Electrolyte Excretion Research Articles

Effect of Alprostadil on the Prevention of Contrast-Induced Nephropathy: A Meta-Analysis of 36 Randomized Controlled Trials.

Contrast-induced nephropathy (CIN) is the third leading cause of acquired acute renal injury in hospitalized patients. Alprostadil plays a role in the maintenance and redistribution of intrarenal blood flow and the excretion of electrolytes and water. However, the effectiveness of alprostadil in preventing CIN remains controversial. Thirty-six articles with a total of 5495 patients were included in this study. Both groups (experimental group and control group) received standard hydration therapy. In the experimental group, patients received different doses of alprostadil. Serum creatinine (SCr), blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), cystatin C, creatinine clearance rate (CCr), and β2-microglobulin (β2-MG) were measured at 24, 48, and 72 hours after contrast media injection. The incidence of CIN in the experimental group was significantly lower than that in the control group (6.56% vs 16.74%). The level of SCr, cystatin C, BUN, and β2-MG in the experimental group was lower than those in the control group; CCr and eGFR in the experimental group were higher than those in the control group. This study demonstrated that alprostadil may reduce the incidence of CIN in patients undergoing coronary angiogram and/or percutaneous coronary intervention.

The selective mineralocorticoid receptor modulator AZD9977 reveals differences in mineralocorticoid effects of aldosterone and fludrocortisone.

Introduction:AZD9977 is a novel mineralocorticoid receptor (MR) modulator, which in preclinical studies demonstrated organ protection without affecting aldosterone-regulated urinary electrolyte excretion. However, when tested in humans, using fludrocortisone as an MR agonist, AZD9977 exhibited similar effects on urinary Na+/K+ ratio as eplerenone. The aim of this study is to understand whether the contradictory results seen in rats and humans are due to the mineralocorticoid used.Materials and methods:Rats were treated with single doses of AZD9977 or eplerenone in combination with either aldosterone or fludrocortisone. Urine was collected for five to six hours and total amounts excreted Na+ and K+ were assessed.Results:AZD9977 dose-dependently increased urinary Na+/K+ ratio in rats when tested against fludrocortisone, but not when tested against aldosterone. Eplerenone dose-dependently increased urinary Na+/K+ ratio when tested against fludrocortisone as well as aldosterone.Conclusions:The data suggest that the contrasting effects of AZD9977 on urinary electrolyte excretion observed in rats and humans are due to the use of the synthetic mineralocorticoid fludrocortisone. Future clinical studies are required to confirm the reduced electrolyte effects of AZD9977 and the subsequent lower predicted hyperkalemia risk.

Association of blood pressure with estimates of 24-h urinary sodium and potassium excretion from repeated single-spot urine samples.

While the association between 24-h urinary sodium and potassium excretion with blood pressure is well established, the relationships of these ions to spot urine measurements are unclear. Our purpose is to assess the association between blood pressure and the estimated 24-h sodium and potassium excretion from repeated single-spot urine samples. Spot urine and blood pressure were collected annually during a 5-year period from 4360 Japanese workers with ages ranging from 19 to 55 years. Estimates of 24-h sodium and potassium excretion were based on Tanaka's formula. Overall, a single standard deviation increase in the estimated sodium excretion (36.5 mmol/day) was associated with a 1.3 mmHg higher systolic blood pressure and a 0.8 mmHg higher diastolic blood pressure (P < 0.001). A single standard deviation increase in estimated potassium excretion (8.9 mmol/day) was associated with a 1.1 mmHg lower systolic blood pressure and a 0.7 mmHg lower diastolic blood pressure (P < 0.001). As a combined measure of the excretion of both electrolytes, the estimated 24-h sodium-to-potassium ratio was positively associated with both blood pressures (P < 0.001). Associations of blood pressure with sodium and the sodium-to-potassium ratio increased with age and were stronger in men compared to women. Associations with potassium and the sodium-to-potassium ratio were stronger in individuals who were overweight. The findings provide evidence for an association between blood pressure and the estimated 24-h sodium and potassium excretion from repeated single-spot urine samples. As convenient measures of dietary intake for each electrolyte, repeated spot urine samples may be useful for assessing hypertension risk, especially in men, older individuals, and overweight individuals.

