FIRE Stones: impact of forced diuresis on the residual fragment rate after flexible ureteroscopy for destruction of kidney stones with laser-protocol for a randomized controlled two-parallel group multicenter trial with blinding evaluation.

BACKGROUND: Lithiasis is a common and recurrent disease. Flexible ureteroscopy (fURS) is the cornerstone of laser treatment of kidney stones. Kidney stones destruction requires its laser pulverization into small fragments in order to remove them through the ureter or improve their spontaneous expulsion along the urinary tract. However, most of the time, all the micro-fragments and dust created cannot be extracted using our surgical tools and may stay intra-renally at the end of the procedure. Adjuvant treatments (such as forced diuresis, inversion or mechanical pressure) were previously described to improve the expulsion of stone fragments after extra-corporeal shock wave lithotripsy. Nevertheless, the impact of adjuvant treatment after fURS remains unclear and mainly theoretical. OBJECTIVE: The primary objective is to show that the injection of 40 mg of furosemide in slow intravenous during 10 min, after the procedure, increases the stone-free rate 3 months after a fURS for destruction of kidney stones with laser. METHODS/DESIGN: The study will be a two-parallel group randomized, controlled, multicentric trial with a blinding evaluation. Nine French departments of urology will participate. Patients will be randomized in 2 groups: the experimental group (injection of 40 mg of furosemide at the end of the surgery) and a control one (usual care). Patients will be followed up for 3 months (± 2 weeks) after the surgery. Then, we will perform a low dose abdomino-pelvic CT scan. The primary outcome is the stone-free rate at 3 months. A centralized review of the images will be performed by two specialized radiologists, in a blind and crossed way to allow a homogenization of the results. The secondary outcomes will include the rate of early post-operative urinary tract infection (UTI), the evaluation of post-operative pain, and the safety of the use of furosemide in patients treated by fURS for renal stone laser destruction. As secondary objectives, it is also planned to look at the effect of the prescription of an alpha-blocker as usual treatment on stone-free rate and to assess the agreement between the imaging analysis of the urologist and the specialized radiologist. DISCUSSION: Lithiasis is a public health problem. It affects about 10% of the general population. This prevalence is increasing (multiplied by 3 in 40 years), partly due to changes in the population's eating habits over the years. The lithiasis patient is a patient with a chronic disease requiring annual follow-up and who may suffer from multiple recurrences, with a recurrence rate at 5 years of 50%. Recurrences are partly due to residual fragments left in the kidneys at the end of the operation. Other risk factors for recurrence include dietary hygiene and the presence of an associated metabolic disease. The metabolic blood and urine tests recommended by the Association Française d'Urologie (AFU) can be used to manage these last two problems. As far as residual fragments are concerned, their presence leads to an early recurrence of stones because they form the bed for a new aggregation of crystals in the kidneys. Being able to reduce the rate of residual fragments in patients with the use of furosemide at the end of the intervention therefore seems essential in the management of recurrences in our patients. This will also improve our patients' quality of life. Indeed, lithiasis disease leads to chronic pain associated with acute pain that motivates consultations to the emergency for specialized management. This study is the first to evaluate the impact of forced diuresis with the use of furosemide on the stone-free rate after a fURS for destruction of kidney stone with laser. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05916963 , first received: 22 June 2023. EU Clinical Trials Register EudraCT Number: 2022-502890-40-00.

Assessment of the Diuretic Properties of Rice Bean Accessions Using a Mouse Model and Identification of Active Polyphenolic Compounds.

