeper decrease in prorenin and renin over time. In addition, each increase in urinary sodium excretion by 2 SDs at year 1 increased prorenin and renin levels by 4 and 5% per year, respectively. Discussion/Conclusions: The cross-sectional clinical factors associated with prorenin and renin values were similar. Overall, both plasma prorenin and renin concentrations decreased over the years, particularly in those with severe CKD at study entry.

The Short-Term Effects of Roux-en-Y Gastric Bypass on Renal Excretion of Sodium and Its Association with Blood Pressure

Bariatric surgery has been shown to be effective in reducing weight and has benefits, such as lowering blood pressure. An increase in urinary sodium excretion has been suggested as a possible mechanism. This study explored changes in sodium excretion and their correlation with blood pressure after Roux-en-Y gastric bypass. This study was conducted on 28 obese participants with body mass index (BMI) of 44.54 ± 7.81kg/m2 who underwent gastric bypass. Before surgery and at the third and sixth months after gastric bypass, blood pressure, urinary sodium concentration, 24-hour (24-h) urinary sodium excretion, and fractional excretion of sodium were evaluated. In addition, serum sodium and potassium levels were determined. Nonparametric tests were used to analyze the data. Blood pressure decreased after surgery and remained at low levels over the 3- and 6-month periods. The urinary sodium concentration increased at 3months after surgery; however, the 24-h urinary sodium excretion and urine volume decreased. Interestingly, although some associations between variables were observed, significant correlations between the 24-h urinary sodium excretion and the systolic, diastolic, and mean blood pressures were found. In addition, the urine volume was higher in the sixth month than in the third month following surgery. In the months immediately following surgery, a low-salt and low-volume diet favors decreases in urine volume and 24-h urinary sodium excretion. In addition, in the sixth month after surgery, an association between blood pressure and 24-h urinary sodium excretion was observed.

Abstract P3020: Therapeutic Induction of Renal Lymphatic Expansion Attenuates Blood Pressure in Mice With L-NAME Hypertension

Renal immune cell infiltration and accompanying inflammation activates renal sodium transporters leading to sodium retention and hypertension. Lymphatic vessels traffic interstitial immune cells to the draining lymph nodes and help resolve inflammation. We have previously demonstrated that genetically inducing renal lymphangiogenesis prevents hypertension associated with a reduction in renal immune cell accumulation; however, it is unknown whether augmenting renal lymphatics can treat hypertension. Our hypothesis was that augmenting renal lymphatics after hypertension is established will lower blood pressure during L-NAME-induced hypertension (LHTN). Transgenic mice that overexpress the lymphangiogenic signal VEGF-D only in the kidney upon doxycycline administration (KidVD+ mice) and KidVD- littermates were administered L-NAME (0.5 mg/mL) in their drinking water for four weeks with doxycycline initiated at the second week of L-NAME. Treatment with L-NAME for one week induced LHTN in both KidVD- and KidVD+ mice (SBP: 134±4 and 142±5 mmHg, respectively). However, doxycycline-induced renal lymphangiogenesis significantly decreased blood pressure in KidVD+ mice compared to KidVD- mice after four weeks of L-NAME (SBP: 127±5 vs. 151±6 mmHg; p&lt;0.05). This was associated with a significant decrease in renal CD11c + F4/80 - monocytes and a significant increase in 24-hour urinary sodium excretion and fractional excretion of sodium in KidVD+ mice. Urinary volume over 24 hours was also increased in KidVD+ mice (1.7±0.8 vs. 3±0.9 mL/24 hours; p&lt;0.05); however, this was not associated with a change in glomerular filtration rate. Thus, augmenting renal lymphatics lowers blood pressure in mice with LHTN and this is associated with a decrease in renal monocyte accumulation and an increase in urinary sodium excretion. Augmenting renal lymphatics may be a promising anti-hypertensive and natriuretic therapeutic strategy.

