Abstract 042: Effects of Diuretics on Sglt2 Inhibitor-induced Changes in Urinary Sodium Excretion Rate In Obese Metabolic Syndrome Rats

Proximal tubular sodium-glucose co-transporter 2 (SGLT2) transports glucose and sodium with a 1:1 stoichiometry. However, studies have indicated that treatment with SGLT2 inhibitors does not substantially increase the urinary excretion rate of sodium, while that of glucose is markedly increased. These data suggest that urinary sodium is reabsorbed by other mechanisms distal to the nephron during SGLT2 inhibition. Here, we aimed to investigate whether diuretics affect the SGLT2 inhibitor-induced changes in the urinary excretion rate of sodium in obese metabolic syndrome SHR/NDmcr-cp(+/+) (SHRcp) rats. Male 13-week-old SHRcp rats were treated with: 1) vehicle (0.5% carboxymethylcellulose), 2) a SGLT2 inhibitor, luseogliflozin (10 mg/kg/day, p.o.), 3) luseogliflozin + hydrochlorothiazide (10 mg/kg/day, p.o.) or 4) luseogliflozin + hydrochlorothiazide + furosemide (5 mg/kg/day, p.o.) for 5 weeks (n = 6-8 per group). Blood pressure and glucose metabolism were evaluated by telemetry and oral glucose tolerance test respectively. Vehicle-treated SHRcp rats developed non-dipper type hypertension (night and day time systolic blood pressure; 186 ± 2 and 185 ± 2 mmHg, respectively) and insulin resistance. As compared with vehicle-treated animals, luseogliflozin-treated rats showed an approximately 4,000-fold increase in urinary glucose excretion and improved glucose metabolism. Luseogliflozin also slightly decreased blood pressure, which was associated with an approximately 30% increase in urinary excretion of sodium. The addition of hydrochlorothiazide or hydrochlorothiazide + furosemide further decreased blood pressure and improved blood pressure circadian rhythm to a dipper profile in luseogliflozin-treated animals. In these animals, urinary sodium excretion tended to be increased by diuretics, although these changes were not statistically significant. These data indicate that SGLT2 inhibitor-induced natriuresis is not enhanced by diuretics. Thus, SGLT2 inhibitors may elicit their beneficial effects on glucose metabolism and hypertension in patients who are treated with diuretics.

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Systolic blood pressure reductions with sotagliflozin (LX4211), a dual SGLT1 and SGLT2 inhibitor, are associated with reductions in urinary sodium excretion

Journal of the American Society of Hypertension ◽

10.1016/j.jash.2015.03.126 ◽

2015 ◽

Vol 9 (4) ◽

pp. e55

Author(s):

Pablo Lapuerta ◽

Talia Biran ◽

Brian Zambrowicz ◽

David Powell ◽

Phillip Banks ◽

...

Keyword(s):

Blood Pressure ◽

Systolic Blood Pressure ◽

Sodium Excretion ◽

Sglt2 Inhibitor ◽

Urinary Sodium Excretion ◽

Urinary Sodium

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Relation of Urinary Sodium Excretion to Blood Pressure, Glucose Metabolism, and Lipid Metabolism in Residents of an Area of Japan with High Sodium Intake.

Hypertension Research ◽

10.1291/hypres.20.287 ◽

1997 ◽

Vol 20 (4) ◽

pp. 287-293 ◽

Cited By ~ 9

Author(s):

Minoru Kawamura ◽

Yasukazu Kimura ◽

Kazue Takahashi ◽

Nori Satoh ◽

Keiko Oku ◽

...

