Electrolyte Excretion Research Articles

A Study on Pharmacological Evaluation of Diuretic Activity of Tinospora cordifolia Stem Ethanolic Extract

This study aimed to assess the diuretic effects of Tinospora cordifolia stem ethanolic extract in Swiss Albino Rats. The administration of the higher dose (200 mg/kg) of the ethanolic extract derived from the stem part of Tinospora cordifolia resulted in a significant increase in diuresis during the 6th hour, with a measured output of 1.93 + 1.21ml, compared to the control group (0.38+ 0.12 ml). This effect was also compared to the reference standard, furosemide, which produced an output of 2.45 + 1.12ml (p < 0.05). Similarly, the higher dose (400 mg/kg) of Tinospora cordifolia stem extract demonstrated significant diuretic activity (2.70 + 1.15 ml) compared to the control group (1.14 + 0.09 ml) (p < 0.05). The increase in urine output was statistically significant (p < 0.01). The study also analysed the impact of furosemide (10 mg/kg) and Tinospora cordifolia extracts at doses of 200 mg/kg and 400 mg/kg on the excretion of electrolytes (Na+ and K+) in the 6-hour urine samples. The pH of the urine samples following treatment with Tinospora cordifolia stem extract at doses of 200 mg/kg and 400 mg/kg was measured to be 5.48 and 6.79, respectively. The results obtained in this study provide a quantitative basis for explaining the diuretic activity of Tinospora cordifolia. The extract displayed notable diuretic activity, thus supporting its traditional use as a diuretic in ethno-pharmacology. Further investigations, including phytochemical and pharmacodynamic studies, are necessary to identify the active constituents responsible for this activity and to understand the exact mechanism of the diuretic effect exhibited by the aqueous extract of Tinospora cordifolia.

Abstract P376: Collecting Duct Renin And Its Receptor Contributes To Unilateral Ureteral Obstruction-induced Kidney Injury Via Activation Of The Intrarenal Ras

The collecting duct (CD) is well known for its role in fine-tuning urinary excretion of electrolytes and water. Emerging evidence suggests a potential role played by the CD in immunity and renal injury but the underlying mechanism largely remains elusive. Within the CD, (pro)renin receptor (PRR) via site-1 protease (S1P)-derived soluble PRR interacts with renin controls the intrarenal renin-angiotensin system (RAS) to regulate Na+ and water balance and blood pressure. The present study attempted to employ mouse models of CD-specific deletion of PRR and renin (CD PRR KO and CD renin KO, respectively) and a specific S1P inhibitor PF-429242 (PF) to explore the pathogenic role of this local system in renal injury induced by unilateral ureteral obstruction (UUO). Male 3-4-month-old CD PRR KO and CD renin KO, and their respective floxed controls were subjected to UUO surgery or sham operation for 3 days, followed by analysis of renal fibrosis, inflammation, and indices of the intrarenal RAS. Male 3-4-month-old C57BL/6 mice were subjected to the same surgical procedures and infused with vehicle or PF at 20 mg/kg/day via minipump for 3 days, followed by analysis of the same parameters. 3-day UUO in floxed mice induced renal abundance of fibronectin and α-SMA by 8.6 folds and 5.8 folds, respectively, as assessed by immunoblotting analysis. qRT-PCR detected similar magnitude of increases in mRNA expression of fibronectin, α-SMA, as well as collagen III, collagen I, and TGF-β in the obstructed kidneys. Similar results were obtained by Trichrome Masson staining. In parallel, the obstructed kidney exhibited 4-5-fold increases in renal medullary renin mRNA, renin activity, and active renin content contrasting to unaltered renin levels in the renal cortex. CD-specific deletion of PRR and renin induced comparable attenuation of various indices of renal fibrosis, inflammation, renal medullary renin levels so did PF treatment. UUO induced a 2-fold increase in plasma sPRR, which was completely blocked by PF treatment. Taken together, our results demonstrated that CD PRR/sPRR-dependent activation of renin represents a key determinant of the intrarenal RAS and thus obstruction-induced renal inflammation and fibrosis.

Acute nitric oxide synthase inhibition induces greater increases in blood pressure in female versus male Wistar Kyoto rats.