Abstract 143: Enhancing Renal Lymphatic Vessel Density Blunts Both Salt-Sensitive and Angiotensin II-Dependent Hypertension in Mice

Sodium retention is a hallmark of most forms of experimental hypertension. Renal lymphatics maintain fluid homeostasis by draining cortical interstitial fluid to the draining lymph node. Our lab has previously demonstrated that augmenting renal lymphatics prevents hypertension, but whether this can treat hypertension and whether expanding renal lymphatics alters renal sodium handling remain unknown. Our hypotheses were that augmenting renal lymphatic vessel density after hypertension is established will treat salt sensitive hypertension (SSHTN) and angiotensin II-induced hypertension (AIIHTN) and that this will be accompanied by an increase in urinary sodium excretion. To test our hypotheses, we utilized transgenic mice that overexpress the lymphangiogenic growth factor VEGF-D specifically in the kidney when administered doxycycline (KidVD+ mice). KidVD+ mice and KidVD- littermates were made salt-sensitive by treatment with L-NAME (0.5 mg/mL) for two weeks, followed by a washout period of two weeks, and then given a 4% high salt diet for four weeks. To induce AIIHTN, mice were infused with angiotensin II (490 ng/kg/min) for four weeks. Doxycycline was administered to all mice a week after beginning the high salt diet or a week after angiotensin II infusion. Prior to doxycycline initiation, KidVD- and KidVD+ mice were hypertensive (SSHTN SBP: 130±2 and 134±2 mmHg, respectively; AIIHTN SBP: 125±2 and 128±2 mmHg, respectively). Compared to KidVD- mice, doxycycline administration for three weeks augmented renal lymphatics in KidVD+ mice and significantly decreased blood pressure after four weeks of high salt diet or angiotensin II (SSHTN SBP: 134±4 vs. 125±2 mmHg; p&lt;0.05; AIIHTN: 145±3 vs. 125±5 mmHg; p&lt;0.05). The reduction in blood pressure was accompanied by an increase in urinary fractional excretion of sodium in SSHTN and AIIHTN KidVD+ mice. AIIHTN induced an elevated glomerular filtration rate (GFR) in KidVD- mice while this was reduced in KidVD+ mice; however, GFR was unaltered in SSHTN KidVD+ mice. Thus, augmenting renal lymphatics increased fractional excretion of sodium and lowered blood pressure in both mouse models of hypertension. Augmenting renal lymphatics may be a promising anti-hypertensive and natriuretic therapeutic strategy.

Effect of liraglutide on ambulatory blood pressure in patients with hypertension and type 2 diabetes: A randomized, double-blind, placebo-controlled trial.

To assess the effect of liraglutide on 24-hour ambulatory blood pressure and heart rate in patients with hypertension (pre- and stage 1 hypertension) and inadequately controlled Type 2 diabetes (glycated haemoglobin 7%-10% [53-86 mmol/mol]). Eligible patients for this investigator-initiated, parallel-group, randomized, double-blind trial were on stable background antihyperglycaemic therapy excluding insulin, glucagon-like peptide-1 receptor agonists and dipeptidyl-peptidase-4 inhibitors. Participants were centrally randomized in a 1:1 ratio to daily liraglutide 0.6 mg, titrated to 1.2 mg after the first week, or placebo for 5 weeks. The primary outcome was change in 24-hour ambulatory systolic blood pressure (SBP), and secondary outcomes included change in ambulatory diastolic blood pressure (DBP) and heart rate. We also assessed renal sodium handling. Of 87 patients assessed for eligibility, 62 (66.1% men) with a mean age of 60.2 years were randomized to liraglutide (n = 31) or placebo (n = 31). All participants received background therapy with metformin, whilst 35.5% were treated concomitantly with sulphonylureas and 14.5% with pioglitazone. Compared with placebo, liraglutide reduced 24-hour SBP by -5.73 mm Hg (95% confidence interval [CI] -9.81 to -1.65) and had a neutral effect on 24-hour DBP (mean difference - 1.42 mm Hg; 95% CI -4.25 to 1.40), whilst increasing 24-hour heart rate by 6.16 beats/min (95% CI 3.25 to 9.07). Findings were consistent for daytime and night-time measurements. Liraglutide did not increase urine sodium excretion. Based on 24-hour ambulatory measurements, short-term treatment with liraglutide had a favourable effect on SBP whilst increasing heart rate.

The Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Sympathetic Nervous Activity.