Rice bean [Vigna umbellata (Thunb.) Ohwi and Ohashi], an annual legume in the genus Vigna, is a promising crop suitable for cultivation in a changing climate to ensure food security. It is also a medicinal plant widely used in traditional Chinese medicine; however, little is known about the medicinal compounds in rice bean. In this study, we assessed the diuretic effect of rice bean extracts on mice as well as its relationship with the contents of eight secondary metabolites in seeds. Mice gavaged with rice bean extracts from yellow and black seeds had higher urinary output (5.44-5.47 g) and water intake (5.8-6.3 g) values than mice gavaged with rice bean extracts from red seeds. Correlation analyses revealed significant negative correlations between urine output and gallic acid (R = -0.70) and genistein (R = -0.75) concentrations, suggesting that these two polyphenols negatively regulate diuresis. There were no obvious relationships between mice diuresis-related indices (urine output, water intake, and weight loss) and rutin or catechin contents, although the concentrations of both of these polyphenols in rice bean seeds were higher than the concentrations of the other six secondary metabolites. Our study findings may be useful for future research on the diuretic effects of rice bean, but they should be confirmed on the basis of systematic medical trials.

Discovery of BMS-986308: A Renal Outer Medullary Potassium Channel Inhibitor for the Treatment of Heart Failure.

Recent literature reports highlight the importance of the renal outer medullary potassium (ROMK) channel in renal sodium and potassium homeostasis and emphasize the potential impact that ROMK inhibitors could have as a novel mechanism diuretic in heart failure patients. A series of piperazine-based ROMK inhibitors were designed and optimized to achieve excellent ROMK potency, hERG selectivity, and ADME properties, which led to the identification of compound 28 (BMS-986308). BMS-986308 demonstrated efficacy in the volume-loaded rat diuresis model as well as promising in vitro and in vivo profiles and was therefore advanced to clinical development.

Effects of sex and hydration status on kappa opioid receptor-mediated diuresis in rats.

Understanding the function of the kappa opioid receptor (KOP) is crucial for the development of novel therapeutic interventions that target KOP for the treatment of pain, stress-related disorders and other indications. Activation of KOP produces diuretic effects in rodents and man. Sex is a vital factor to consider when assessing drug response in pre-clinical and clinical studies. In this study, the diuretic effect of the KOP agonist, U50488 (1-10 mg/kg), was investigated in both adult female and male Wistar rats that were either normally hydrated or water-loaded. The KOP antagonist norbinaltorphimine (norBNI, 10 mg/kg) was administered 24 h prior to U50488 to confirm the involvement of KOP. U50488 elicited a significant diuretic response at doses ≥ 3 mg/kg in both female and male rats independent of hydration status. U50488 diuretic effects were inhibited by norBNI pre-administration. Water-loading reduced data variability for urine volume in males, but not in females, compared with normally hydrated rats. Sex differences were also evident in U50488 eliciting a significant increase in sodium and potassium ion excretion only in males. This may suggest different mechanisms of U50488 diuretic action in males where renal excretion mechanisms are directly affected more than in females.

Cannabinoid receptor type 1 activation causes a water diuresis by inducing an acute central diabetes insipidus in mice.

Cannabis and synthetic cannabinoid consumption are increasing worldwide. Cannabis contains numerous phytocannabinoids that act on the G protein-coupled cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 expressed throughout the body, including the kidney. Essentially every organ, including the kidney, produces endocannabinoids, which are endogenous ligands to these receptors. Cannabinoids acutely increase urine output in rodents and humans, thus potentially influencing total body water and electrolyte homeostasis. As the kidney collecting duct (CD) regulates total body water, acid/base, and electrolyte balance through specific functions of principal cells (PCs) and intercalated cells (ICs), we examined the cell-specific immunolocalization of CB1R in the mouse CD. Antibodies against either the C-terminus or N-terminus of CB1R consistently labeled aquaporin 2 (AQP2)-negative cells in the cortical and medullary CD and thus presumably ICs. Given the well-established role of ICs in urinary acidification, we used a clearance approach in mice that were acid loaded with 280 mM NH4Cl for 7 days and nonacid-loaded mice treated with the cannabinoid receptor agonist WIN55,212-2 (WIN) or a vehicle control. Although WIN had no effect on urinary acidification, these WIN-treated mice had less apical + subapical AQP2 expression in PCs compared with controls and developed acute diabetes insipidus associated with the excretion of large volumes of dilute urine. Mice maximally concentrated their urine when WIN and 1-desamino-8-d-arginine vasopressin [desmopressin (DDAVP)] were coadministered, consistent with central rather than nephrogenic diabetes insipidus. Although ICs express CB1R, the physiological role of CB1R in this cell type remains to be determined.NEW & NOTEWORTHY The CB1R agonist WIN55,212-2 induces central diabetes insipidus in mice. This research integrates existing knowledge regarding the diuretic effects of cannabinoids and the influence of CB1R on vasopressin secretion while adding new mechanistic insights about total body water homeostasis. Our findings provide a deeper understanding about the potential clinical impact of cannabinoids on human physiology and may help identify targets for novel therapeutics to treat water and electrolyte disorders such as hyponatremia and volume overload.

