Sodium Balance Research Articles

Empagliflozin significantly prevents QTc prolongation due to amitriptyline intoxication via intracellular calcium regulation

Abstract Background Empagliflozin is a SGLT-2 inhibitor used in the treatment of Type 2 diabetes and has positive effects on cardiovascular outcomes. Amitriptyline can be used in many clinical indications but leads to cardiotoxicity by causing QT prolongation. Aim Our aim in the present study is to observe the effect of the concomitant use of amitriptyline and empagliflozin together, which have an effect on sodium and calcium balance in myocytes, on QTc by using ECG. Materials and methods Twenty-four male Wistar-Albino rats were randomized into four groups. The control group received only serum physiologic (1ml) via orogastric gavage (OG). The EMPA group received empagliflozin (10 mg/kg) via OG. The AMT group received amitriptyline (100 mg/kg) via OG. The AMT+EMPA group (n: 6) received amitriptyline and empagliflozin at same dose. Under anesthesia; QT and QTC intervals were measured at baseline, first, and second hours. Results The differences in QT and QTc values between the AMT group and control group were observed from the 1nd hour (Table 1, Figure 1). It was detected that the measurements of the control group were within normal limits. In the control group, QT was 77.33±9.02 ms at the basal, 73.50±2.26 ms at the 1st hour, 78.17±6.18 ms at the 2nd hour. QTc calculation was 165.42±18.34±10.5 ms at the basal, 166.63±17.92 msat the 1st hour, 184.65±12.86 ms at the 2nd hour. ECG findings of the EMPA group were within normal limits and similar to the control group (Table 1). The durations of QT interval and QTc calculations were found to be statistically longer in the AMT group than the control group at the 1st and 2nd hour (p≤0.001). Empagliflozin significantly ameliorated AMT-induced QT and QTc prolongation. The durations of QT interval were significantly lower at first (p<0,001) and 2nd hours (p<0.01) in the AMT+EMPA group compared to the AMT group. Moreover, QTc calculation was significantly lower in the AMT+EMP group than the AMT group at 1st and 2nd hour (P<0.01) (Table 1). Electrocardiographic comparisons of all groups for one second within the second hour can be seen in Figure 2. Conclusion In the present study, we have detected that empagliflozin significantly ameliorates amitriptyline induced QT prolongation. This effect is probably due to the opposite effects of these two agents in the intracellular calcium balance. It's known that; toxic dose of amitriptyline increases the amount of Sarcoplasmic Ca and the calcium permeability of Ryanodine channels, decreases SERCA-mediated Ca-reuptake by decreasing the calcium binding capacity of calsequestrin, and these leads QTc prolongation. It has been shown that empagliflozin increases Ca reuptake by causing a significant increase in SERCA activity, and decreases Ca sparks by causing inhibition of Ryanodine activity. With more clinical trials, the routine use of empagliflozin may be suggested to prevent QTc prolongation in the diabetic patients receiving amitriptyline. Funding Acknowledgement Type of funding sources: None. Table 1. QT, QTc durations and HR for groupsFigure 1. ECG traces – a: CON, b: EMPA, c: AMT, d: AMT+EMP

Evidence for local aldosterone synthesis in the large intestine of the mouse.

Aldosterone, the main physiological mineralocorticoid, regulates sodium and potassium balance in the distal convoluted tubule of the kidney. Aldosterone is synthesized from cholesterol in the adrenal cortex in a sequence of enzymatic steps. Recently however, several tissues or cells e.g. brain, heart, blood vessels, kidneys and adipocytes have been shown to possess capability to produce aldosterone locally, and there is some evidence that this occurs also in the intestine. Colon expresses mineralocorticoid receptors and is capable of synthesizing corticosterone, the second last intermediate on the route to aldosterone from cholesterol. Based on such reports and on our preliminary finding, we hypothesized that aldosterone could be synthesized locally in the intestine and therefore we measured the concentration of aldosterone as well as the protein and gene expression of aldosterone synthase (CYP11B2), an enzyme responsible on aldosterone synthesis, from the distal section of the gastrointestinal tract of 10-week-old Balb/c male mice. It is known that sodium deficiency regulates aldosterone synthesis in adrenal glands, therefore we fed the mice with low (0.01%), normal (0.2%) and high-sodium (1.6%) diets for 14 days. Here we report that, aldosterone was detected in colon and cecum samples. Measurable amounts of CYP11B2 protein were detected by Western blot and Elisa analysis from both intestinal tissues. We detected CYP11B2 gene expression from the large intestine along with immunohistochemical findings of CYP11B2 in colonic wall. Sodium depletion increased the aldosterone concentration in plasma compared to control and high-sodium groups as well as in the intestine compared to mice fed with the high-sodium diet. To summarize, this study further supports the presence of aldosterone and the enzyme needed to produce this mineralocorticoid in the murine large intestine.