The EMPA-REG OUTCOME study revealed that a sodium-glucose cotransporter 2 (SGLT2) inhibitor, empagliflozin, can remarkably reduce cardiovascular (CV) mortality and heart failure in patients with high-risk type 2 diabetes. Recently, the CANVAS program also showed that canagliflozin, another SGLT2 inhibitor, induces a lower risk of CV events. However, the precise mechanism by which an SGLT2 inhibitor elicits CV protective effects is still unclear. Possible sympathoinhibitory effects of SGLT2 inhibitor have been suggested, as significant blood pressure (BP) reduction, following treatment with an SGLT2 inhibitor, did not induce compensatory changes in heart rate (HR). We have begun to characterize the effects of SGLT2 inhibitor on BP and sympathetic nervous activity (SNA) in salt-treated obese and metabolic syndrome rats, who develop hypertension with an abnormal circadian rhythm of BP, a non-dipper type of hypertension, and do not exhibit a circadian rhythm of SNA. Treatment with SGLT2 inhibitors significantly decreased BP and normalized circadian rhythms of both BP and SNA, but did not change HR; this treatment was also associated with an increase in urinary sodium excretion. Taken together, these data suggest that an SGLT2 inhibitor decreases BP by normalizing the circadian rhythms of BP and SNA, which may be the source of its beneficial effects on CV outcome in high-risk patients with type 2 diabetes. In this review, we briefly summarize the effects of SGLT2 inhibitors on BP and HR, with a special emphasis on SNA.

Abstract P409: Defective Renal Ang III and AT2 Receptor Signaling in Pre-hypertensive Spontaneously Hypertensive Rats (SHR)

The intrarenal renin-angiotensin (RAS) system controls blood pressure and electrolyte balance. Angiotensin II (Ang II), the principal RAS effector peptide, is metabolized by aminopeptidase A to des-apartyl 1 -Ang II (Ang III). Our previous studies showed that Ang III, not Ang II, is the preferred endogenous agonist for Ang type-2 receptor (AT 2 R)-induced natriuresis in normal rats, and that hypertensive 12-week old SHR lack natriuretic responses to Ang III. The present study tested whether Ang III induced natriuresis in 4 week old pre-hypertensive SHR by activating/translocating intrarenal AT 2 Rs and internalizing the major renal proximal tubule (RPT) sodium transporter NHE-3. Female 4 week old SHR (N=6) and WKY (N=6) rats were studied after 24 h systemic AT 1 R blockade with candesartan. The left kidney received a 30 min renal interstitial (RI) infusion of vehicle followed by cumulative RI infusions of Ang III (3.5, 7.0, 14, and 28 nmol/kg/min; each dose for 30 min). The right kidney received vehicle RI infusions. In 4 week old WKY, RI Ang III increased urine sodium excretion (U Na V) dose dependently from control of 0.04 ± 0.01 to 0.08 ± 0.02 (P&lt;0.05), 0.09 ± 0.02 (P&lt;0.01), 0.07 ± 0.01 (P&lt;0.05), and 0.07 ± 0.01 (P&lt;0.05) μmol/min. In 4 week old pre-hypertensive SHR, RI Ang III failed to induce natriuresis at all doses except 28 nmol/kg/min (0.03 ± 0.01 vs. 0.05 ± 0.01 μmol/min; P&lt;0.05). There was no change in U Na V in right control kidneys of WKY or SHR. Also, Ang III had no effect on mean arterial pressure (MAP) in WKY or SHR. However, MAP was slightly higher, but normotensive, in SHR than WKY. Control and Ang III infused kidneys were processed for confocal microscopy from a separate group of rats. In WKY, RI Ang III induced translocation of AT 2 Rs from subapical to apical membranes of RPT cells [RPTC] (1767 ± 41 vs. 1313 ± 47 RFU; P&lt;0.001). Simultaneously, Ang III induced retraction of NHE-3 from in SHR, intrarenal Ang III failed to induce AT 2 R translocation, NHE-3 retraction, and pSer 552 -NHE-3 upregulation. These results apical to subapical membranes of RPTCs (1703 ± 90 vs. 1388 ± 91 RFU; P&lt;0.05). Consistent with NHE-3 retraction, Ang III increased pSer 552 -NHE-3 (1102 ± 57 vs. 830 ± 66 RFU; P&lt;0.01). In contrast,demonstrate defective Ang III and AT 2 R signaling in pre-hypertensive SHR.

Endothelin-1 mediates natriuresis but not polyuria during vitamin D-induced acute hypercalcaemia.