Predicting sex differences in the effects of diuretics in renal epithelial transport during angiotensin II-induced hypertension.

Chronic angiotensin II (ANG II) infusion is an experimental model that induces hypertension in rodents. The natriuresis, diuresis, and blood pressure responses differ between males and females. This is perhaps not unexpected, given the rodent kidney, which plays a key role in blood pressure regulation, exhibits marked sex differences. Under normotensive conditions, compared with males, the female rat nephron exhibits lower Na+/H+ exchanger 3 (NHE3) activity along the proximal tubule but higher Na+ transporter activities along the distal segments. ANG II infusion-induced hypertension induces a pressure natriuretic response that reduces NHE3 activity and shifts Na+ transport capacity downstream. The goals of this study were to apply a computational model of epithelial transport along a rat nephron 1) to understand how a 14-day ANG II infusion impacts segmental electrolyte transport in male and female rat nephrons and 2) to identify and explain any sex differences in the effects of loop diuretics, thiazide diuretics, and K+-sparing diuretics. Model simulations suggest that the NHE3 downregulation in the proximal tubule is a major contributor to natriuresis and diuresis in hypertension, with the effects stronger in males. All three diuretics are predicted to induce stronger natriuretic and diuretic effects under hypertension compared with normotension, with relative increases in sodium excretion higher in hypertensive females than in males. The stronger natriuretic responses can be explained by the downstream shift of Na+ transport load in hypertension and by the larger distal transport load in females, both of which limit the ability of the distal segments to further elevate their Na+ transport.NEW & NOTEWORTHY Sex differences in the prevalence of hypertension are found in human and animal models. The kidney, which regulates blood pressure, exhibits sex differences in morphology, hemodynamics, and membrane transporter distributions. This computational modeling study provides insights into how the sexually dimorphic responses to a 14-day angiotensin II infusion differentially impact segmental electrolyte transport in rats. Simulations of diuretic administration explain how the natriuretic and diuretic effects differ between normotension and hypertension and between the sexes.

Warming Yang Promoting Blood Circulation and Diuresis Alleviates Myocardial Damage by Inhibiting Collagen Fiber and Myocardial Fibrosis and Attenuating Mitochondria Signaling Pathway Mediated Apoptosis in Chronic Heart Failure Rats.

Warming Yang promoting blood circulation and diuresis (WYPBD) has been proven effective in treating some diseases. This study aimed to evaluate therapeutic effect of WYPBD in treating chronic heart failure (CHF). CHF rats were established by intraperitoneally injecting doxorubicin (DOX). Therapeutic effects of WYPBD on cardiac function and hemodynamic parameters of myocardial tissues were analyzed. Collagen fiber production and myocardial fibrosis were evaluated. Transcriptions of COL1A1 gene, COL3A1 gene, and TGFB1 gene were evaluated with RT-PCR. Expression of BNP, AVP, PARP, caspase-3, and Bcl-2 in myocardial tissues were evaluated. TUNEL assay was used to identify apoptosis of cardiomyocytes. WYPBD alleviated degree of myocardial hypertrophy in CHF rats compared to the rats in CHF model group (P < 0.05). WYPBD significantly improved cardiac hemodynamics (increased LVEF and LVSF) of CHF rats compared to rats in the CHF model group (P < 0.05). WYPBD protected myocardial structure and inhibited collagen fiber production in myocardial tissues of CHF rats. WYPBD markedly decreased myocardial fibrosis mediators (Col1α, Col3α, TGF-ß1) transcription in myocardial tissues of CHF rats compared to rats in CHF model group (P < 0.05). WYPBD significantly reduced BNP and AVP expression in myocardial tissues of CHF rats compared to rats in the CHF model group (P < 0.05). WYPBD markedly reduced the expression of PRAP and caspase-3, and increased Bcl-2 expression in myocardial tissues of CHF rats compared to rats in the CHF model group (P < 0.05). In conclusion, WYPBD alleviated CHF myocardial damage by inhibiting collagen fiber and myocardial fibrosis, attenuating apoptosis associated with the mitochondria signaling pathway of cardiomyocytes.