Electrolytes, albumin and acid base equilibrium during laparoscopic surgery.

Surgery, causing inflammation, disrupts endothelial permeability leading to movement of fluids and albumin across the vascular barrier. Fluid therapy for restoring circulatory homeostasis may lead to positive fluid balance which has been shown to increase morbidity and mortality in surgical patients. The current investigation aims to describe physio-pathological changes in circulating albumin, fluid and electrolyte balance, and acid-base equilibrium in a cohort of patients undergoing laparoscopic surgery under general anesthesia. Single-center prospective observational study. Patients undergoing laparoscopic colorectal surgery were screened for eligibility. Before surgery, the baseline fasting conditions were homogenized. Hemoglobin, urinary and plasmatic were collected before surgery and then at pre-defined timepoints. Albumin/creatinine ratio was measured before and after surgery. Expected and actual circulating Sodium concentrations were compared according to a physiological theoretical model. Assessment and quantification of changes in major electrolytes, albumin and acid-base balance was defined as the primary outcome of the study. Thirty-eight patients were enrolled in the protocol. Patients had a positive electrolytes (Na+ 295 [244-375] mmol, Cl- 234 [195-295] mmol, K+ 16.8 [12.0-21.4] mmol) and fluid balance (2165 [1727-2728] mL). The positive fluid balance was associated with stable chloride (105 [103-107], end study vs. 103 [102-106] mmol/L, baseline, P not significant) and potassium (4.2 [3.8-4.4], end study vs. 4.1 [3.6-4.4] mmol/L, baseline, P not significant) levels, but sodium concentrations decreased over time (138 [137-140], end study vs. 139 [138-141] mmol/L, baseline, P<0.05). The albumin/creatinine ratio was higher at the end of surgery 134 [61-267] vs. 7 [4-14], P<0.001). Data from patients undergoing colorectal laparoscopic surgery showed a positive fluid balance, decreased circulating albumin and increased albuminuria. A positive sodium balance was not always associated with an increase in sodium plasma concentration.

Effects of Dried Aloe Vera Gel and Diclofenac on Sodium and Potassium Homeostasis: An Experimental Study on Hypertensive Rats

Background: Anti-inflammatory role of Aloe vera gel is well established. Diclofenac is extensively used for acute and chronic inflammation. The present study was conducted to compare dried Aloe vera gel and diclofenac effects on sodium and potassium balance in hypertensive rats.&#x0D; Material and Methods: This experimental study was conducted at Sargodha Medical College from May to November 2016. Twenty-four healthy male Sprague Dawley rats 7-8 weeks of age were included in study. Any unhealthy-looking rat was excluded from the study. Rats were equally and randomly divided into four groups Normal control (group A), Model control (group B), Aloe vera (group C) &amp; Diclofenac (group D). Hypertension was induced by a 20 % sucrose diet in all groups except group A in 8 weeks’ time. Group B, C &amp; D received distilled water and Aloe vera dried gel 400 mg/kg &amp; diclofenac powder 12 mg/kg body weight respectively orally between 8 to 10 weeks. Serum and urine analysis was performed for hematocrit, sodium, and potassium concentrations at zero, eight and ten weeks. Twenty-four-hour urinary sodium excretion was calculated. Data was analyzed using Graph Pad Prism version 6.&#x0D; Result: After 2-week administration of aloe vera and diclofenac powder, serum potassium significantly decreased in Group C (p &lt;0.001) while increased in Group B and D (p &lt;0.001) as compared to group A. Urinary sodium concentration and excretion increased significantly in Group C (p &lt;0.01) as compared to Group A whereas result of Group D was insignificant. No significant change in serum sodium and hematocrit of any group was observed.&#x0D; Conclusion: Aloe vera causes less sodium retention than diclofenac but decreases serum potassium contrary to the effect of diclofenac in hypertensive rats.

Total Body Sodium Balance in Chronic Kidney Disease

Excess sodium intake is a leading but modifiable risk factor for mortality, with implications on hypertension, inflammation, cardiovascular disease, and chronic kidney disease (CKD). This review will focus mainly on the limitations of current measurement methods of sodium balance particularly in patients with CKD who have complex sodium physiology. The suboptimal accuracy of sodium intake and excretion measurement is seemingly more marked with the evolving understanding of tissue (skin and muscle) sodium. Tissue sodium represents an extrarenal influence on sodium homeostasis with demonstrated clinical associations of hypertension and inflammation. Measurement of tissue sodium has been largely unexplored in patients with CKD. Development and adoption of more comprehensive and dynamic assessment of body sodium balance is needed to better understand sodium physiology in the human body and explore therapeutic strategies to improve the clinical outcomes in the CKD population.