Nitric oxide (NO) contributes to blood pressure (BP) regulation via its vasodilatory and anti-inflammatory properties. We and others previously reported sex differences in BP in normotensive and hypertensive rat models where females have lower BP than age-matched males. As females are known to have greater NO bioavailability than age-matched males, the current study was designed to test the hypothesis that anesthetized female normotensive Wistar Kyoto rats (WKY) are more responsive to acute NOS inhibition-induced increases in BP compared to male WKY. Twelve-week-old male and female WKY were randomized to infusion of the nonspecific NOS inhibitor NG -nitro-L-arginine methyl ester (L-NAME, 1 mg/kg/min) or selective NOS1 inhibition with vinyl-L-NIO (VNIO, 0.5 mg/kg/min) for 60 min. Mean arterial BP, glomerular filtration rate (GFR), urine volume, and electrolyte excretion were assessed before, and during L-NAME or VNIO infusion. L-NAME and VNIO significantly increased BP in both sexes; however, the increase in BP with L-NAME infusion was greater in females versus males compared to baseline BP values. Acute infusion of neither L-NAME nor VNIO for 60 min altered GFR in either sex. However, urine volume, sodium, chloride and potassium excretion levels increased comparably in male and female WKY with L-NAME and VNIO infusion. Our findings suggest sex differences in BP responses to acute non-isoform-specific NOS inhibition in WKY, with females being more responsive to L-NAME-induced elevations in BP relative to male WKY. However, sex differences in the BP response did not coincide with sex differences in renal hemodynamic responses to acute NOS inhibition.

Phytochemical Screening and Diuretic Activity of selected Palestinian Medicinal plants in Mice using an Aqueous Extract Division of Physiology, Pharmacology and Toxicology

Purpose: Man used various natural materials as a remedy for the treatment of various diseases and recently witnessed a vastly growing and renewed interest in herbal medicine globally. In Palestinian folk medicine, Crataegus aronia, Rosmarinus officinalis known as rosemary and Nigella sativa is used as a diuretic and for treatment of hypertension. This study aimed to assess the preliminary phytochemical properties and the diuretic effect of the aqueous extracts of these plants in mice after its intraperitonial administration.
 Methods: It is an experimental trial applied on mice (n=8, Male, CD-1, weight range: [25-30 gram]), which are divided into two groups (4 in each). The first group administered with the plant extract (500 mg/kg), and the second with normal saline as negative control group. Then urine output and electrolyte contents were quantified up to 6 hours for the three groups and then compared to the control one.
 Results: Preliminary phytochemical screening reveals the presence of tannins, alkaloids and flavoniods as major phytoconstituents in aqueous extract. Significant diuresis was noted in those received the aqueous extract of Crataegus aronia (p < 0.05) compared to controls. Moreover, aqueous extract had an acidic pH and a mild increase in the electrolyte excretion (Na, K).On the contrary, the aqueous extracts from the Rosemary and Nigella sativa showed no diuretic activity.
 Conclusions: Our results revealed that Crataegus aronia aqueous extract has a significant potential diuretic effect. Further studies are needed to evaluate this diuretic effect in the relief of diseases characterized by volume overload.

Kir7.1 knockdown and inhibition alter renal electrolyte handling but not the development of hypertension in Dahl salt-sensitive rats.

High K+ supplementation is correlated with a lower risk of the composite of death, major cardiovascular events, and ameliorated blood pressure, but the exact mechanisms have not been established. Inwardly rectifying K+ (Kir) channels expressed in the basolateral membrane of the distal nephron play an essential role in maintaining electrolyte homeostasis. Mutations in this channel family have been shown to result in strong disturbances in electrolyte homeostasis, among other symptoms. Kir7.1 is a member of the ATP-regulated subfamily of Kir channels. However, its role in renal ion transport and its effect on blood pressure have yet to be established. Our results indicate the localization of Kir7.1 to the basolateral membrane of aldosterone-sensitive distal nephron cells. To examine the physiological implications of Kir7.1, we generated a knockout of Kir7.1 (Kcnj13) in Dahl salt-sensitive (SS) rats and deployed chronic infusion of a specific Kir7.1 inhibitor, ML418, in the wild-type Dahl SS strain. Knockout of Kcnj13 (Kcnj13-/-) resulted in embryonic lethality. Heterozygous Kcnj13+/- rats revealed an increase in K+ excretion on a normal-salt diet but did not exhibit a difference in blood pressure development or plasma electrolytes after 3 wk of a high-salt diet. Wild-type Dahl SS rats exhibited increased renal Kir7.1 expression when dietary K+ was increased. K+ supplementation also demonstrated that Kcnj13+/- rats excreted more K+ on normal salt. The development of hypertension was not different when rats were challenged with high salt for 3 wk, although Kcnj13+/- rats excrete less Na+. Interestingly, chronic infusion of ML418 significantly increased Na+ and Cl- excretion after 14 days of high salt but did not alter salt-induced hypertension development. Here, we found that reduction of Kir7.1 function, either through genetic ablation or pharmacological inhibition, can influence renal electrolyte excretion but not to a sufficient degree to impact the development of SS hypertension.NEW & NOTEWORTHY To investigate the role of the Kir7.1 channel in salt-sensitive hypertension, its function was examined using complementary genetic and pharmacological approaches. The results revealed that although reducing Kir7.1 expression had some impact on maintaining K+ and Na+ balance, it did not lead to a significant change in the development or magnitude of salt-induced hypertension. Hence, it is probable that Kir7.1 works in conjunction with other basolateral K+ channels to fine-tune membrane potential.