Antidiarrheal and protein conservative activities of Psidium guajava in diarrheal rats

ObjectivePsidium guajava occurs worldwide in tropical and subtropical areas. It has been used to treat inflammation, diabetes, fever, hypertension and ulcers. However, its antidiarrheal and protein conservative activities still need to be investigated. MethodsFifty-four male rats were divided into normal and diarrheal rats. The normal rats were divided into 4 groups: control, low-dose P. guajava leaf extract (50 mg/kg), high-dose P. guajava leaf extract (100 mg/kg) and gallic acid. Treatments were administrated orally in 1 mL saline for a 1-month period. The diarrheal rats were divided into 5 groups: desmopressin (0.2 mg/kg) drug, low-dose P. guajava leaf extract (50 mg/kg), high-dose P. guajava leaf extract (100 mg/kg), gallic acid and an untreated control. Doses were given daily for a 1-month period while the untreated control received no treatment. ResultsDiarrhea was responsible for an observed decline in kidney weight and serum sodium, potassium and chloride. Further, diarrhea was positively correlated with a significant increase in urine volume, and excretion of electrolytes, serum urea, creatinine and uric acid in the urine. In contrast, there was a proportional increase in the lipid peroxidation value in diarrhea and a significant decline was observed in serum superoxide dismutase, glutathione peroxidase and glutathione levels in diarrhea. Also, diarrhea inhibited blood proteins. The oral intake of P. guajava leaf extract by diarrheal rats restored all of these parameters to near normal levels. High-dose P. guajava leaf extract was more effective than the same compound at a low dose. ConclusionP. guajava leaf extract elicited antidiarrheal and protein conservative effects.

24-Hour Profile of Blood Pressure, Heart Rate, Excretion of Electrolytes, and Locomotor Activity in Wistar-Kyoto and SHR Rats Under Conditions of Free-Run Rhythm.

We presented the results of our study of chronostructure of BP, HR, electrolyte excretion, and locomotor activity under conditions of "free-run rhythm" (light deprivation). In adult male Wistar-Kyoto (normotensive) and SHR (spontaneously hypertensive) rats, BP, biopotentials of the heart (ECG), and locomotor activity were recorded over 24 h by telemetric monitoring and the rate of excretion of electrolytes (Na+, K+, Ca2+, and Mg2+) during the nighttime and daytime hours was measured. It was found that under free-run rhythm, 24-h profiles of BP, HR, excretory function of the kidneys, and locomotor activity underwent more considerable changes in normotensive Wistar-Kyoto rats in comparison with hypertensive SHR rats. However, hypertensive rats demonstrated pronounced changes in rhythmic characteristics of HR, which can restrict adaptation reserves of the cardiovascular system.

Effect of calcium sources in the diets of adult cats on urinary parameters and acid-base balance

ABSTRACT: Calcium is a macroelement that is part of the mineral composition of the diet of companion animals, and is considered a cation of strong alkalizing power, increasing urinary pH. Calcium salts have different solubilities and depending on the anion to which calcium is associated with, it can be more or less absorbed, modifying the pH of the urine. The aim of this study was to evaluate the efficiency of calcium sources on alkalinization of urinary pH, as well as excretion of urinary electrolytes and acid-base balance of adult cats. An extruded diet for cats was selected, and had 160mEq/kg of calcium from the sources of either calcium carbonate (CaCO3) or calcium gluconate (C12H22CaO14) added. In the control treatment there was no addition of calcium sources, resulting in three treatments. Nine adult cats were used, mixed breed, in two experimental periods, with six replicates per treatment. Animal average age was 4±1.3 years old and average weight was 3.96±0.71kg. The cats remained in metabolic cages for an adaptation period of seven days, followed by six days of urine total collection, with volume, density, pH and calcium concentration (g/d) measurements. The acid-base balance was studied by blood gas analysis of venous blood. The two sources of calcium alkalinized the urine (P&lt;0.001). However, calcium gluconate had less alkalinization power compared to the calcium carbonate (P&lt;0.05). Urinary calcium was not affected by treatments, and represented less than 0.5% of calcium intake. The experiment showed that calcium, although an alkaline cation and considered strong influencer of the EB of the diet, cannot be evaluated individually, because depending on its associated anion it may have greater or lesser influence on cats urine pH.