Sodium alterations impair the prognosis of hospitalized patients with COVID-19 pneumonia.

ObjectiveDysnatremia is common in hospitalized patients, often worsening the prognosis in pneumopathies and critical illnesses. Information on coronavirus disease-19 (COVID-19)-related hyponatremia is partially conflicting, whereas data on hypernatremia in this context are scarce. We assessed, in a cohort of COVID-19 inpatients: the prevalence of sodium alterations at admission and throughout their hospitalization; their association with inflammation/organ damage indexes; their short-term prognostic impact.Study design and methods117 patients (81 males, 64 ± 13 years) hospitalized for COVID-19 between 1 March and 30 April 2020 were retrospectively followed-up for their first 21 days of stay by collecting all serum sodium measurements, basal CRP and serum lactate levels, maximum IL-6 and information on care setting, required ventilation, length of hospitalization, in-hospital death.ResultsAt admission, 26.5% patients had hyponatremia, and 6.8% had hypernatremia. During their hospitalization, 13.7% patients experienced both disorders ('mixed dysnatremia'). Lower sodium levels at admission were correlated with higher C reactive protein (CRP) (P = 0.039) and serum lactate levels (P = 0.019), but not interleukin-6 (IL-6). Hypernatremia and a wider sodium variability were associated with maximum required ventilation, need for ICU assistance and duration of the hospitalization. Mean estimated time to Intensive Care Unit (ICU) admission was 20 days shorter in patients exposed to sodium alterations at any time of their hospital course (log-rank test P = 0.032).ConclusionsSodium alterations frequently affect hospitalized COVID-19 patients. Hyponatremia could indicate pulmonary involvement, whereas hypernatremia is associated to prolonged hospitalization and the need for intensive care/mechanical ventilation, particularly when resulting from prior hyponatremia. Optimizing in-hospital sodium balance is crucial to improve patients’ prognosis.

Compensatory post-diuretic renal sodium reabsorption is not a dominant mechanism of diuretic resistance in acute heart failure.

In healthy volunteers, the kidney deploys compensatory post-diuretic sodium reabsorption (CPDSR) following loop diuretic-induced natriuresis, minimizing sodium excretion and producing a neutral sodium balance. CPDSR is extrapolated to non-euvolemic populations as a diuretic resistance mechanism; however, its importance in acute decompensated heart failure (ADHF) is unknown. Patients with ADHF in the Mechanisms of Diuretic Resistance cohort receiving intravenous loop diuretics (462 administrations in 285 patients) underwent supervised urine collections entailing an immediate pre-diuretic spot urine sample, then 6-h (diuretic-induced natriuresis period) and 18-h (post-diuretic period) urine collections. The average spot urine sodium concentration immediately prior to diuretic administration [median 15 h (13-17) after last diuretic] was 64 ± 33 mmol/L with only 4% of patients having low (<20 mmol/L) urine sodium consistent with CPDSR. Paradoxically, greater 6-h diuretic-induced natriuresis was associated with larger 18-h post-diuretic spontaneous natriuresis (r = 0.7, P < 0.001). Higher pre-diuretic urine sodium to creatinine ratio (r = 0.37, P < 0.001) was the strongest predictor of post-diuretic spontaneous natriuresis. In a subgroup of patients (n = 43) randomized to protocol-driven intensified diuretic therapies, the mean diuretic-induced natriuresis increased three-fold. In contrast to the substantial decrease in spontaneous natriuresis predicted by CPDSR, no change in post-diuretic spontaneous natriuresis was observed (P = 0.47). On a population level, CPDSR was not an important driver of diuretic resistance in hypervolemic ADHF. Contrary to CPDSR, a greater diuretic-induced natriuresis predicted a larger post-diuretic spontaneous natriuresis. Basal sodium avidity, rather than diuretic-induced CPDSR, appears to be the predominant determinate of both diuretic-induced and post-diuretic natriuresis in hypervolemic ADHF.

Role of Fluid and Sodium Retention in Experimental Ventilator-Induced Lung Injury.