Diuretics in neonatology: a narrative review and update.

Diuretics are medications that promote the excretion of water and electrolytes. They are primarily used in the management and treatment of states of inappropriate salt and water retention. Diuretics represent one of the most common classes of drugs administered to sick neonates, the more so in very low birth weight infants. Diuretic drugs, especially loop diuretics, are often administered in the neonatal intensive care unit as off-label medications. This is the case for a variety of clinical situations, in which an increase in sodium excretion is not the primary goal of treatment (transitory tachypnoea of the newborn at term, hyaline membrane disease, patent ductus arteriosus of preterm infants). Thiazides and furosemide are widely used to treat preterm infants with oxygen-dependent chronic lung disease, despite a lack of data on beneficial effect of long-term therapy on pulmonary function or clinical outcome. This article reviews the mechanism of action, indications, administration, posology, adverse effects and contraindications of diuretics in newborn infants. Based on the most recent information available in the literature, we will discuss data supporting (or questioning) the use of diuretic in specific neonatal diseases. Research priorities over this issue will be briefly presented.

Fractional excretion of electrolytes and neutrophil gelatinase-associated lipocalin as early biomarkers of acute kidney injury in dogs with acute pancreatitis.

To determine if fractional excretion of urinary electrolytes and neutrophil gelatinase-associated lipocalin could detect different degrees of kidney injury in dogs with naturally occurring acute pancreatitis. We included dogs with acute pancreatitis. Dogs with a history of kidney disease, urinary tract infection, dogs which received potentially nephrotoxic drugs and dogs managed with haemodialysis were excluded. Acute kidney injury was diagnosed if there was an acute onset of clinical signs, haemato-chemical results compatible with acute kidney injury. Students or staff-owned dogs were selected to build the healthy group. The study population was composed of 53 dogs: acute pancreatitis with AKI (n=15), acute pancreatitis alone (n=23), and healthy dogs (n=15). In dogs with acute pancreatitis and AKI, all the FEs of urine electrolytes were significantly higher than dogs with acute pancreatitis alone and healthy ones. Dogs with acute pancreatitis alone had higher uNGAL/uCr than healthy dogs (median 54 ng/mg vs. 0.1 ng/mg) and lower compared to AP-AKI patients (54 ng/mg vs 209 ng/mg). Some fractional excretion of electrolytes are increased acute kidney injury dogs, however their role in the early detection of renal injury in acute pancreatitis dogs remains doubtful. On the contrary, urinary neutrophil gelatinase-associated lipocalin had higher concentrations in dogs with acute pancreatitis with or without acute kidney injury compared to healthy controls, suggesting that it may be used as an early marker of renal tubular damage in acute pancreatitis dogs.

Chronic circadian disruption impairs cardiovascular rhythms and leads to kidney disease in mice