Hypercalcaemia can occur under various pathological conditions, such as primary hyperparathyroidism, malignancy or granulomatosis, and it induces natriuresis and polyuria in various species via an unknown mechanism. A previous study demonstrated that hypercalcaemia induced by vitamin D in rats increased endothelin (ET)-1 expression in the distal nephron, which suggests the involvement of the ET system in hypercalcaemia-induced effects. In the present study, we demonstrate that, during vitamin D-induced hypercalcaemia, the activation of ET system by increased ET-1 is responsible for natriuresis but not for polyuria. Vitamin D-treated hypercalcaemic mice showed a blunted response to amiloride, suggesting that epithelial sodium channel function is inhibited. We have identified an original pathway that specifically mediates the effects of vitamin D-induced hypercalcaemia on sodium handling in the distal nephron without affecting water handling. Acute hypercalcaemia increases urinary sodium and water excretion; however, the underlying molecular mechanism remains unclear. Because vitamin D-induced hypercalcaemia increases the renal expression of endothelin (ET)-1, we hypothesized that ET-1 mediates the effects of hypercalcaemia on renal sodium and water handling. Hypercalcaemia was induced in 8-week-old, parathyroid hormone-supplemented, male mice by oral administration of dihydrotachysterol (DHT) for 3days. DHT-treated mice became hypercalcaemic and displayed increased urinary water and sodium excretion compared to controls. mRNA levels of ET-1 and the transcription factors CCAAT-enhancer binding protein β and δ were specifically increased in the distal convoluted tubule and downstream segments in DHT-treated mice. To examine the role of the ET system in hypercalcaemia-induced natriuresis and polyuria, mice were treated with the ET-1 receptor antagonist macitentan, with or without DHT. Mice treated with both macitentan and DHT displayed hypercalcaemia and polyuria similar to that in mice treated with DHT alone; however, no increase in urinary sodium excretion was observed. To identify the affected sodium transport mechanism, we assessed the response to various diuretics in control and DHT-treated hypercalcaemic mice. Amiloride, an inhibitor of the epithelial sodium channel (ENaC), increased sodium excretion to a lesser extent in DHT-treated mice compared to control mice. Mice treated with either macitentan+DHT or macitentan alone had a similar response to amiloride. In summary, vitamin D-induced hypercalcaemia increases the renal production of ET-1 and decreases ENaC activity, which is probably responsible for the rise in urinary sodium excretion but not for polyuria.

Relationships between urinary electrolytes excretion and central hemodynamics, and arterial stiffness in hypertensive patients.

High sodium intake plays an important role in the onset and exacerbation of hypertension. However, the relationships between urinary electrolytes excretion and central hemodynamics and between urinary electrolyte excretion and arterial stiffness are still the subject of debate. This study sought to clarify the associations of salt intake with central aortic pressure and arterial stiffness indicators. A total of 431 untreated hypertensive individuals were recruited into the study. Twenty-four-hour urinary samples were collected to measure the excretion of urinary electrolytes. Central hemodynamics parameters and brachial-ankle pulse wave velocity (baPWV) were measured. We evaluated the independent relationship between urinary sodium or potassium excretion and the abovementioned indices. The mean 24-h urinary sodium of all subjects was 166.6±70.0 mmol/24 h. With increases in urinary sodium excretion, central blood pressure and baPWV values markedly increased. Multiple regression analysis showed that urinary sodium was independently associated with increases in central systolic blood pressure, central diastolic blood pressure, the augmentation index, and baPWV. Significant correlations were identified between high dietary sodium and central hemodynamics and between high dietary sodium and arterial elasticity. Prospective interventional studies in hypertensive patients may be required to determine the effect of salt intake on central hemodynamics.

Hypotensive effects of renal denervation in spontaneously hypertensive rat based on ultrasonic contrast imaging

BackgroundSympathetic nerves-fire rate is generally enhanced in some types of hypertension models. Renal sympathetic denervation(RSD) by the radiofrequency ablation was used to treat the hypertension has achieved curative effect.HTN-1 and HTN-2 trial reported catheter-based renal denervation may cause substantial and sustained blood-pressure reduction in patients with resistant hypertension. However, recent controlled HTN-3 trial questioned the BP lowering effect of Renal denervation treatment. The controversial results maybe arised from the incompleted RSD which implemented inside the renal artery. Now renal denervation therapy for resistant hypertension is in attractive and controversial status. Our aim is to define the hyotensive value of complete renal denervation in adult spontaneous hypertensive rats. MethodsMale spontaneous hypertensive rats(SHR) aged 12 weeks were randomly selected for either unilateral renal artery sympathetic nerves ablation (URSNA), or conventional technique of renal denervation (CRD), or bilateral renal artery sympathetic nerves ablation (BRSNA) and sham operation. Blood pressure, sodium and water balance,serum reninangiotensin II and Norepinephrine concentration were measured during 20 weeks after renal denervation operation. Internal diameters of renal arteries and renal blood flow rate was tested by ultrasonic contrast imaging. ResultsThe continued increased blood pressure in SHR was delayed and significantly reduced by conventional renal denervation over a period of 8 weeks. Both the bilateral and unilateral renal sympathetic nerve ablation procedure did not prevent the development of hypertension in SHR. The attenuation of hypertension was accompanied with the increase of urinary sodium excretion and depression of rennin angiotensin system (RAS). ConclusionsWe concluded that renal denervation may not be an effective therapeutic method in the long-term control of hypertension in adult SHR.