Background: Ventilator-induced lung injury (VILI) via respiratory mechanics is deeply interwoven with hemodynamic, kidney and fluid/electrolyte changes. We aimed to assess the role of positive fluid balance in the framework of ventilation-induced lung injury.Methods:Post-hoc analysis of seventy-eight pigs invasively ventilated for 48 h with mechanical power ranging from 18 to 137 J/min and divided into two groups: high vs. low pleural pressure (10.0 ± 2.8 vs. 4.4 ± 1.5 cmH2O; p < 0.01). Respiratory mechanics, hemodynamics, fluid, sodium and osmotic balances, were assessed at 0, 6, 12, 24, 48 h. Sodium distribution between intracellular, extracellular and non-osmotic sodium storage compartments was estimated assuming osmotic equilibrium. Lung weight, wet-to-dry ratios of lung, kidney, liver, bowel and muscle were measured at the end of the experiment.Results: High pleural pressure group had significant higher cardiac output (2.96 ± 0.92 vs. 3.41 ± 1.68 L/min; p < 0.01), use of norepinephrine/epinephrine (1.76 ± 3.31 vs. 5.79 ± 9.69 mcg/kg; p < 0.01) and total fluid infusions (3.06 ± 2.32 vs. 4.04 ± 3.04 L; p < 0.01). This hemodynamic status was associated with significantly increased sodium and fluid retention (at 48 h, respectively, 601.3 ± 334.7 vs. 1073.2 ± 525.9 mmol, p < 0.01; and 2.99 ± 2.54 vs. 6.66 ± 3.87 L, p < 0.01). Ten percent of the infused sodium was stored in an osmotically inactive compartment. Increasing fluid and sodium retention was positively associated with lung-weight (R2 = 0.43, p < 0.01; R2 = 0.48, p < 0.01) and with wet-to-dry ratio of the lungs (R2 = 0.14, p < 0.01; R2 = 0.18, p < 0.01) and kidneys (R2 = 0.11, p = 0.02; R2 = 0.12, p = 0.01).Conclusion: Increased mechanical power and pleural pressures dictated an increase in hemodynamic support resulting in proportionally increased sodium and fluid retention and pulmonary edema.

The Effect of The Cucumber Consumption To The Level of Sodium Potassium in Mus Muscullus’s Urine Production

Cucumber (Cucumis sativus L.). was known for lowering blood pressure agents. Some researches show that Cucumber had a similar mechanism with a loop diuretic (Furosemide), exceeding sodium and potassium excretion. However, a part of Cucumber that gives a better effect on managing water and sodium balance remains unknown. This study was to explain the differences potential diuretic among parts of Cucumber (Cucumis sativus L.). This study was using a post-test only control group designed in animals. There were 44 male Mus musculus tested in this study. All of the animal testings was divided into 9 different treatment groups and 2 control groups. All Mus musculus got 1 mL methanol extract of Cucumber (Cucumis sativus L.) according to their group. The animal testing was put on metabolic cage to measure urine volume for 24 hours. The flesh and rind part of Cucumber (Cucumis sativus L.) showed a similar result with furosemide as diuretics agents. However, whole part of the fruit of Cucumber (Cucumis sativus L.) (flesh, rind, and seed) showed as natriuretic dan kaliuretic, Cucumber (Cucumis sativus L.) has a similar potential diuretic with Furosemide. Even in low concentrations of Cucumber extract, it led to having a potential diuretic, with natriuretic and kaliuretic effects in the whole part of the fruit. This could be suggested to people with chronic kidney diseases to prevent hyperkalemia.

Ovariectomy and high salt increase blood pressure and alter sodium transport proteins in peripheral blood mononuclear cells of adult Wistar rats.

What is the central question of this study? In a model of salt-sensitive hypertension in ovariectomized (oVx) adult Wistar rats, what is the expression of proteins related to sodium transport in peripheral blood mononuclear cells (PBMCs), and how does the response of proteins to high sodium intake compare with changes in blood pressure in intact female rats? What is the main finding and its importance? Sodium transport proteins in PBMCs react to high sodium and blood pressure markedly differently in oVx versus intact female rats. Protein expression shows sodium and pressure sensitivity. Renal immune cells increase in oVx under high salt. Hypertension is a worldwide public health problem. High sodium consumption is associated with hypertension, and hypertensive mechanisms involve immunity cells. Peripheral blood mononuclear cells (PBMCs) are endowed with proteins related to sodium transport. We studied their abundance in PBMCs from intact (IF) or ovariectomized (oVx) adult Wistar rats under normal (NS) or high (HS) salt intake. Ovariectomy was performed at 60days of life. At 145days, one group of IF and oVx rats received NS or HS intake for 5days. Another group of IF HS and oVx HS rats received hydralazine (HDZ) to reduce blood pressure (BP). Sodium balance and BP were recorded. Expression of Na+ ,K+ -ATPase (NKA), Na+ -K+ -2Cl- cotransporter 1 (NKCC1), serum/glucocorticoid-regulated kinase 1 (SGK1), dopamine D1 like receptor (D1DR), CD4+ and CD8+ were determined in PBMCs and CD45+ leukocytes in renal tissue. IF HS rats showed increased natriuresis and normal BP. NKA and CD4+ expression diminished in IF HS. Instead, oVx HS rats had sodium retention and high BP and increased the expression of NKA, NKCC1, D1DR, CD4+ and CD8+ in PBMCs. Renal CD45+ leukocytes increased in oVx HS rats. HDZ decreased BP in all rats. Upon HDZ treatment, NKA did not change, NKCC1 decreased in oVx HS rats, while SGK1 increased in both IF HS and oVx HS rats. Hormonal background determines BP response and the expression of proteins related to sodium transport in PBMCs and renal immune cells at HS intake. The analysis of NKA, NKCC1 and SGK1 expression in PBMCs differentiated salt-sensitivity from BP variations.