Keyword(s):

Blood Pressure ◽

Lipid Metabolism ◽

Glucose Metabolism ◽

Sodium Excretion ◽

Sodium Intake ◽

Urinary Sodium Excretion ◽

Urinary Sodium ◽

High Sodium ◽

High Sodium Intake

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Faculty Opinions recommendation of Urinary sodium excretion, blood pressure, cardiovascular disease, and mortality: a community-level prospective epidemiological cohort study.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733790826.793552587 ◽

2018 ◽

Author(s):

Carmine Zoccali ◽

Davide Bolignano

Keyword(s):

Blood Pressure ◽

Cardiovascular Disease ◽

Cohort Study ◽

Sodium Excretion ◽

Urinary Sodium Excretion ◽

Urinary Sodium ◽

Community Level ◽

Epidemiological Cohort

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Association between 24-h urinary sodium and potassium excretion and blood pressure among Chinese adults aged 18–69 years

Scientific Reports ◽

10.1038/s41598-021-83049-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Xiaofu Du ◽

Le Fang ◽

Jianwei Xu ◽

Xiangyu Chen ◽

Yamin Bai ◽

...

Keyword(s):

Blood Pressure ◽

Sodium Excretion ◽

Sodium Intake ◽

Urinary Sodium Excretion ◽

Urinary Sodium ◽

Inverse Association ◽

Potassium Excretion ◽

Chinese Adults ◽

Potassium Intake ◽

Sodium And Potassium

AbstractThe direction and magnitude of the association between sodium and potassium excretion and blood pressure (BP) may differ depending on the characteristics of the study participant or the intake assessment method. Our objective was to assess the relationship between BP, hypertension and 24-h urinary sodium and potassium excretion among Chinese adults. A total of 1424 provincially representative Chinese residents aged 18 to 69 years participated in a cross-sectional survey in 2017 that included demographic data, physical measurements and 24-h urine collection. In this study, the average 24-h urinary sodium and potassium excretion and sodium-to-potassium ratio were 3811.4 mg/day, 1449.3 mg/day, and 4.9, respectively. After multivariable adjustment, each 1000 mg difference in 24-h urinary sodium excretion was significantly associated with systolic BP (0.64 mm Hg; 95% confidence interval [CI] 0.05–1.24) and diastolic BP (0.45 mm Hg; 95% CI 0.08–0.81), and each 1000 mg difference in 24-h urinary potassium excretion was inversely associated with systolic BP (− 3.07 mm Hg; 95% CI − 4.57 to − 1.57) and diastolic BP (− 0.94 mm Hg; 95% CI − 1.87 to − 0.02). The sodium-to-potassium ratio was significantly associated with systolic BP (0.78 mm Hg; 95% CI 0.42–1.13) and diastolic BP (0.31 mm Hg; 95% CI 0.10–0.53) per 1-unit increase. These associations were mainly driven by the hypertensive group. Those with a sodium intake above about 4900 mg/24 h or with a potassium intake below about 1000 mg/24 h had a higher risk of hypertension. At higher but not lower levels of 24-h urinary sodium excretion, potassium can better blunt the sodium-BP relationship. The adjusted odds ratios (ORs) of hypertension in the highest quartile compared with the lowest quartile of excretion were 0.54 (95% CI 0.35–0.84) for potassium and 1.71 (95% CI 1.16–2.51) for the sodium-to-potassium ratio, while the corresponding OR for sodium was not significant (OR, 1.28; 95% CI 0.83–1.98). Our results showed that the sodium intake was significantly associated with BP among hypertensive patients and the inverse association between potassium intake and BP was stronger and involved a larger fraction of the population, especially those with a potassium intake below 1000 mg/24 h should probably increase their potassium intake.

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Urinary sodium excretion and the risk of cardiovascular disease: A community-based cohort study in Taiwan

British Journal Of Nutrition ◽

10.1017/s0007114521001768 ◽

2021 ◽

pp. 1-42

Author(s):

Yi-Jie Wang ◽

Kuo-Lioug Chien ◽

Hsiu-Ching Hsu ◽

Hung-Ju Lin ◽

Ta-Chen Su ◽

...