Shift workers have an increased risk of developing hypertension and reduced kidney function. Disruption of behavioral or environmental circadian rhythms increases cardiometabolic disease risk in humans and animals. We hypothesized that chronic circadian disruption (CCD) impairs cardiovascular rhythms and increases renal injury markers. Male C57BL/6J mice starting at 8-week of age were maintained under a normal light/dark cycle (12-h light, 12-h dark, control) or a CCD protocol (10-h light, 10-h dark, T20) with ad libitum food and water for 10 weeks. T20 mice gained significantly more body weight compared to control mice. Control mice showed a diurnal variation in food intake, while T20 mice had similar food intake during both light and dark phases with more food consumed in the light phase compared to control mice. Mean arterial pressure (MAP), heart rate (HR), and locomotor activity were measured by telemetry after 10 weeks of CCD. MAP between the light and dark periods was significantly different in control mice (12:12 LD), while T20 mice (10:10 LD) lacked diurnal variation (control 119±3 vs.101±2 mm Hg, dark vs. light, respectively, p<0.001; T20 114±13 vs.113±12 mm Hg, dark vs. light, respectively, p=0.86; n=3-4). Control mice showed a diurnal variation in HR, whereas T20 mice did not show a light-dark difference (Control- 584±11 vs. 511±4 bpm, dark vs. light, respectively, p=0.001; T20- 537±14 vs. 526±5 bpm, dark vs. light, respectively, p=0.48; n=3-4). Dark phase HR was significantly decreased in T20 mice (p=0.01, control vs. T20). Control mice had a light-dark difference in activity, while T20 mice lacked diurnal variation in activity with significantly higher activity during the light phase (p=0.04, control vs. T20). Mice were placed in metabolic cages for urine collection during the light (control: ZT0-12; T20: ZT0-10) and dark (control: ZT12-0; T20: ZT10-0) phases. Urinary excretion of renal tubular injury markers albumin, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) were measured (ELISA). Control mice had significantly higher albumin and NGAL excretion in dark vs. light phases, while T20 mice lacked a significant diurnal pattern with significantly elevated albumin and NGAL during the light phase compared to control mice (albumin: control 1.00±0.23 vs. 0.09±0.05 ug/hr dark vs. light, p=0.04, control light vs. T20 light, p=0.04; NGAL: control 1410±223 vs. 89±58 pg/hr dark vs. light, p=0.02, control light vs.T20 light, p=0.04, n=4-6). CCD also blunted the diurnal rhythm of KIM-1 excretion (light cycle, p=0.04, n=3-6). The diurnal variation in sodium and potassium excretion was also lost in T20 mice. These results indicate that CCD impairs cardiovascular rhythms as well as diurnal excretion of electrolytes and renal injury markers, which may increase risk for kidney disease. P01HL136267, AHA 856877 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Peculiarities of ionoregulatory renal function of rats in the dynamics of experimental diabetes mellitus development

Background. The purpose of the research was to study the peculiarities of ionoregulatory renal function in the dynamics of alloxan-induced experimental diabetes mellitus. Materials and methods. The experiments were carried out on 63 white non-linear mature male rats, 53 with experimental diabetes mellitus of varying duration induced by intraperitoneal administration of alloxan in a dose of 160 mg/kg of body weight, and 10 intact rats (control group). Ten, 20, 25, 30, 40 and 45 days after administration of the diabetogenic substance, the animals were withdrawn from the experiment. Ionoregulatory function of the kidneys was studied by means of the clearance method under condition of water induced 2-hour diuresis to determine the clearance of endogenous creatinine, glomerular filtration rate, sodium and potassium content in the urine and blood plasma. It was followed by calculation of the electrolyte excretion, intensity of their filtration, absolute and relative reabsorption, their proximal and distal tubular transport (including standardized by glomerular filtrate volume). Results. The ionoregulatory function of the kidneys in rats with alloxan-induced experimental diabetes is characterized by the intensification of natriuresis and kaliuresis at all stages of the experiment. An increase in the urinary sodium loss in the early stages of alloxan-induced experimental diabetes is primarily stipulated by glomerular hyperfiltration, followed by an enhancement of filtration sodium load to the nephron. The loss of proportionality between the filtered amount of sodium and its proximal reabsorption causes a decrease in the total reabsorption potential of the tubular segment of the nephron in the dynamics of alloxan-induced experimental diabetes. It is reflected primarily on the proximal tubules, and subsequently induces a functional weakening of the tubule-tubular connection and relative dysfunction of the distal segment of the nephron with subsequent inhibition of aldosterone-dependent regulatory mechanisms. Conclusions. The kaliuric reaction of the diabetic kidney may serve as one of the signs of decompensation of the renal blood flow autoregulation by tubuloglomerular feedback, which is an initiating factor for the dysfunction of the tubular apparatus of diabetic kidney.