Comparison of Diuretic Effects between Empagliflozin, a Sodium-Glucose Co-Transporter 2 Inhibitor With Osmotic Diuresis, and Tolvaptan, a Water Diuretic, in Two Type 2 Diabetic Patients Taking Sodium Diuretics

Empagliflozin, one of sodium-glucose co-transporter 2 (SGLT2) inhibitors, has been demon- strated to have beneficial effects on cardiovascular morbidity and mortality in patients with type 2 diabetes at high risk for cardiovascular events. The mechanisms behind these benefits of empagliflozin are presumed to include osmotic diuresis, being rather close to water diuresis than sodium diuresis. Two cases are presented here, where distinct changes in urinary water and sodium excretion were seen immediately after replacing tolvaptan, a water diuretic, with empagliflozin. Case 1 with heart failure showed a large decrease in urinary sodium excretion with a slight decrease in urine volume. By contrast, Case 2 with nephrotic syndrome showed a large increase in urinary sodium excretion with an increase in urine volume. The differences were probably due to distinct diuretic effects of empagliflozin and tolvaptan in the presence of sodium diuretics as well as distinct pathological conditions. In addition, the amount of urine protein was reduced after the replacement in Case 2. SGLT2 inhibitors would be expected to have the potential to exert some beneficial effects other than lowering blood glucose levels by increasing urinary glucose excretion.

OS 32-05 EFFECTS OF SGLT2 INHIBITORS ON CIRCADIAN RHYTHM OF BLOOD PRESSURE IN RATS

Disrupted circadian rhythm of blood pressure is associated with cardiovascular events in metabolic syndrome and obesity. Experiments were conducted to examine the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on circadian rhythm of blood pressure in a genetic model of obese metabolic syndrome (SHR/NDmcr-cp (+/+) (SHRcp)) and salt-treated obese Otsuka Long Evans Tokushima Fatty (OLETF) rats. Luseogliflozin (10 mg/kg/day, p.o.) and empagliflozin (10 mg/kg/day, p.o.) were administered for 5 weeks in metabolic syndrome SHRcp rats and 1% NaCl (in drinking water)-treated obese OLETF rats, respectively. Blood pressure was measured continuously by telemetry system. Glucose metabolism and insulin resistance were evaluated by oral glucose tolerance test. Both SHRcp and salt-treated OLETF rats developed non-dipper type of hypertension with altered glucose metabolism and insulin resistance. Administration of luseogliflozin and empagliflozin resulted in a remarkable increase in urinary glucose excretion and improved glucose metabolism and insulin resistance in SHRcp and salt-treated OLETF rats, respectively. Furthermore, luseogliflozin and empagliflozin significantly attenuated the development of hypertension with normalization of circadian rhythm of blood pressure, which was associated with an increase in urinary sodium excretion. These data suggest that SGLT2 inhibitors elicit beneficial effects on circadian rhythm of blood pressure during the development of hypertension in subjects with metabolic syndrome and obese.

Carbonylation Modification Regulates Na/K-ATPase Signaling and Salt Sensitivity: A Review and a Hypothesis.

Na/K-ATPase signaling has been implicated in different physiological and pathophysiological conditions. Accumulating evidence indicates that oxidative stress not only regulates the Na/K-ATPase enzymatic activity, but also regulates its signaling and other functions. While cardiotonic steroids (CTS)-induced increase in reactive oxygen species (ROS) generation is an intermediate step in CTS-mediated Na/K-ATPase signaling, increase in ROS alone also stimulates Na/K-ATPase signaling. Based on literature and our observations, we hypothesize that ROS have biphasic effects on Na/K-ATPase signaling, transcellular sodium transport, and urinary sodium excretion. Oxidative modulation, in particular site specific carbonylation of the Na/K-ATPase α1 subunit, is a critical step in proximal tubular Na/K-ATPase signaling and decreased transcellular sodium transport leading to increases in urinary sodium excretion. However, once this system is overstimulated, the signaling, and associated changes in sodium excretion are blunted. This review aims to evaluate ROS-mediated carbonylation of the Na/K-ATPase, and its potential role in the regulation of pump signaling and sodium reabsorption in the renal proximal tubule (RPT).