Keyword(s):

Blood Pressure ◽

Metabolic Syndrome ◽

Systolic Blood Pressure ◽

Sodium Excretion ◽

Urinary Sodium Excretion ◽

Salt Sensitivity ◽

Urinary Sodium ◽

Mediating Effect ◽

Cvd Risk ◽

Media Thickness

Abstract Urinary sodium excretion is a potential risk factor for cardiovascular diseases (CVD). However, the underlying biological mechanisms and effects of salt sensitivity are unclear. The purpose of this study was to characterize the relative contribution of biological factors to the sodium-CVD association. A total of 2112 participants were enrolled in this study. Structured questionnaires and blood and urine samples were obtained. Twenty-four-hour sodium excretion was estimated using a single overnight urine sample. Hypertension, metabolic syndrome, and overweight status were considered to indicate salt sensitivity. Cox proportional hazard models were used to investigate the effects of salt sensitivity on urinary sodium excretion and CVD risk. The traditional mediation approach was used to calculate the proportion of mediation. The mean age (standard deviation) of the 2112 participants was 54.5 (12.2) years, and they were followed up for a mean of 14.1 [8.1] years. Compared with those in the lowest quartile, the highest baseline urinary sodium excretion (>4.2g/24 hours) was associated with a 43% higher CVD risk (hazard ratio, 1.43; 95% confidence interval, 1.02-1.99). Participants with high urinary sodium excretion, hypertension, or metabolic syndrome had a significantly high risk of CVD. The carotid intima-media thickness had the largest mediating effect (accounting for 35% of the sodium-CVD association), followed by systolic blood pressure (33%), left ventricular mass (28%), and diastolic blood pressure (14%). Higher urinary sodium excretion increased the risk of CVD, which was explained largely by carotid media-thickness and systolic blood pressure.

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Direct Proportionality of Urinary Excretion Rate and Serum Level of Tetracycline in Human Subjects

Nature ◽

10.1038/198450a0 ◽

1963 ◽

Vol 198 (4879) ◽

pp. 450-453 ◽

Cited By ~ 28

Author(s):

T. CHULSKI ◽

R. H. JOHNSON ◽

C. A. SCHLAGEL ◽

J. G. WAGNER

Keyword(s):

Serum Level ◽

Urinary Excretion ◽

Excretion Rate ◽

Human Subjects ◽

Urinary Excretion Rate ◽

Direct Proportionality

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Compartmental transfer of mercury released from amalgam

Human & Experimental Toxicology ◽

10.1177/096032719701601107 ◽

1997 ◽

Vol 16 (11) ◽

pp. 667-672 ◽

Cited By ~ 5

Author(s):

S. Halbach ◽

L. Kremers ◽

H. Willruth ◽

A. Mehl ◽

G. Welzl ◽

...

Keyword(s):

Oral Cavity ◽

Urinary Excretion ◽

Total Mercury ◽

Excretion Rate ◽

Absorbed Dose ◽

Correlation Coefficients ◽

Urinary Excretion Rate ◽

Amalgam Fillings

The number of amalgam-covered surfaces and the occlusal area of the fillings, the concentrations of total mercury in plasma, erythrocytes and urine, the urinary excretion rate, and the absorbed daily doses estimated by two separate methods from intra-oral Hg emission were determined in 29 volunteers with a low amalgam load. The transfer ofHg from the fillings via the oral cavity and blood to urinary excretion was evaluated by multiple correla tions between these variables. In addition, the combina tion of variables most representative of the entire compartmental transfer of amalgam Hg was determined. Urinary excretion (1), Hg concentration in plasma (2) and absorbed dose (3) were most closely correlated to each other, followed by correlations with the variables of the fillings (4). Correlation coefficients were 0.75 for variables 1 vs 2 and 2 vs 3, and 0.49 for variables 3 vs 4. It was concluded that variables 1-3 best reflected the transfer of mercury from amalgam fillings throughout the organism and that they were relatively insensitive to dietary mercury. The determination of total mercury in plasma and of its urinary excretion rate appears, under practical aspects, most suitable for the investigation of Hg uptake from amalgam.