MP10-03 INFLUENCE OF SGLT2 INHIBITORS ON 24-HOUR URINE PARAMETERS AMONG KIDNEY STONE PATIENTS IN THE MEDICARE POPULATION

You have accessJournal of UrologyCME1 Apr 2023MP10-03 INFLUENCE OF SGLT2 INHIBITORS ON 24-HOUR URINE PARAMETERS AMONG KIDNEY STONE PATIENTS IN THE MEDICARE POPULATION Joseph Crivelli, Ryan Hsi, Mary Oerline, John Asplin, Naim Maalouf, and John M Hollingsworth Joseph CrivelliJoseph Crivelli More articles by this author , Ryan HsiRyan Hsi More articles by this author , Mary OerlineMary Oerline More articles by this author , John AsplinJohn Asplin More articles by this author , Naim MaaloufNaim Maalouf More articles by this author , and John M HollingsworthJohn M Hollingsworth More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003225.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Sodium/glucose cotransporter 2 inhibitors (SGLT2is) are widely used for patients with type 2 diabetes. Recent epidemiologic studies have shown a reduction in stone events in diabetic patients treated with SGLT2is, but changes in urine chemistries that may account for this have not been identified. The purpose of this study was to evaluate the effect of SGLT2is on urine chemistry and supersaturation among patients with kidney stone disease. METHODS: From a Medicare-Litholink database (years 2010-2018), we identified patients who received two, 24-hour urine tests, of which the first was performed without SGLT2i use, and the second was collected during SGLT2i use. Patients were excluded if they started using alkali citrate, thiazide, or xanthine oxidase inhibitor between the two collections, and excluded if the creatinine excretions in the 2 collections differed by >30%. Bivariate comparisons using the t-test were compared between 24-hour urine variables with p<0.05 considered statistically significant. RESULTS: Among 30 patients identified, the cohort had mean±SD age 66.6±8.9 years, 80% were male, and all with Medicare Part A/B available information (n=24) had a baseline diagnosis of diabetes mellitus type 2. The SGLT2i used included canagliflozin (in 56.7%), dapagliflozin (20.0%), and empagliflozin (23.3%). The mean±SD time from the first to second collection was 18.5±17.4 months. Comparison of 24-hour parameters between the first collection (pre-SGLT2i) and the second collection (on SGLT2i) is shown in the Table 1. Notable findings include a trend to higher 24-hour urine volume by 0.38 L/day (p=0.065), and significantly lower urine pH (p=0.046), with non-significant changes in urine excretion rate of calcium, oxalate, citrate, uric acid, and phosphorus. This resulted in a significant reduction in urine supersaturation with respect to calcium phosphate (likely from combination of greater urine volume and slightly lower pH), but non-significant changes in SS calcium oxalate and uric acid. CONCLUSIONS: Chronic SGLT2i use is associated with a lower urine pH with non-significant changes in volume and the excretion of major stone-related electrolytes. Larger studies are needed to confirm these findings and explore the impact of SGLT2i on stone recurrence rate. Source of Funding: Supported by National Institutes of Health Grant 1R01DK121709 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e114 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Joseph Crivelli More articles by this author Ryan Hsi More articles by this author Mary Oerline More articles by this author John Asplin More articles by this author Naim Maalouf More articles by this author John M Hollingsworth More articles by this author Expand All Advertisement PDF downloadLoading ...

The Role of Macula Densa Nitric Oxide Synthase 1 Beta Splice Variant in Modulating Tubuloglomerular Feedback.

Abnormalities in renal electrolyte and water excretion may result in inappropriate salt and water retention, which facilitates the development and maintenance of hypertension, as well as acid-base and electrolyte disorders. A key mechanism by which the kidney regulates renal hemodynamics and electrolyte excretion is via tubuloglomerular feedback (TGF), an intrarenal negative feedback between tubules and arterioles. TGF is initiated by an increase of NaCl delivery at the macula densa cells. The increased NaCl activates luminal Na-K-2Cl cotransporter (NKCC2) of the macula densa cells, which leads to activation of several intracellular processes followed by the production of paracrine signals that ultimately result in a constriction of the afferent arteriole and a tonic inhibition of single nephron glomerular filtration rate. Neuronal nitric oxide (NOS1) is highly expressed in the macula densa. NOS1β is the major splice variant and accounts for most of NO generation by the macula densa, which inhibits TGF response. Macula densa NOS1β-mediated modulation of TGF responses plays an essential role in control of sodium excretion, volume and electrolyte hemostasis, and blood pressure. In this article, we describe the mechanisms that regulate macula densa-derived NO and their effect on TGF response in physiologic and pathologic conditions. © 2023 American Physiological Society. Compr Physiol 13:4215-4229, 2023.