Nocturnal Blood Pressure Dipping in Normotensive Adults: Effect of Dietary Sodium and Sex

Normal nocturnal blood pressure (BP) dipping is arbitrarily defined as a decrease in mean daytime to mean nighttime BP by 10% to 20%. Individuals that have impaired nocturnal BP dipping (i.e., &lt;10%) have an increased risk of cerebrovascular and cardiovascular diseases. Excess sodium consumption is associated with increased cardiovascular disease risks and no studies have examined nocturnal BP dipping under a controlled sodium diet.PURPOSETo assess nocturnal BP dipping during low (LS) and high sodium (HS) diets in men and women. We hypothesized that a HS diet would impair nocturnal BP dipping, and men would have a greater impairment than women.METHODSEighty‐seven healthy normotensive men (n = 41; age: 35 ± 2 years) and women (n = 46; age: 40 ± 2 years) participated in a controlled feeding study where LS (20 mmol Na+/day) and HS (300 mmol Na+/day) diets were provided for 7 days each in random order. Subjects wore a 24‐hour ambulatory BP monitor, and we collected a 24‐hour urine sample and fasted blood sample on the final day of each diet. Nocturnal BP dipping was calculated as: ((mean daytime BP – mean nighttime BP)/mean daytime pressure)*100.RESULTSAs expected, there was a significant increase in urinary sodium excretion during the HS diet (women: LS = 26.0 ± 2.1 vs. HS = 238.4 ± 14.1 mmol/24hr; men: LS = 31.5 ± 4.4 vs. HS = 234.4 ± 13.3 mmol/24hr; p &lt; 0.01) and serum sodium (women: LS = 137.7 ± 0.3 vs. HS = 139.7 ± 0.2 mmol/L; men: LS 137.9 ± 0.4 vs. HS = 139.8 ± 0.3; p &lt; 0.05) with no differences observed between the sexes. Nocturnal BP dipping was not different between the diets (women: LS = 10 ± 1% vs. HS = 10 ± 1% mmHg; men: LS = 9 ± 1% vs. HS = 10 ± 1% mmHg; p &gt; 0.05) with no differences observed between the sexes.CONCLUSIONOur findings suggest that increased dietary sodium does not influence nocturnal BP dipping responses in normotensive men and women.Support or Funding InformationNIH Grant R01 HL104106

Chronic subcutaneous brain natriuretic peptide therapy in asymptomatic systolic heart failure.

We have previously reported that asymptomatic systolic heart failure (HF) is characterized by an impaired renal response to volume expansion due to lack of activation of urinary cGMP which is corrected by subcutaneous (SQ) BNP. In the current study, we sought to define the cardiorenal response to intravascular volume expansion after 12 weeks of SQ BNP therapy. We utilized a double-blinded, placebo-controlled study to compare 12 weeks of twice-daily SQ BNP 10 µg/kg (n = 22) or placebo (n = 12) in asymptomatic systolic HF. Subjects underwent two study visits: baseline and after 12 weeks of therapy. At each study visit, echocardiography, renal, and neurohumoral assessments were performed before and after intravascular volume expansion. The primary endpoint was change in urinary sodium excretion in response to volume expansion at 12 weeks, and we observed a greater increase in urinary sodium excretion [166 (77, 290) vs. 15 (-39, 72) mEq/min; P = 0.02] with SQ BNP treatment vs. placebo. Secondary endpoints included change in urine flow and glomerular filtration rate (GFR) in response to volume expansion at 12 weeks. We observed a significant increase in urine flow (P < 0.01) and trend for differential response in GFR (P = 0.08) with SQ BNP treatment vs. placebo. Among patients with asymptomatic systolic HF, twice-daily SQ BNP therapy improved the cardiorenal response to volume expansion at 12-week follow-up. Further studies are warranted to determine if these beneficial physiological observations with chronic natriuretic peptide administration translate into a delay in the progression to symptomatic HF.