Circadian rhythms and the kidney

Numerous physiological functions exhibit substantial circadian oscillations. In the kidneys, renal plasma flow, the glomerular filtration rate and tubular reabsorption and/or secretion processes have been shown to peak during the active phase and decline during the inactive phase. These functional rhythms are driven, at least in part, by a self-sustaining cellular mechanism termed the circadian clock. The circadian clock controls different cellular functions, including transcription, translation and protein post-translational modifications (such as phosphorylation, acetylation and ubiquitylation) and degradation. Disruption of the circadian clock in animal models results in the loss of blood pressure control and substantial changes in the circadian pattern of water and electrolyte excretion in the urine. Kidney-specific suppression of the circadian clock in animals implicates both the intrinsic renal and the extrarenal circadian clocks in these pathologies. Alterations in the circadian rhythm of renal functions are associated with the development of hypertension, chronic kidney disease, renal fibrosis and kidney stones. Furthermore, renal circadian clocks might interfere with the pharmacokinetics and/or pharmacodynamics of various drugs and are therefore an important consideration in the treatment of some renal diseases or disorders.

Comparative evaluation of daily rhythm of urinary excretion in Equus caballus and Bos taurus by means of fractional clearance

ABSTRACTThe aim of this study was to evaluate the daily variations of urinary excretion of the main electrolytes in Equus caballus and Bos taurus maintained under natural photoperiod. Animals were housed in individual indoor stalls under natural conditions. Urine and blood samples were taken from all the subjects every 4 h for 24 h period and were analyzed to assess the creatinine, calcium, phosphorus, magnesium, and chloride concentration. The fractional excretions of Na (%CrNa), K (%CrK), Cl (%CrCl), P (%CrP), Ca (%CrCa), and Mg (%CrMg) were calculated. Daily oscillations with nighttime acrophases of %CrNa, %CrK, and %CrCl are observed in horse; the acrophases of the parameters which resulted periodic in cow, including %CrNa, %CrCa, and %CrMg, are verified during the light phase. This study brings a contribution to the knowledge of the periodic phenomenon of the urinary excretion in the equine and bovine species. The results suggest that horse and cow are characterized by different circadian patterns for renal fractional clearance and that in these species, in addition to the external circadian stimuli, the renal excretion rhythms are also controlled by a self-sustained intrinsic renal clock that contribute to define the temporal patterns (daytime and nighttime).

The Diuretic Activity of Ephedra alata and Plumbago europaea in Mice using an Aqueous Extract

Throughout history, man used various natural materials as a remedy for treatment of various diseases and recently witnessing a vastly growing and renewed interest in herbal medicine globally. In Palestinian folk medicine Ephedra alata and Plumbago europaea used as diuretics and for treatment of hypertension. This study aimed to evaluate the diuretic and acute toxicity effects of the aqueous extracts for these two plants in mice following oral administration. Aqueous E. alata and P. europaea extracts (500 mg/kg) were administered orally to adult mice. Urine output and electrolytes were then measured after 4 h of administration and compared with those received furosemide 10 mg/kg (positive control group) and those received normal saline (negative control group). Significant diuresis was noted in those received the aqueous extract of E. alata (p < 0.001), while the P. europaea aqueous extract had shown mild diuresis at the end of the forth hour compared to controls. Moreover, both aqueous extracts had an alkaline pH and a mild increase in the electrolyte excretion (Na, K). Our results revealed that E. alata aqueous extract has potential diuretic effect. Further studies are needed to evaluate this diuretic effect in the relief of diseases characterized by volume overload.

The effects of sucrose on urine collection in metabolic cages.

Representative urine collection that respects the standards of animal welfare is still an issue in experimental nephrology. The commonly used metabolic cages induce stress in rodents. In mice, the volume of collected urine is sometimes insufficient for further analysis. The aim of this experiment was to analyse the effects of time of day, temperature and 2%, 5% or 10% sucrose solutions on diuresis, weight change and liquid intake of adult mice placed in metabolic cages for urine collection. Mice were placed in metabolic cages for 12 h during the day or night at standard ambient (22℃) and thermoneutral (28℃) temperatures. To determine the effect of acclimatisation, mice were placed in metabolic cages for five consecutive days. Diuresis increased with concentrations of sucrose. Body weight reduction was most rapid in the group given tap water and decreased with increasing sucrose concentrations. A drastic drop in body weight was observed in mice placed in metabolic cages for four consecutive days with access to tap water and food, indicating that time spent in metabolic cages should be kept to a minimum, as prolonged confinement in metabolic cages can be harmful to mice. The administration of concentrated sucrose solutions can potentially aid in mouse urine collection by reducing the time spent in metabolic cages. Sucrose supplementation increased the albumin/creatinine ratio. However, without showing estimates of glomerular filtration rate, renal haemodynamics, plasma electrolytes and urinary electrolyte excretions, the results of this study do not provide any conclusion about the effect of sucrose on renal function.