Normonatremic Transient Renal Salt Wasting (TRSW) Is Not Rare in a Department of Internal Medicine.

We previously reported that for around 5% of patients hospitalized with hyponatremia, it was related to what is called "transient renal salt wasting" (TRSW). In the present study we ask whether TRSW can also be observed in patients without hyponatremia. In this observational retrospective study we analyze the urine solute excretion of 200 consecutive normonatremic patients with normal kidney function and admitted in our department over one year. Patients were selected for analyses of FE.K, UCa/UCr and FE.PO4 if FE.Na was higher than 2% (N &lt; 1.6%) before any treatment, and only if they were not taking diuretics. Eleven normonatremic patients presented with transient high FE.Na &gt; 2% on admission (2.9 ± 0.6% with a high FE.K of 28 ± 6.4%; a high UCa/UCr of 0.37 ± 0.13 and a high FE.PO4 of 23.2 ± 9.6%). All of these patients were elderly. Seven were female and four were male. Neurological disorders were observed in six patients (three strokes, one transient ischemic attack, one syncope and one epileptic attack). Heart problems were observed in three patients (all angina pectoris, two of which also had HBP). One patient presented with rectal bleeding with HBP, and another presented COPD with a pneumothorax. One patient with angina pectoris showed a transient relapse after four days of hospitalization (FE.Na 3.6%). The urine electrolyte excretion in these patients are similar to those observed after furosemide intake. Normonatremic TRSW is not a rare observation, particularly in patients with neurological or cardiac problems.

Effects of Low Dietary Cation and Anion Difference on Blood Gas, Renal Electrolyte, and Acid Excretions in Goats in Tropical Conditions.

Goats can suffer from intermittent heat stress in high ambient temperature (HTa) conditions, which causes sporadic respiratory hypocapnia. Obstructive urolithiasis is a common urological problem in goats. Sandy uroliths can be partially relieved by urine acidification with short-term ammonium chloride (NH4Cl) treatment. However, the outcome of urine acidification and the physiological responses to short-term NH4Cl supplementation under respiratory hypocapnia of HTa have rarely been reported. The present study investigated the effect of NH4Cl supplementation that produced a low dietary cation-anion different (l-DCAD) diet on acid-base balance and renal function under HTa conditions. The first experiment investigated the physiological responses to natural HTa to prove whether the peak HTa during the afternoon could induce HTa responses without a change in the plasma cortisol. The partial pressure of CO2 also tended to decrease during the afternoon. The second experiment examined the short-term effect of l-DCAD under HTa conditions. Although the blood pH was within the normal range, there was a clear acid-base response in the direction of metabolic acidosis. The major responses in renal function were an increase in tubular function and acid excretion. With a comparable level of creatinine clearance, the fractional excretions (FE) of chloride and calcium increased, and the FE of potassium decreased. Acid excretion increased significantly in the l-DCAD group. We conclude that under HTa conditions, the tubular excretion of electrolytes and acids was the major response to acid loading without changing the filtration rate. The l-DCAD formulation can be used to acidify urine effectively.

Effects of an intravenous infusion of diltiazem on glomerular filtration rate, electrolyte excretion, and urine output in healthy dogs.

Acute kidney injury (AKI) in dogs has a high case fatality rate. Diltiazem might improve renal function, but effect of intravenous infusion has not been adequately studied in dogs. To determine if an intravenous infusion of diltiazem improves renal function through changes in glomerular filtration rate (GFR), fractional excretion of sodium (FENa), and urine output (UOP) in healthy dogs. Ten healthy adult dogs. Prospective, unmasked, crossover study. Dogs were randomized to receive diltiazem (loading dose of 240 μg/kg followed by 6μg/kg/min for 300 min) or the same volume of 5% dextrose in water (D5W). The opposite treatment was given after a 7-day washout period. GFR and FENa were obtained at baseline and after infusion. UOP was measured starting 1hour before diltiazem administration. GFR did not significantly increase from baseline with diltiazem (before diltiazem median=2.371 mL/min/kg, range=1.605-4.359; after diltiazem median=2.305 mL/min/kg, range=1.629-4.387; median difference=0.080 mL/min/kg, 95% confidence interval [CI]=-0.417 to 0.757; P=.85), and there was no difference in D5W GFR before and after diltiazem (median=2.389 mL/min/kg, range=1.600-3.557; median difference=0.036 mL/min/kg, 95% CI=-0.241 to 1.112; P=.69). FENa did not increase from baseline after administration of diltiazem (median difference=0%, 95% CI=-0.1 to 0.1; P=.81), and there was no difference in D5W FENa (median difference=0.1%, 95% CI=-0.1 to 0.2; P=.26). UOP did not increase with diltiazem (P=.06). Intravenous administration of diltiazem does not improve markers of renal function in healthy dogs. Further studies are needed in dogs with AKI.