Role of Ang1-7 in renal haemodynamics and excretion in streptozotocin diabetic rats.

The contribution of angiotensin (1-7) (Ang1-7) to control of extrarenal and renal function may be modified in diabetes. We investigated the effects of Ang1-7 supplementation on blood pressure, renal circulation and intrarenal reactivity (IVR) to vasoactive agents in normoglycaemic (NG) and streptozotocin diabetic rats (DM). In Sprague Dawley DM and NG rats, 3 weeks after streptozotocin (60 mg/kg i.p.) or solvent injection, Ang1-7 was administered (400 ng/min) over the next 2 weeks using subcutaneously implanted osmotic minipumps. For a period of 5 weeks, blood pressure (BP), 24 h water intake and diuresis were determined weekly. In anaesthetised rats, BP, renal total and cortical (CBF), outer (OMBF) and inner medullary (IMBF) perfusion and urine excretion were determined. To check IVR, a short-time infusion of acetylcholine or norepinephrine was randomly given to the renal artery. Unexpectedly, BP did not differ between NG and DM, and this was not modified by Ang-1-7 supplementation. Baseline IMBF was higher in NG vs. DM, and Ang1-7 treatment did not change it in NG but decreased it in DM. In the latter, Ang1-7 increased cortical IVR to vasoconstrictor and vasodilator stimuli. IMBF decrease after high acetylcholine dose seen in untreated NG was reverted to an increase in Ang1-7 treated rats. Irrespective of the glycaemia level, Ang1-7 did not modify BP. However, it impaired medullary circulation in DM, whereas in NG it rendered the medullary vasculature more sensitive to vasodilators. Possibly, the medullary hypoperfusion in DM was mediated by Ang1-7 activation of angiotensin AT-1 receptors which are upregulated by hyperglycaemia.

Nalfurafine, a G-Protein-Biased KOR (Kappa Opioid Receptor) Agonist, Enhances the Diuretic Response and Limits Electrolyte Losses to Standard-of-Care Diuretics.

Nalfurafine is a G-protein-biased KOR (kappa opioid receptor) agonist that produces analgesia and lacks central nervous system adverse effects. Here, we examined the cardiovascular and renal responses to intravenous and oral nalfurafine alone and in combination with furosemide, hydrochlorothiazide, or amiloride. We hypothesized that nalfurafine, given its distinct mechanism of vasopressin inhibition, would increase urine output to these diuretics and limit electrolyte loss. Following catheterization, conscious Sprague-Dawley rats received an isotonic saline infusion and were then administered an intravenous bolus of nalfurafine, a diuretic, or a combination. Mean arterial pressure, heart rate, and urine output were recorded for 90 minutes. In another study, rats were placed in metabolic cages and administered drug in an oral volume load. Hourly urine samples were then collected for 5 hours. Intravenous and oral nalfurafine produced a marked diuresis, antinatriuresis, antikaliuresis, and a decrease in mean arterial pressure. Compared with diuretic treatment alone, intravenous coadministration with nalfurafine significantly increased urine output to furosemide and hydrochlorothiazide and decreased sodium and potassium excretion. Notably, mean arterial pressure was reduced with nalfurafine/diuretic combination therapy compared to diuretics alone. Similarly, oral coadministration of nalfurafine significantly increased urine output to hydrochlorothiazide and decreased sodium and potassium excretion, whereas combination with furosemide only limited the amount of sodium excreted. Further, both intravenous and oral coadministration of nalfurafine enhanced the diuresis to amiloride and decreased sodium excretion. Together, these findings demonstrate that nalfurafine enhances the diuresis to standard-of-care diuretics without causing an excessive loss of electrolytes, offering a new approach to treat several cardiovascular conditions.