Intestinal Barrier Function in Chronic Kidney Disease.

The kidneys are key contributors to body homeostasis, by virtue of controlled excretion of excessive fluid, electrolytes, and toxic waste products. The syndrome of uremia equals the altered physiology due to irreversible loss of kidney function that is left uncorrected for, despite therapeutic intervention(s). The intestines and its microbial content are prime contributors to this syndrome. The intestinal barrier separates the self (or the so-called “milieu intérior”) from the environment. In the large intestine, the intestinal barrier keeps apart human physiology and the microbiota. The enterocytes and the extracellular mucin layer functions form a complex multilayered structure, facilitating complex bidirectional metabolic and immunological crosstalk. The current review focuses on the intestinal barrier in chronic kidney disease (CKD). Loss of kidney function results in structural and functional alterations of the intestinal barrier, contribution to the syndrome of uremia.

Discovery, Characterization, and Effects on Renal Fluid and Electrolyte Excretion of the Kir4.1 Potassium Channel Pore Blocker, VU0134992

The inward rectifier potassium (Kir) channel Kir4.1 (KCNJ10) carries out important physiologic roles in epithelial cells of the kidney, astrocytes in the central nervous system, and stria vascularis of the inner ear. Loss-of-function mutations in KCNJ10 lead to EAST/SeSAME syndrome, which is characterized by epilepsy, ataxia, renal salt wasting, and sensorineural deafness. Although genetic approaches have been indispensable for establishing the importance of Kir4.1 in the normal function of these tissues, the availability of pharmacological tools for acutely manipulating the activity of Kir4.1 in genetically normal animals has been lacking. We therefore carried out a high-throughput screen of 76,575 compounds from the Vanderbilt Institute of Chemical Biology library for small-molecule modulators of Kir4.1. The most potent inhibitor identified was 2-(2-bromo-4-isopropylphenoxy)-N-(2,2,6,6-tetramethylpiperidin-4-yl)acetamide (VU0134992). In whole-cell patch-clamp electrophysiology experiments, VU0134992 inhibits Kir4.1 with an IC50 value of 0.97 µM and is 9-fold selective for homomeric Kir4.1 over Kir4.1/5.1 concatemeric channels (IC50 = 9 µM) at -120 mV. In thallium (Tl+) flux assays, VU0134992 is greater than 30-fold selective for Kir4.1 over Kir1.1, Kir2.1, and Kir2.2; is weakly active toward Kir2.3, Kir6.2/SUR1, and Kir7.1; and is equally active toward Kir3.1/3.2, Kir3.1/3.4, and Kir4.2. This potency and selectivity profile is superior to Kir4.1 inhibitors amitriptyline, nortriptyline, and fluoxetine. Medicinal chemistry identified components of VU0134992 that are critical for inhibiting Kir4.1. Patch-clamp electrophysiology, molecular modeling, and site-directed mutagenesis identified pore-lining glutamate 158 and isoleucine 159 as critical residues for block of the channel. VU0134992 displayed a large free unbound fraction (fu) in rat plasma (fu = 0.213). Consistent with the known role of Kir4.1 in renal function, oral dosing of VU0134992 led to a dose-dependent diuresis, natriuresis, and kaliuresis in rats. Thus, VU0134992 represents the first in vivo active tool compound for probing the therapeutic potential of Kir4.1 as a novel diuretic target for the treatment of hypertension.

Fractional excretion of electrolytes in volume-responsive and intrinsic acute kidney injury in dogs: Diagnostic and prognostic implications.