Chloride in Heart Failure Syndrome: Its Pathophysiologic Role and Therapeutic Implication.

Until recently, most studies of heart failure (HF) focused on body fluid dynamics through control of the sodium and water balance in the body. Chloride has remained largely ignored in the medical literature, and in clinical practice, chloride is generally considered as an afterthought to the better-known electrolytes of sodium and potassium. In recent years, however, the important role of chloride in the distribution of body fluid has emerged in the field of HF pathophysiology. Investigation of HF pathophysiology according to the dynamics of serum chloride is rational considering that chloride is an established key electrolyte for tubulo-glomerular feedback in the kidney and a possible regulatory electrolyte for body fluid distribution. The present review provides a historical overview of HF pathophysiology, followed by descriptions of the recent attention to the electrolyte chloride in the cardiovascular field, the known role of chloride in the human body, and recent new findings regarding the role of chloride leading to the proposed ‘chloride theory’ hypothesis in HF pathophysiology. Next, vascular and organ congestion in HF is discussed, and finally, a new classification and potential therapeutic strategy are proposed according to the ‘chloride theory’.

Specific disruption of calcineurin-signaling in the distal convoluted tubule impacts the transcriptome and proteome, and causes hypomagnesemia and metabolic acidosis

Adverse effects of calcineurin inhibitors (CNI), such as hypertension, hyperkalemia, acidosis, hypomagnesemia and hypercalciuria, have been linked to dysfunction of the distal convoluted tubule (DCT). To test this, we generated a mouse model with an inducible DCT-specific deletion of the calcineurin regulatory subunit B alpha (CnB1-KO). Three weeks after CnB1 deletion, these mice exhibited hypomagnesemia and acidosis, but no hypertension, hyperkalemia or hypercalciuria. Consistent with the hypomagnesemia, CnB1-KO mice showed a downregulation of proteins implicated in DCT magnesium transport, including TRPM6, CNNM2, SLC41A3 and parvalbumin but expression of calcium channel TRPV5 in the kidney was unchanged. The abundance of the chloride/bicarbonate exchanger pendrin was increased, likely explaining the acidosis. Plasma aldosterone levels, kidney renin expression, abundance of phosphorylated sodium chloride-cotransporter and abundance of the epithelial sodium channel were similar in control and CnB1-KO mice, consistent with a normal sodium balance. Long-term potassium homeostasis was maintained in CnB1-KO mice, but in-vivo and ex-vivo experiments indicated that CnB1 contributes to acute regulation of potassium balance and sodium chloride-cotransporter. Tacrolimus treatment of control and CnB1-KO mice demonstrated that CNI-related hypomagnesemia is linked to impaired calcineurin-signaling in DCT, while hypocalciuria and hyponatremia occur independently of CnB1 in DCT. Transcriptome and proteome analyses of isolated DCTs demonstrated that CnB1 deletion impacts the expression of several DCT-specific proteins and signaling pathways. Thus, our data support a critical role of calcineurin for DCT function and provide novel insights into the pathophysiology of CNI side effects and involved molecular players in the DCT.

Cannabinoid Receptor 1 Inhibition in Chronic Kidney Disease: A New Therapeutic Toolbox.