Effect of Phytopreparations Based on Bioreactor-Grown Cell Biomass of Dioscorea deltoidea, Tribulus terrestris and Panax japonicus on Carbohydrate and Lipid Metabolism in Type 2 Diabetes Mellitus.

In the present study, we explored the therapeutic potential of bioreactor-grown cell cultures of the medicinal plant species Dioscorea deltoidea, Tribulus terrestris and Panax japonicus to treat carbohydrate metabolism disorders (CMDs) in laboratory rats. In the adrenaline model of hyperglycemia, aqueous suspensions of cell biomass pre-administered at a dose of 100 mg dry biomass/kg significantly reduced glucose level in animal blood 1-2.5 h (D. deltoidea and T. terrestris) or 1 h (P. japonicus) after adrenaline hydrochloride administration. In a streptozotocin-induced model of type 2 diabetes mellitus, the cell biomass of D. deltoidea and T. terrestris acted towards normalization of carbohydrate and lipid metabolism, as evidenced by a significant reduction of daily diuresis (by 39-57%), blood-glucose level (by 46-51%), blood content in urine (by 78-80%) and total cholesterol (25-36%) compared to animals without treatment. Bioactive secondary metabolites identified in the cell cultures and potentially responsible for their actions were deltoside, 25(S)-protodioscin and protodioscin in D. deltoidea; furostanol-type steroidal glycosides and quinic acid derivatives in T. terrestris; and ginsenosides and malonyl-ginsenosides in P. japonicus. These results evidenced for high potential of bioreactor-grown cell suspensions of these species for prevention and treatment of CMD, which requires further investigation.

FGF-23 (Fibroblast Growth Factor-23) and Cardiorenal Interactions.

BACKGROUND: Animal models implicate FGF-23 (fibroblast growth factor-23) as a direct contributor to adverse cardiorenal interactions such as sodium avidity, diuretic resistance, and neurohormonal activation, but this has not been conclusively demonstrated in humans. Therefore, we aimed to evaluate whether FGF-23 is associated with parameters of cardiorenal dysfunction in humans with heart failure, independent of confounding factors. METHODS: One hundred ninety-nine outpatients with heart failure undergoing diuretic treatment at the Yale Transitional Care Center were enrolled and underwent blood collection, and urine sampling before and after diuretics. RESULTS: FGF-23 was associated with several metrics of disease severity such as higher home loop diuretic dose and NT-proBNP (N-terminal pro-B-type natriuretic peptide), and lower estimated glomerular filtration rate, serum chloride, and serum albumin. Multivariable analysis demonstrated no statistically significant association between FGF-23 and sodium avidity measured by fractional excretion of sodium, or proximal or distal tubular sodium reabsorption, either before diuretic administration or at peak diuresis (P≥0.11 for all). Likewise, FGF-23 was not independently associated with parameters of diuretic resistance (diuretic excretion, cumulative urine and sodium output, and loop diuretic efficiency [P≥0.33 for all]) or neurohormonal activation (plasma or urine renin [P≥0.36 for all]). Moreover, the upper boundary of the 95% CI of all the partial correlations were ≤0.30, supporting the lack of meaningful correlations. FGF-23 was not associated with mortality in multivariable analysis (P=0.44). CONCLUSIONS: FGF-23 was not meaningfully associated with any cardiorenal parameter in patients with heart failure. While our methods cannot rule out a small effect, FGF-23 is unlikely to be a primary driver of cardiorenal interactions.

Contradiction between genetic analysis and diuretic loading test in type I Bartter syndrome: a case report.