BackgroundThe value of fractional excretion (FE) of electrolytes to characterize and prognosticate acute kidney injury (AKI) is poorly documented in dogs.ObjectivesTo evaluate the diagnostic and prognostic roles of FE of electrolytes in dogs with AKI.AnimalsDogs (n = 135) with AKI treated with standard care (February 2014‐December 2016).MethodsProspective study. Clinical and laboratory variables including FE of electrolytes, were measured upon admission. Dogs were graded according to the AKI‐IRIS guidelines and grouped according to AKI features (volume‐responsive, VR‐AKI; intrinsic, I‐AKI) and outcome (survivors/non‐survivors). Group comparison and regression analyses with hazard ratios (HR) evaluation for I‐AKI and mortality were performed. P < .05 was considered significant.ResultsFifty‐two of 135 (39%) dogs had VR‐AKI, 69/135 (51%) I‐AKI and 14/135 (10%) were unclassified. I‐AKI dogs had significantly higher FE of electrolytes, for example, FE of sodium (FENa, %) 2.39 (range 0.04‐75.81) than VR‐AKI ones 0.24 (range 0.01‐2.21; P < .001). Overall, case fatality was 41% (55/135). Increased FE of electrolytes were detected in nonsurvivors, for example, FENa 1.60 (range 0.03‐75.81) compared with survivors 0.60 (range 0.01‐50.45; P = .004). Several risk factors for death were identified, including AKI‐IRIS grade (HR = 1.39, P = .002), FE of electrolytes, for example, FENa (HR = 1.03, P < .001), and urinary output (HR = 5.06, P < .001).Conclusions and Clinical ImportanceFractional excretion of electrolytes performed well in the early differentiation between VR‐AKI and I‐AKI, were related to outcome, and could be useful tools to manage AKI dogs in clinical practice.

Renal injury in Seipin-deficient lipodystrophic mice and its reversal by adipose tissue transplantation or leptin administration alone: adipose tissue-kidney crosstalk.

Seipin deficiency is responsible for type 2 congenital generalized lipodystrophy with severe loss of adipose tissue (AT) and could lead to renal failure in humans. However, the effect of Seipin on renal function is poorly understood. Here we report that Seipin knockout (SKO) mice exhibited impaired renal function, enlarged glomerular and mesangial surface areas, renal depositions of lipid, and advanced glycation end products. Elevated glycosuria and increased electrolyte excretion were also detected. Relative renal gene expression in fatty acid oxidation and reabsorption pathways were impaired in SKO mice. Elevated glycosuria might be associated with reduced renal glucose transporter 2 levels. To improve renal function, AT transplantation or leptin administration alone was performed. Both treatments effectively ameliorated renal injury by improving all of the parameters that were measured in the kidney. The treatments also rescued insulin resistance and low plasma leptin levels in SKO mice. Our findings demonstrate for the first time that Seipin deficiency induces renal injury, which is closely related to glucolipotoxicity and impaired renal reabsorption in SKO mice, and is primarily caused by the loss of AT and especially the lack of leptin. AT transplantation and leptin administration are two effective treatments for renal injury in Seipin-deficient mice.-Liu, X.-J., Wu, X.-Y., Wang, H., Wang, S.-X., Kong, W., Zhang, L., Liu, G., Huang, W. Renal injury in Seipin-deficient lipodystrophic mice and its reversal by adipose tissue transplantation or leptin administration alone: adipose tissue-kidney crosstalk.

Hyperhydration Acutely Increases Bioelectrical Impedance Analysis Body Fat Estimates

Bioelectrical impedance analysis (BIA) is a common and non-invasive method to evaluate body composition by measuring the electrical impedance of the body. Altering blood electrolyte concentration or blood volume may impact BIA measurements by directly influencing the electrical conductivity of the body. While dehydration and sweat induced electrolyte loss certainly impacts BIA, it is unclear how simultaneous hyperhydration and electrolyte loading effects BIA measurements. PURPOSE: To examine the effects of acute hyperhydration and salt loading on the impact of BIA derived body fat estimates. METHODS: Each participant ate a standardized meal followed by ≥4hr fast, prior to the experimental visit. Adequate hydration (urine SG ≤1.020) of each participant was confirmed prior to the start of the visit. Tanita TBF-300A BIA and a blood sample were performed at baseline and every 30min for 3hr following the consumption of 3.8 grams of table salt dissolved into 466mL of deionized water (sodium: 1500mg, 140mmol). All urine produced during the 3hr follow-up was collected to assess volume and electrolyte excretion. RESULTS: Seven healthy participants (3M/4W, 29±2 years, 67.0±4kg, urine SG 1.007±0.001, hemoglobin 13.7±0.2g/dL, hematocrit 45±1%, serum sodium 140.0±0.5mmol/L) were studied. Participants excreted 646±55mL of urine containing 17.1±6.8mmol of sodium during the 3hr follow-up period. Consumption of the salt water solution increased plasma volume 7.0±0.7% and serum sodium 1.3±0.4% with each statistically elevated above baseline during the time points ≥60min and ≥120min, respectfully (all p<0.05). Both body mass (+0.4±0.1kg) and BIA estimated body fat percentage (+0.6±0.2%) (both p<0.05) increased immediately and returned to baseline levels by 90min. Leg to leg electrical impedance was not affected by the consumption of the salt water beverage (p=0.660). CONCLUSION: This preliminary data suggests that when starting in a hydrated state, concurrent consumption of salt and water temporarily increases body mass causing an increase in body fat estimates. However, differences in temporal patterns suggest increased plasma volume with small elevations in electrolyte concentration does not directly affect body fat estimates when using bioelectrical impedance analysis.