Difelikefalin, a peripherally restricted KOR (kappa opioid receptor) agonist, produces diuresis through a central KOR pathway

Difelikefalin is a peripherally restricted kappa opioid receptor (KOR) agonist that was recently approved by the FDA to treat pruritis in dialysis patients. Here, we investigated the cardiovascular and renal responses to difelikefalin, and using the KOR antagonist norbinaltorphimine (norBNI), examined whether any difelikefalin-induced changes in the renal excretion of water and/or electrolytes were mediated through a central or peripheral KOR pathway. The effects of norBNI pretreatment on nalfurafine, a KOR agonist that crosses the blood-brain barrier, were also examined. We hypothesized that difelikefalin would alter urine output differently than nalfurafine, given that KOR agonists produce diuresis via activating central KORs to inhibit vasopressin release. Following catheterization, conscious Sprague-Dawley rats were infused i.v. with isotonic saline and pretreated with norBNI centrally via an intracerebroventricular (ICV) cannula or peripherally via an intravenous catheter. After stabilization, difelikefalin or nalfurafine was administered i.v. and urine output, heart rate and mean arterial pressure (MAP) were recorded for 90 min. Difelikefalin produced a significant increase in urine output, and significant decrease in urinary sodium and potassium excretion, urine osmolality, and MAP. ICV norBNI pretreatment markedly attenuated the increase in urine output caused by difelikefalin and nalfurafine but did not inhibit the electrolyte effects. However, IV norBNI pretreatment prevented all responses to difelikefalin and nalfurafine. Together, these findings demonstrate that difelikefalin and nalfurafine utilize central KOR pathways to elicit diuresis and a decrease in MAP but enhance renal tubular electrolyte reabsorption through a peripheral KOR pathway, providing important insight into two clinically useful KOR agonists.

Diuretic activity of whole plant extract of Leptadenia pyrotechnic

In the Indian traditional medicine, Leptadenia pyrotechnica (Apocynaceae) whole plant is claimed to possess powerful diuretic activity. The aim of this study was to evaluate the diuretic potential of methanol extract of Leptadenia pyrotechnica (MELP) in male albino rats. Group I, Control (2% CMC saline solution, 10 ml/kg, b.w), Group II, serves as a standard drug furosemide (10 mg/kg b.w) and different concentrations of LP (100, 200 and 400 mg/kg b.w) were intraperitoneally administered (n = 3 per each treatment group) to hydrated rats and their urine output was monitored over a period of 5 h after drug administration. The diuretic responses with its electrolyte excretion potency of the extract were highly remarkable in comparison with control animals. The MELP at dose of 400 mg/kg shows a significant increase in volume of urine with increase in Na+ excretion accompanied by the excretion of K+ in dose dependent manner. This study suggests that the active component in L.P. had similar diuretic effect to that of furosemide. These results validate the traditional use of Leptadenia pyrotechnica as a diuretic agent.

Responses to Ang II (Angiotensin II), Salt Intake, and Lipopolysaccharide Reveal the Diverse Actions of TNF-α (Tumor Necrosis Factor-α) on Blood Pressure and Renal Function.

TNF-α (tumor necrosis factor-alpha) is the best known as a proinflammatory cytokine; yet, this cytokine also has important immunomodulatory and regulatory functions. As the effects of TNF-α on immune system function were being revealed, the spectrum of its activities appeared in conflict with each other before investigators defined the settings and mechanisms by which TNF-α contributed to both host defense and chronic inflammation. These effects reflect self-protective mechanisms that may become harmful when dysregulated. The paradigm of physiological and pathophysiological effects of TNF-α has since been uncovered in the lung, colon, and kidney where its role has been identified in pulmonary edema, electrolyte reabsorption, and blood pressure regulation, respectively. Recent studies on the prohypertensive and inflammatory effects of TNF-α in the cardiovascular system juxtaposed to those related to NaCl and blood pressure homeostasis, the response of the kidney to lipopolysaccharide, and protection against bacterial infections are helping define the mechanisms by which TNF-α modulates distinct functions within the kidney. This review discusses how production of TNF-α by renal epithelial cells may contribute to regulatory mechanisms that not only govern electrolyte excretion and blood pressure homeostasis but also maintain the appropriate local hypersalinity environment needed for optimizing the innate immune response to bacterial infections in the kidney. It is possible that the wide range of effects mediated by TNF-α may be related to severity of disease, amount of inflammation and TNF-α levels, and the specific cell types that produce this cytokine, areas that remain to be investigated further.