Chronic kidney disease (CKD) concerns millions of individuals worldwide, with few therapeutic strategies available to date. Recent evidence suggests that the endocannabinoid system (ECS) could be a new therapeutic target to prevent CKD. ECS combines receptors, cannabinoid receptor type 1 (CB1R) and type 2 (CB2R), and ligands. The most prominent receptor within the kidney is CB1R, its endogenous local ligands being anandamide and 2-arachidonoylglycerol. Therefore, the present review focuses on the therapeutic potential of CB1R and not CB2R. In the normal kidney, CB1R is expressed in many cell types, especially in the vasculature where it contributes to the regulation of renal hemodynamics. CB1R could also participate to water and sodium balance and to blood pressure regulation but its precise role remains to decipher. CB1R promotes renal fibrosis in both metabolic and non-metabolic nephropathies. In metabolic syndrome, obesity and diabetes, CB1R inhibition not only improves metabolic parameters, but also exerts a direct role in preventing renal fibrosis. In non-metabolic nephropathies, its inhibition reduces the development of renal fibrosis. There is a growing interest of the industry to develop new CB1R antagonists without central nervous side-effects. Experimental data on renal fibrosis are encouraging and some molecules are currently under early-stage clinical phases (phases I and IIa studies). In the present review, we will first describe the role of the endocannabinoid receptors, especially CB1R, in renal physiology. We will next explore the role of endocannabinoid receptors in both metabolic and non-metabolic CKD and renal fibrosis. Finally, we will discuss the therapeutic potential of CB1R inhibition using the new pharmacological approaches. Overall, the new pharmacological blockers of CB1R could provide an additional therapeutic toolbox in the management of CKD and renal fibrosis from both metabolic and non-metabolic origin.

Cardiorenal Systems Modeling: Left Ventricular Hypertrophy and Differential Effects of Antihypertensive Therapies on Hypertrophy Regression.

Cardiac and renal function are inextricably connected through both hemodynamic and neurohormonal mechanisms, and the interaction between these organ systems plays an important role in adaptive and pathophysiologic remodeling of the heart, as well as in the response to renally acting therapies. Insufficient understanding of the integrative function or dysfunction of these physiological systems has led to many examples of unexpected or incompletely understood clinical trial results. Mathematical models of heart and kidney physiology have long been used to better understand the function of these organs, but an integrated model of renal function and cardiac function and cardiac remodeling has not yet been published. Here we describe an integrated cardiorenal model that couples existing cardiac and renal models, and expands them to simulate cardiac remodeling in response to pressure and volume overload, as well as hypertrophy regression in response to angiotensin receptor blockers and beta-blockers. The model is able to reproduce different patterns of hypertrophy in response to pressure and volume overload. We show that increases in myocyte diameter are adaptive in pressure overload not only because it normalizes wall shear stress, as others have shown before, but also because it limits excess volume accumulation and further elevation of cardiac stresses by maintaining cardiac output and renal sodium and water balance. The model also reproduces the clinically observed larger LV mass reduction with angiotensin receptor blockers than with beta blockers. We further provide a mechanistic explanation for this difference by showing that heart rate lowering with beta blockers limits the reduction in peak systolic wall stress (a key signal for myocyte hypertrophy) relative to ARBs.

Sodium and ultrafiltration profiling in hemodialysis: A long-forgotten issue revisited.

Sodium and ultrafiltration profiling are method of dialysis in which dialysate sodium concentration and ultrafiltration rate are altered during the course of the dialysis session. Sodium and ultrafiltration profiling have been used, commonly simultaneously, to improve hemodynamic stability during hemodialysis. Sodium profiling is particularly effective in decreasing the incidence of intradialytic hypotension, while ultrafiltration profiling is suggested to decrease subclinical repeated end organ ischemia during dialysis. However, complications such as increased interdialytic weight gain and thirst due to sodium excess have prevented widespread use of sodium profiling. Evidence suggest that different sodium profiling techniques may lead to different clinical results, and preferring sodium balance neutral sodium profiling may mitigate adverse effects related to sodium overload. However, evidence is lacking on the long-term clinical outcomes of different sodium profiling methods. Optimal method of sodium profiling as well as the utility of sodium/ultrafiltration profiling in routine practice await further clinical investigation.

Maturational changes in sodium metabolism in periviable infants.

Sodium depletion results in impaired somatic growth. The sodium requirements of extremely preterm (periviable) infants early in life are not known. We therefore investigated sodium homeostasis in this population over the first 10 weeks following birth. This was a longitudinal, observational study of sodium intake and urine sodium excretion in a convenience cohort of 23 infants born at 22 0/7-23 6/7-week gestation. Sodium intake ranged from 5.2 ± 0.4 to a maximum of 7.9 ± 0.5 mEq/kg/day at 2 and 8 weeks of postnatal age, respectively, while urinary sodium loss was 7.7 ± 1.0 mEq/kg/day and 6.9 ± 0.7 mEq/kg/day at these time points. Sodium balance (sodium intake-urine sodium output) was first positive at 6 weeks of age, though a positive sodium balance exceeding 1.4 mEq/kg/day (i.e., a balance associated with weight gain of 30 g/day) was not observed until 10 weeks. Infants born at 22-23-week gestational age have a prolonged period of high urinary losses of sodium and negative sodium balance. Sodium intakes greater than those currently recommended by the American Academy of Pediatrics are needed to achieve a significant positive sodium balance in this population.