Fractional excretion of electrolytes and paradoxical aciduria in dairy cows with left displaced abomasum

ABSTRACT: The fractional excretion of electrolytes is used to assess renal function and interpret electrolyte and acid-base imbalances. Left displaced abomasum is a common disorder in dairy cows, which causes hypokalemic, hypochloremic metabolic alkalosis. There is limited information on fractional excretion of electrolytes in cows with displaced abomasum. This study aimed to measure the fractional excretion of sodium, potassium, and chloride and paradoxical aciduria in dairy cows with displaced abomasum. Blood and urine samples were collected from 30 dairy cows before and 24, 48, and 72 h after surgery. The cows were divided into two groups (G1: laparoscopy and G2: laparotomy) with 15 cows each. The concentrations of chloride, sodium, potassium, and creatinine were measured in serum and urine. Urinary pH and packed cell volume were measured. Fractional excretion of sodium, potassium, and chloride and urinary strong ion difference [SID]urine were calculated using published formulas. Cows in both groups showed hypokalemic, metabolic alkalosis before surgery; however, hypochloremia was observed only in G2. Potassium concentration significantly increased 24, 48, and 72 h after surgery in G1 and 48 and 72 h after surgery in G2. There were no significant changes in fractional excretion of sodium, chloride, and potassium and urinary pH and [SID]urine between treatments and time points. Paradoxical aciduria was observed before and 24 h following surgery in G1. Fractional excretion and urinary SID are valuable tools to understand hypochloremic, hypokalemic alkalosis in dairy cows with displaced abomasum, as well as paradoxical aciduria and return of abomasal flux.

Gallic acid, a phenolic compound isolated from Mimosa bimucronata (DC.) Kuntze leaves, induces diuresis and saluresis in rats.

Although present in the leaves of Mimosa bimucronata (DC.) and many other medicinal plants commonly used to augment urinary volume excretion, the effects of gallic acid as a diuretic agent remain to be studied. Wistar rats were orally treated with vehicle, hydrochlorothiazide, or gallic acid. The effects of gallic acid in the presence of hydrochlorothiazide, furosemide, amiloride, L-NAME, atropine, and indomethacin were also investigated. Diuretic index, pH, conductivity, and electrolyte excretion were evaluated at the end of the experiment (after 8 or 24h). Gallic acid induced diuretic and saluretic (Na+ and Cl-) effects, without interfering with K+ excretion, when orally given to female and male rats at a dose of 3mg/kg. These effects were associated with increased creatinine and conductivity values while pH was unaffected by any of the treatments. Plasma Na+, K+, and Cl- levels were not affected by any of the acute treatments. The combination with hydrochlorothiazide or furosemide was unable to intensify the effects of gallic acid when compared with the response obtained with each drug alone. On the other hand, the treatment with amiloride plus gallic acid amplified both diuresis and saluresis, besides to a marked potassium-sparing effect. Its diuretic action was significantly prevented in the presence of indomethacin, a cyclooxygenase inhibitor, but not with the pretreatments with L-NAME or atropine. Although several biological activities have already been described for gallic acid, this is the first study demonstrating its potential as a diuretic agent.