The antihypertensive and diuretic effect of crude root extract and saponins from Solanum sisymbriifolium Lam., in L-NAME-induced hypertension in rats

Ethnopharmacological relevanceSolanum sisymbriifolium Lam., is used in Paraguayan folk medicine claiming antihypertensive and diuretic properties. Aim of the studyThis study aimed to determine the influence of chronic oral administration of the crude root extract and saponins obtained from S. sisymbriifolium Lam., on the blood pressure of male and female rats with hypertension induced by L-NAME, and its consequences on diuresis, the body weight, blood glucose, and level of serum parameters of liver and kidney functionality. Materials and methodsWistar rats were randomly divided into seven male, and seven female groups (8 animals each), which received as 6-week pretreatment, 0.9% saline solution (two groups; 0.1mL/10 g of b.w.), L-arginine (100.0 mg/kg/day), enalapril (15.0 mg/kg/day), crude extract (CESs 100.0 mg/kg/day), and saponin purified fraction (1.0, and 10.0 mg/kg/day), and treated with L-NAME (20 mg/kg/day/i.p.) twice, 1, and 6 h after pre-treatment. The animals' body weight, glycemia, and blood pressure were recorded weekly, while serum, hepatic, renal, and histological parameters were analyzed at the end of 6-week of treatment. ResultsA protective effect of CESs (100.0 mg/kg/day), and saponins (1.0, and 10.0 mg/kg/day) against hypertension induced by L-NAME was verified in the systolic, diastolic, and mean blood pressure values, which were significantly lower than the positive L-NAME-hypertensive control group (male and female) at the end of the 6-week treatment. Also, pretreatment with enalapril (15.0 mg/kg/day) induced an efficient protective activity, which validates the method used. Likewise, the volume of urine, creatinine, uric acid, urea, and electrolyte excretion was enhanced at the end of 6-week of treatment in concordance with the reduction in serum level of the same parameters, compatible with the improvement of the diuretic activity. The glycemia, body weight, heart rate, and functional hepato-renal parameters were not modified after a 6-week of treatment, in comparison to the control group, indicating relatively acceptable harmless properties of CESs and saponins. Interestingly, the HDL level in females was increased in contrast to male rats by chronic saponins treatment when compared with the negative control group. ConclusionsIt can be concluded that either the increment in blood pressure (systolic, diastolic, and median) or cardiorenal remodeling effects in male and female rats submitted to L-NAME-induced hypertensive condition, were prevented and well-preserved without a significant variation during a period of 6-week of pretreatment with CESs and saponins pretreatments. Likewise, an important diuretic effect was revealed after this period of treatment.

Effect of quertine on electrolyte metabolism indicators in patients with urate nephrolithiasis comorbid with metabolic syndrome

The treatment of urate nephrolithiasis (UN) comorbid with metabolic syndrome (MS) is greatly interested in flavonoids, which are actively involved in purine, electrolyte, nitrogen, lipid, and carbohydrate metabolism. The aim of the study was to study the effect of quertine on electrolyte metabolism and excretion of stone-forming compounds in patients with UN comorbid with MS.The indicators of stone-forming compounds excretion were studied by the values of inorganic phosphorus, ionized calcium, magnesium, sodium, and potassium in blood serum and urine. Urine pH was determined by test indicator strips. Normalization of indicators of stone-forming compounds excretion under the influence of quertine, traditional therapy and drugs that correct metabolic processes, contributed to an increase of magnesium crystallization inhibitor in blood serum and urine. Besides, it is also important to increase daily diuresis and normalize urine pH, which contributed to the reduction of stone formation and recurrence of urolithiasis. It is important to prescribe quertine, traditional therapy and drugs that correct metabolic disorders, taking into account metabolic disorders, urinary pH and daily diuresis.

Jeremiah Stamler, MD (1919-2022).

Jeremiah Stamler, MD (1919-2022).