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Pregnancy Enhances the Angiotensin (Ang)-(1–7) Vasodilator Response in Mesenteric Arteries and Increases the Renal Concentration and Urinary Excretion of Ang-(1–7)

Endocrinology ◽

10.1210/en.2003-0009 ◽

2003 ◽

Vol 144 (8) ◽

pp. 3338-3343 ◽

Cited By ~ 35

Author(s):

Liomar A. A. Neves ◽

Aleck F. Williams ◽

David B. Averill ◽

Carlos M. Ferrario ◽

Michael P. Walkup ◽

...

Keyword(s):

Urinary Excretion ◽

Excretion Rate ◽

Virgin Female ◽

Cardiovascular Regulation ◽

Mesenteric Arteries ◽

Female Rats ◽

Resistance Arteries ◽

Urinary Excretion Rate ◽

Response Curves ◽

Mesenteric Vessels

Abstract The vasoactive effect of angiotensin (Ang)-(1–7) in mesenteric resistance arteries together with its plasma and kidney concentration and urinary excretion was assessed in pregnant and virgin rats. Mesenteric arteries (230–290 μm) were mounted in a pressurized myograph system and Ang-(1–7) concentration-dependent response curves (10−10–10−5m) were determined in arteries preconstricted with endothelin-1 (10−7m). The Ang-(1–7) response was investigated in vessels with and without pretreatment with the Ang-(1–7) antagonist [d-[Ala7]-Ang-(1–7)] (10−7m). Ang-(1–7) caused a significantly enhanced, concentration-dependent dilation of mesenteric vessels (EC50 = 2.7 nm) from pregnant compared with virgin female rats. d-[Ala7]-Ang-(1–7) eliminated the vasodilator effect of Ang-(1–7). There was no significant change in plasma concentration of Ang-(1–7) in pregnant animals. On the other hand, 24 h urinary excretion and kidney concentration of Ang-(1–7) were significantly higher in pregnant animals. The increased mesenteric dilation to Ang-(1–7) with enhanced kidney concentration and 24 h urinary excretion rate of Ang-(1–7) suggests an important role for this peptide in cardiovascular regulation during pregnancy.

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Functional significance of exaggerated renal thromboxane A2 synthesis induced by cyclosporin A

AJP Renal Physiology ◽

10.1152/ajprenal.1986.251.4.f581 ◽

1986 ◽

Vol 251 (4) ◽

pp. F581-F587 ◽

Cited By ~ 3

Author(s):

N. Perico ◽

A. Benigni ◽

C. Zoja ◽

F. Delaini ◽

G. Remuzzi

Keyword(s):

Urinary Excretion ◽

Cyclosporin A ◽

Chronic Treatment ◽

Excretion Rate ◽

Thromboxane A2 ◽

Significant Negative Correlation ◽

Progressive Increase ◽

Urinary Excretion Rate ◽

Acid Clearance ◽

Selective Increase

Animals and humans undergoing a chronic treatment with cyclosporin A (CyA) show a reduction in glomerular filtration rate (GFR). The cause of this abnormality has not been established. Since CyA interferes with arachidonic acid (AA) metabolism in various cells, we wished to determine whether alterations in renal AA metabolites contribute to deteriorating renal function in rats on CyA. We show that chronic CyA treatment induces a progressive increase in the renal synthesis of thromboxane (TX) A2. This is a selective abnormality in that CyA does not influence the renal synthesis of prostaglandin E2 (PGE2) and prostacyclin (PGI2). A significant negative correlation has been found between TXB2 urinary excretion rate and inulin clearance. No correlation has been observed between TXB2 excretion and p-aminohippuric acid clearance. The withdrawal of CyA is followed by a normalization of both TXB2 urinary excretion rate and GFR. The administration of a selective TXA2 inhibitor, UK-38,485, resulted in a significant reduction in urinary excretion of TXB2 accompanied by a significant increase in GFR. We conclude that chronic treatment with CyA in rats is associated with a selective increase in renal TXA2 synthesis and suggest that this abnormality may play a role in the reduction of GFR.

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