Timing of food intake differentially impacts urinary electrolyte and aldosterone excretion

The time‐of‐day variation in sodium excretion can be regulated by many different peptides and hormones, such as aldosterone. Numerous studies have shown that the circadian clock modulates the ability of aldosterone to regulate sodium balance, indicating a functional consequence of their interaction. Normally, renal sodium excretion has a distinct diurnal pattern, independent of time of intake, yet the interaction between the time of intake and the amount of salt ingested has yet to be determined. Our lab sought to determine what effect the timing of food intake has on the diurnal rhythm of renal electrolyte excretion, and whether or not this timing affects aldosterone as well. Male Sprague Dawley rats were implanted with telemetry devices to monitor mean arterial pressure (MAP). Following at least 7 days of recovery, rats were housed in metabolic cages and placed on a normal salt diet (0.49% NaCl). Following two days of baseline urine collections at 12‐hour intervals (Zeitgeber Time [ZT] 0 to ZT12 [lights on] or ZT12‐ZT24 [lights off]) under ad libitum feeding conditions, we restricted their access to food for 7 days to only their inactive period (ZT0‐ZT12). Rats were given free access to water during the reverse feeding (RF) conditions. As expected, rats allowed food ad libitum had a diurnal rhythm in sodium excretion as evidenced by a significantly higher sodium excretion during their active period (P&lt;0.05); active:inactive (A/I) sodium excretion was (2.82 ± 0.20). The rhythm in sodium excretion was not significantly different after 7 days of RF compared to ad libitum rats (2.03 ± 0.28 A/I, P=NS vs. ad libitum). As expected, potassium excretion was significantly greater during the active period in rats fed under ad libitum conditions (P&lt;0.05; A/I = 2.32 ± 0.16). Interestingly, RF significantly reduced the diurnal variation in urinary potassium excretion (0.89 ± 0.16, P&lt;.05 vs. ad libitum) as potassium excretion remained high during the inactive period. Although urinary aldosterone levels were similar in both ad libitum and RF conditions during the active period (89 ± 17 vs. 97 ± 18 pg/12 hr, P=NS), RF prevented the normal diurnal rhythm in aldosterone excretion resulting in significantly higher levels during the inactive period compared to ad libitum (138 ± 25 pg/12 hr vs. 25 ± 8, respectively, P&lt;0.05). There were no differences in 12‐hour MAP or activity between ad libitum and reverse feeding conditions. Our findings suggest that consuming food during the inactive phase impairs the diurnal variation in aldosterone production. In addition, the inappropriately high aldosterone excretion during the inactive period appears to be consistent with elevated potassium excretion during this period as well.Support or Funding InformationThis research was supported in part by the NHLBI Program Project grant HL136267, the NIH Career Development Award K99 HL127178, the NIGMS Pre‐doctoral Training Grant in Cell and Molecular Biology (CMB) T‐32 Training Grant T32GM008111‐30, and the UAB School of Medicine AMC21 Multi‐Investigator Grant.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Chronic Potassium Adaptation Decreases Thiazide‐Sensitive Sodium Excretion with Preserved Potassium Excretion independent of NCC phosphorylation

Acute increases in K intake decrease Na‐Cl cotransporter (NCC) phosphorylation and NCC‐mediated Na reabsorption. This decrease in NCC phosphorylation, coupled with increased distal delivery of Na and enhanced ENaC activity, is one mechanism to augment kaliuresis. We sought to dissect the role of adaptation to a high K diet in which the plasma K concentration was unchanged between a normal and high K diet. To test this, we measured thiazide‐sensitive electrolyte excretion in acutely fasted mice fed a chronic normal or high K diet with and without the addition of benzamil, an ENaC antagonist.We placed C57Bl/6J mice on either a normal (0.7% w/w) or high (5% w/w) K diet for 1 week. We fasted mice, performed an intraperitoneal injection of either 30 mg/kg hydrochlorothiazide to inhibit NCC, 1.4 mg/kg benzamil to inhibited ENaC, or both, and collected urine for 4 hours. After a washout period, we sacrificed mice after an acute fast for tissue analysis. We measured plasma aldosterone concentration from a separate, similarly treated group of normal or high K‐fed mice.Mice demonstrated decreased thiazide‐induced Na excretion on a high K diet compared to a normal K diet, yet thiazide‐induced K excretion remained unchanged (0.138 +/− 0.017 vs. 0.109 +/− 0.006 μmol/min, normal vs. high K diet, respectively, p=0.28) and significantly higher than vehicle. Aldosterone was significantly higher in the high K diet‐fed group (141 +/− 13 vs. 516 +/− 171 pg/ml, normal vs. high K diet, respectively; p&lt;0.05). Benzamil increased urine flow on the high K (1.03 +/− 0.05 μl/min, p&lt;0.05) but not normal K diet (0.42 +/− 0.19 μl/min, p=0.2) compared to vehicle (0.46 +/− 0.11 μl/min), congruent with increased ENaC‐mediated Na reabsorption. Plasma K concentrations in acutely fasted mice were no different between mice on normal or high K diets (4.98 +/− 0.22 vs. 4.53 +/− 0.17 mmol/L, normal vs. high K diet, respectively, p=0.2). Membrane preparations of kidney lysate blotted for total and phosphorylated NCC were not significantly different on a normal vs. high K diet. The increase in K excretion in high K diet‐fed mice after thiazide administration suggests that NCC activity is not significantly diminished. The decrease in thiazide‐induced Na excretion may be explained by an aldosterone‐mediated increase in ENaC activity with a chronic, high K diet. These data provide evidence that both NCC phosphorylation and activity are not tonically suppressed with high K adaptation in the absence of elevated plasma K concentrations. ENaC activity is also increased on a high K diet in the absence of elevated plasma K. Furthermore, plasma K‐mediated regulation of NCC phosphorylation may be relevant for short‐term, rather than chronic K adaptation.Support or Funding InformationJMN receives support from the NIH (1K08 DK114567‐01). JMN was previously supported by an American Heart Association Postdoctoral Fellowship (16POST27770003). VB receives support from the NIH (1R01 DK091565).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Na+ transporters, electrolyte excretion and renal injury in female and male C57Bl/6 and IL17A−/− mice during AngII hypertension