BACKGROUND: In typical cases of Bartter syndrome (BS), assessing response to diuretics (furosemide and thiazide), hereinafter referred to as diuretic loading test, may be used to diagnose the type by detecting which part of the kidney tubule is not functioning correctly. However, the diuretic loading test may not always agree with the results of genetic analyses. CASE PRESENTATION: A 5-year-old boy was admitted due to lower extremity weakness and abnormal gait. He had a recurrent episode of muscle weakness and laboratory results showed severe hypokalemia. The direct genomic sequencing of the case revealed a new mutation in the SLC12A1 gene, which is associated with type I Bartter syndrome. Because there was the difference between the phenotype and genotype, we conducted a diuretic loading test to confirm the diagnosis. However, the results showed a clear increase in urine excretion of Na and Cl. These results were not consistent with typical type I BS, but consistent with the patient's phenotype. CONCLUSION: The diuretic loading test has limited utility for diagnosis especially in atypical cases. On the other hand, this test, which allows assessment of channel function, is useful for better understanding of the genotype-phenotype correlation.

Renal negative pressure treatment as a novel therapy for heart failure-induced renal dysfunction.

Congestion is the primary pathophysiological lesion in most heart failure (HF) hospitalizations. Renal congestion increases renal tubular pressure, reducing glomerular filtration rate (GFR) and diuresis. Because each nephron is a fluid-filled column, renal negative pressure therapy (rNPT) applied to the urinary collecting system should reduce tubular pressure, potentially improving kidney function. We evaluated the renal response to rNPT in congestive HF. Ten anesthetized ∼80-kg pigs underwent instrumentation with bilateral renal pelvic JuxtaFlow catheters. GFR was determined by iothalamate clearance (mGFR) and renal plasma flow (RPF) by para-aminohippurate clearance. Each animal served as its own control with randomization of left versus right kidney to -30 mmHg rNPT or no rNPT. mGFR and RPF were measured simultaneously from the rNPT and no rNPT kidney. Congestive HF was induced via cardiac tamponade maintaining central venous pressure at 20-22.5 mmHg throughout the experiment. Before HF induction, rNPT increased natriuresis, diuresis, and mGFR compared with the control kidney (P < 0.001 for all). Natriuresis, diuresis, and mGFR decreased following HF (P < 0.001 for all) but were higher in rNPT kidney versus control (P < 0.001 for all). RPF decreased during HF (P < 0.001) without significant differences between rNPT treatments. During HF, the rNPT kidney had similar diuresis and natriuresis (P > 0.5 for both) and higher fractional excretion of sodium (P = 0.001) compared with the non-rNPT kidney in the no HF period. In conclusion, rNPT resulted in significantly increased diuresis, natriuresis, and mGFR, with or without experimental HF. rNPT improved key renal parameters of the congested cardiorenal phenotype.

The Forgotten Antiproteinuric Properties of Diuretics.

BACKGROUND: Although diuretics are one of the most widely used drugs by nephrologists, their antiproteinuric properties are not generally taken into consideration. SUMMARY: Thiazide diuretics have been shown to reduce proteinuria by >35% in several prospective controlled studies, and these values are markedly increased when combined with a low-salt diet. Thiazide-like diuretics (indapamide and chlorthalidone) have shown similar effectiveness. The antiproteinuric effect of mineralocorticoid receptor antagonists (spironolactone, eplerenone, and finerenone) has been clearly established through prospective and controlled studies, and treatment with finerenone reduces the risk of chronic kidney disease progression in type-2 diabetic patients. The efficacy of other diuretics such as amiloride, triamterene, acetazolamide, or loop diuretics has been less explored, but different investigations suggest that they might share the same antiproteinuric properties of other diuretics that should be evaluated through controlled studies. Although the inclusion of sodium-glucose cotransporter-2 inhibitors (SGLT2i) among diuretics is a controversial issue, their renoprotective and cardioprotective properties, confirmed in various landmark trials, constitute a true revolution in the treatment of patients with kidney disease. Recent subanalyses of these trials have shown that the early antiproteinuric effect induced by SGLT2i predicts long-term preservation of kidney function. Key Message: Whether the early reduction in proteinuria induced by diuretics other than finerenone and SGLT2i, as summarized in this review, also translates into long-term renoprotection requires further prospective and observational studies. In any case, it is important for the clinician to be aware of the antiproteinuric properties of drugs so often used in daily clinical practice.