Potential Sex Differences in Blood Pressure and Sodium Excretion in Spironolactone‐Treated Mice Transitioning from a Normal Diet to a Salt‐Deficient Diet to a High‐Salt Diet

Mineralocorticoid receptor (MR) antagonism is a therapeutic approach that has beneficial effects for patients with heart failure and renal disease. Recent reports of sex differences with respect to MR antagonism could eventually lead to differential treatment of men and women with hypertension and cardiovascular disease. The purpose of this study was to investigate sex differences in blood pressure and sodium excretion in mice treated with the MR antagonist spironolactone. Intact male and female CD-1 mice, 5 – 7 weeks old, were purchased from ENVIGO, Inc. Mice were placed in metabolic cages for a 5-day baseline (BL) period consuming normal food with water. After BL, either a placebo (P) or spironolactone (Sp) pellet (25mg, 21-day release, Innovative Research of America) was implanted sc and mice consumed a salt-deficient (SD) diet (Teklad, TD90228) with water for seven days. After the SD period, mice consumed a high-salt (HS) diet of 4% NaCl with 1% saline for seven days. Groups included male-P (MP), male-Sp (MSp), female-P (FP), and FSp (n=6/group). Systolic blood pressure (SBP, mmHg) was measured daily via the tail-cuff technique. Sodium balance was measured daily via sodium intake – sodium excretion, which was determined by urine volume × urine sodium concentration. In male mice, SBP decreased in the SD period in both MP & MSp mice: (BL vs SD: 105.0 ± 1.1 vs 100.8 ± 1.2 p<0.005; 108.7 ± 2.0 vs 102.5 ± 1.8, p<0.01 respectively). In MP mice, SBP increased in the HS period (107.2 ± 1.9, p<0.02 compared to SD) whereas in MSp mice SBP was not different (98.3 ± 3.7, p<0.08 compared to SD). In female mice, SBP was not different between BL and SD periods in either FP or FSp mice: (BL vs SD: 97.5 ± 1.7 vs 96.2 ± 1.1; 98.8 ± 1.8 vs 100.6 ± 1.4, respectively). As in the males, SBP increased in FP mice in the HS period (104.2 ± 2.3, p<0.02 vs SD), but did not change in FSp mice (100.6 ± 2.3). Sodium excretion was significantly higher in FSp compared to FP mice in both the SD and HS periods whereas sodium excretion was not significantly different between MP and MSp mice in both SD and HS periods. In summary, consuming the SD diet for seven days lowered SBP in male mice but not in female mice. In transitioning from the SD to HS diets, SBP increased in the untreated male and female mice but remained stable in spironolactone-treated male and female mice. We conclude MR antagonism prevents HS-induced elevation in blood pressure. MR is a ubiquitous transcription factor and thus potential sex differences regarding in not only renal sodium handling but also other physiological mechanisms related to blood pressure need further investigation.