Experimental AngII hypertension is reported to be blunted in female (F) vs. male (M) mice and in mice lacking the inflammatory cytokine IL17A (time point dependent). This study aimed to determine how sex impacts renal Na+ transporters, Na+ and K+ excretion, and markers of renal injury during AngII hypertension (A) in both C57Bl/6 (WT) and IL17A−/− (IL17−/−) mice.11–16 wk old F and M mice were infused with AngII (490 ng/kg/min) or sham treated for 3 wk (n=6/group). Rate of excretion of a saline load (10% b.wt. subcutaneous) was slowed in all AngII infused groups, indicating Na+ reabsorption activation. Blood pressure (BP), by tail cuff, increased similarly across groups (in Δ mmHg): WTMA: 40 ± 1.6, WTFA: 37 ± 10, IL17−/−MA: 37 ± 3.8, IL17−/−FA: 46.4 ± 4.7. Thus, no blunting of hypertension was detected at 3 wk time point by tail cuff in F or in IL17−/−.In both M and F WT and IL17−/−, AngII provoked activation (‐phosphorylation) of NKCC2 and NCC, and activation of ENaC (more ‐cleaved (Cl), less full length (FL)). These distal anti‐natriuretic responses were balanced by natriuretic responses including: decreased abundance of proximal NHE3, NaPi2, and decreased medullary thick ascending limb NHE3, NKCC2 and NaK‐ATPase (see Figure). We previously proposed that increased ‐NCCp is a secondary compensation, driven by AngII activation of ENaC, to minimize K+ secretion (PMID27600183). Providing further support for this idea, urinary Na/K ratio (UNa/K), collected overnight (during fasting +water), was significantly reduced by AngII (WTM: from 0.71 ± 0.1 at baseline to 0.41 ± 0.9 with AngII, WTF: 0.80 ± 0.1 to 0.28 ±0.05, IL17−/−M: 0.99 ±0.13 to 0.41 ± 0.041, IL17−/−F: 1.05 ± 0.07 to 0.46 ± 0.46). UNa/K fell due to decreased o/n UNa as o/n UK was unaltered by AngII. Urine volume (V), unaltered by AngII treatment, was 2‐fold higher in M vs. F of both genotypes, and 2‐fold higher in IL17−/− vs. WT within each sex.During AngII, the injury marker U albumin increased across groups. Renal cortical angiotensinogen was lower in IL17−/− vs. WT (by 50% in F and 25% in M). KIM1 also tended to be lower in IL17−/− vs. WT in both sexes during AngII.From these results, we propose: AngII stimulation of ENaC drives UK secretion which activates NCCp (more in WT than IL17−/− males), thus reducing UNa to limit K secretion and lowering UNa/K which may contribute to BP elevation. IL17−/− mice exhibit higher UV and lower intrarenal angiotensinogen and KIM1 which suggests less tissue injury.Support or Funding InformationAHA GIA (15GRNT23160003) and an NIH NIDDK R01 (DK083785) to A.A. McDonough, NIH NHLBI K08 award (HL121671), Gilead Cardiovascular Scholars Grant, and NIH DP2 award (HL137166) to M.S. MadhurThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.