Tagetes erecta L. flowers, a medicinal plant traditionally used to promote diuresis, induced diuretic and natriuretic effects in normotensive and hypertensive rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Tagetes erecta L., known as marigold, belongs to the Asteraceae family and is mainly found in South America. Despite reports that T. erecta flowers are used in folk medicine to treat cardiovascular and renal diseases, there is no study regarding its diuretic effect. AIM: This study aimed to evaluate the chemical composition and the diuretic efficacy of the hydroethanolic extract from T. erecta (HETE) in normotensive (NTR) and hypertensive (SHR) rats. MATERIAL AND METHODS: The HETE was analyzed by liquid chromatography coupled to diode array detector and mass spectrometry (LC-DAD-MS). Female and male NTR and SHR received the treatment with vehicle, HETE (0.01 mg/kg, 0.1 mg/kg, and 1 mg/kg) or hydrochlorothiazide (HCTZ; 5 mg/kg) orally. The urinary parameters were measured at the end of the 8-h experiment. RESULTS: From HETE, saccharides and triterpenes were the main annotated compounds, such as erythrodiol and ß-amyrin. The urine volume was significantly increased in the groups treated with HETE, in both male and female NTR and SHR rats, compared to the respective vehicle-treated groups. Regarding electrolytes elimination, the treatment with HETE did not reveal significant changes in the urine levels of K+ or Cl-, but it showed a natriuretic and Ca2+-sparing effects. The HETE beneficial result in reducing Ca2+ excretion was confirmed through the protective effect found in front of the urinary calcium oxalate precipitation and crystallization. The combination with HCTZ, a classic diuretic and saluretic medicine, significantly enhanced HETE-induced diuresis, natriuresis, and the Ca2+-sparing effect. On the other hand, the K+-sparing action was improved in the combination of HETE with amiloride, a standard K+-sparing diuretic. In contrast, the combination of HETE with atropine (a non-selective muscarinic receptor antagonist) and indomethacin (an inhibitor of the cyclooxygenase enzyme), promoted an important reduction in urinary volume, but interestingly the natriuretic effect was maintained. CONCLUSION: This study contributed to the preclinical validation of the diuretic efficacy of T. erecta, highlighting this species as promising for the development of new pharmacological strategies for the management of kidney disorders.

Association study of fasting blood glucose and salt sensitivity of blood pressure in community population: The EpiSS study.

BACKGROUND AND AIMS: To evaluate the association between fasting blood glucose (FBG) and salt sensitivity of blood pressure (SSBP). METHODS AND RESULTS: This study is based on the baseline survey of systemic epidemiology of salt sensitivity study. Subjects were classified into salt sensitive (SS) and salt resistant groups according to blood pressure (BP) changes during the modified Sullivan's acute oral saline load and diuresis shrinkage test. Multivariate logistic and linear regression were used to evaluate associations between FBG with SS or BP changes. A total of 2051 participants were included in the analyses with 581 (28.33%) for SS. Multiple analysis showed that for every interquartile range increase in FBG, the OR (95%CI) for SS was 1.140 (1.069, 1.215), ß (95%CI) for mean arterial pressure change (ΔMAP1), systolic and diastolic BP changes during saline load were 0.421 (0.221, 0.622), 0.589 (0.263, 0.914) and 0.340 (0.149, 0.531), respectively. Compared to the lowest FBG quartile (Q1), the OR (95%CI) for SS in Q3 and Q4 were 1.342 (1.014, 1.776) and 1.577 (1.194, 2.084), respectively. Compared to subjects with normal FBG, the ß (95%CI) for ΔMAP1 was 0.973 (0.055, 1.891) in subjects with impaired FBG, and was 1.449 (0.602, 2.296) in patients with diabetes mellitus. Stratified analyses showed significant and stronger associations between FBG with SSBP in youngers, females, hypertensives, non-diabetics, non-current smokers and non-current drinkers. CONCLUSION: Our findings suggest FBG is an independent, dose-dependent associated factor for SSBP, and prevention of SS focusing on controlling FBG elevation in the early stage is important.