Гостра токсичність і діуретична активність похідних аміно-3-метилксантинів

A vital problem of the contemporary pharmacology lies in creation of safer and more efficient medicinal products. Regulation of sodium balance and water being one of the important homeostatic functions is essential for developing the methods of rational therapy through means of diuretics of renal function of kidneys. This work is aimed to study the dependence of acute toxicity and diuretic activity on chemical structure of the newly synthesized 7-substituted-8-amino-3-methylxanthines in experiments on rats. The acute toxicity of 7-(2-hydroxy-3-p-methoxyphenoxy) propyl-8-substituted theophylline has been studied on the intact white nonlinear mice weighing 20-24 LD50 and has been calculated according to the method of Korber. The study of the diuretic activity of the above-mentioned compounds has been carried out on white rats of Wistar line weighing 180-195g according to the method of Y.B. Berkhina. The gained outcome of research into the acute toxicity of 7-substituted-8-amino-3-methylxanthines (compounds 1-11) has shown that LD50 of the synthesized compounds is in the range from 290 to 835 mg/kg. The most toxic (LD50=290 mg/kg) compound is the 6th one: 3-methyl-7-(2-hydroxy-3-p-methoxyphenoxy-) propyl-8-n-butylaminoethyl. Substitution in the 8th position of the molecule of 7-substituted-8-amino-3-methylxanthines n-butylamine (compound 6) of radical with 4-benzylpiperazine-1-ilne (compound 11), p-ethoxyphenyl-amic (compound 10) N,N-diethylaminoethylamine (compound 4), 4-methylpiperazine-1- ilne (compound 1), N,N-diethylaminoethylamine (compound 3), N-methyl-N-benzylamine (compound 2), (pyrrolidine-1- ilne (compound 7), m-tolylamine (compound 9), β-hydroxyethylepiperazine-1- ilne (compound 8), (furil-2)methylamine (compound 5) causes a reduction of the acute toxicity of the aforesaid substances. Analysis of the diuretic activity research shows that derivatives of 7-substituted-8-amino-3-methylxanthines (compounds 1-11) increases excretion of urine in the range from 25.1% to 201.4% (p<0.05). The most signifying diuretic activity has been shown by the compound 5: 3-methyl-7-(2-hydroxy-3-p-methoxyphenoxy-) propyl-8-(furil-2)methylaminoxanthine, which in the dose of 41.8 mg/kg enhances the water diuresis for 201.4% (p<0.01). Introduction to the 8th position of the molecule of 7-substituted-8-amino-3-metylxanthines instead of furil-2-methylamine (compound 5) radical of m-tolylamine (compound 9), n-butylamine (compound 6) and p-ethoxyphenylamine (compound 10) fragments leads to a reduction in renal excretory function for 143.5%; 131.8% and 111%, accordingly. Hydrochlorothiazide in the dose of 25 mg/kg enhances the water diuresis for 90.1%. Thus, the most signifying diuretic effect is observed in the compound 5, which exceeds the effect of the hydrochlorothiazide for 111.3% (p<0.05) and has been selected for further study of the specific activity.

44. RELATIONSHIP BETWEEN HYPERTENSION AND HYPONATREMIA IN CORONAVIRUS DISEASE PATIENTS: A CROSS-SECTIONAL STUDY

Background : Hypertension has been presumed to be associated with the severity of coronavirus disease (COVID-19) related to angiotensin-converting enzyme 2 (ACE2). Besides, hyponatremia is the most common electrolyte disorder in COVID-19 patients and has been reported to be associated with increased mortality. Objective: This study aimed to evaluate the association between hypertension and hyponatremia in COVID-19 patients who were admitted to Wahidin Sudirohusodo General Hospital Mojokerto. Method: In this study, we cross-sectionally investigated COVID-19 patients who were admitted to Wahidin Sudirohusodo General Hospital Mojokerto between December 2020 and January 2021. According to medical records, we evaluated COVID-19 patients who have hypertension as comorbidities and hyponatremia from laboratory results. Result: There were 98 COVID-19 patients consisted of 50 men and 48 women included in this study. The mean number of patients’ age was 55.6 ± 12.4 years. The prevalence of hypertension among patients was 55.1%. The mean number of sodium level was 131.50 ± 11.29 mmol/L. There was a strong correlation between blood pressure and sodium balance disorders (p &lt; 0.002). Hypertension was associated with a nearly 5.5-fold increased risk of hyponatremia in COVID-19 patients (OR 5.06; 95% CI: 1.66–15.4; p &lt; 0.05). Conclusion: Hypertension comorbidity was associated with a higher risk of hyponatremia in COVID-19 patients.

NFAT5 Is Involved in GRP-Enhanced Secretion of GLP-1 by Sodium.

Gastrin, secreted by G-cells, and glucagon-like peptide-1 (GLP-1), secreted by L-cells, may participate in the regulation of sodium balance. We studied the effect of sodium in mice in vivo and mouse ileum and human L-cells, on GLP-1 secretion, and the role of NFAT5 and gastrin-releasing peptide receptor (GRPR) in this process. A high-sodium diet increases serum GLP-1 levels in mice. Increasing sodium concentration stimulates GLP-1 secretion from mouse ileum and L-cells. GRP enhances the high sodium-induced increase in GLP-1 secretion. High sodium increases cellular GLP-1 expression, while low and high sodium concentrations increase NFAT5 and GRPR expression. Silencing NFAT5 in L-cells abrogates the stimulatory effect of GRP on the high sodium-induced GLP-1 secretion and protein expression, and the sodium-induced increase in GRPR expression. GLP-1 and gastrin decrease the expression of Na+-K+/ATPase and increase the phosphorylation of sodium/hydrogen exchanger type 3 (NHE3) in human renal proximal tubule cells (hRPTCs). This study gives a new perspective on the mechanisms of GLP-1 secretion, especially that engendered by ingested sodium, and the ability of GLP-1, with gastrin, to decrease Na+-K+/ATPase expression and NHE3 function in hRPTCs. These results may contribute to the better utilization of current and future GLP-1-based drugs in the treatment of hypertension.