Effects of SGLT2 inhibitor ipragliflozin alone and combined with pioglitazone on fluid retention in type 2 diabetic mice with NASH.

Several antidiabetic agents, including thiazolidinediones and sodium-glucose cotransporter (SGLT) 2 inhibitors, attenuate the symptoms of nonalcoholic steatohepatitis (NASH). However, thiazolidinediones have serious side effects such as fluid retention and increased risk of congestive heart failure. We examined the effects of SGLT2 inhibitor ipragliflozin, pioglitazone, and ipragliflozin + pioglitazone on fluid retention in type 2 diabetic mice with NASH. Four-week repeated administration of pioglitazone caused significant increases in heart weight (31% increase in 30 mg/kg pioglitazone-treated group compared to vehicle-treated group) concomitant with fluid retention, as estimated by a decrease in plasma osmolality and increase in water intake/urine volume ratio. In addition, pioglitazone significantly increased (by 1.5 to 2-fold) mRNA expression of α, ß, and γ subtypes of ENaC and AQP2 and 3 subtypes in the renal medulla. Thus, pioglitazone-induced fluid retention may arise from enhanced reabsorption of sodium and water associated with increased expression of these channels in the kidney. In contrast, ipragliflozin alone did not induce these symptoms and did not affect ENaC or AQP expression. Combination treatment with ipragliflozin + pioglitazone attenuated these symptoms by ipragliflozin-induced osmotic diuresis. These findings demonstrate that treatment with ipragliflozin monotherapy or coadministered with pioglitazone may be a potential therapeutic option for the treatment of type 2 diabetes with NASH without fluid retention as a side effect.

1,3,5,6-tetrahydroxyxanthone promotes diuresis, renal protection and antiurolithic properties in normotensive and hypertensive rats.

OBJECTIVES: This study investigated the prolonged diuretic and renal effects of 1,3,5,6- tetrahydroxyxanthone (THX) in rats. METHODS: Normotensive (NTR) and hypertensive rats (SHR) received orally the treatment with THX, hydrochlorothiazide or vehicle (VEH). Urine volume, urinary, plasma and kidney parameters were evaluated daily or at the end of 7 days of the experiment. KEY FINDINGS: The urinary volume of both NTR and SHR were significantly augmented with the THX treatment, an effect associated with increased levels of urinary Na+ and K+, besides a Ca2+-sparing effect. As well, THX decreased the quantity of monohydrate crystals in urines from NTR and SHR when compared with VEH-group. Regarding the renal analyses, the glutathione levels and the activities of superoxide dismutase, glutathione S-transferase and myeloperoxidase in kidney homogenates of the SHR group were decreased. In contrast, the generation of lipid hydroperoxides (LOOH) and catalase activity was significantly increased. THX reduced the content of LOOH and increased nitrite levels in kidney homogenates obtained from SHR. Additionally, THX also augmented the levels of nitrite in the plasma from the SHR group. CONCLUSIONS: Therefore, THX can be highlighted as a natural diuretic agent with renal protective properties and antiurolithic action.

The Mechanism of the Solute-Free Water Reabsorption Increase in the Rat Kidney by Oxytocin Saluresis.

We found an experimental solution to the paradox when the reabsorption of solute-free water increases with a simultaneous increase in diuresis and saluresis in the rat kidney under the oxytocin action. Injection of oxytocin to rats (0.25 nmol/100 g of body weight) increases diuresis from 0.16 ± 0.03 to 0.26 ± 0.02 mL/h, the excretion of solutes from 134 ± 13.7 to 300 ± 16.3 µOsm/h, and the reabsorption of solute-free water, which correlates with the renal excretion of oxytocin (p < 0.001). The mechanism of the effect is that oxytocin decreases the reabsorption of ultrafiltrate in the proximal tubule (the clearance of lithium increases) and increases the fluid flow through the distal segment of the nephron. In vivarium rats, urine osmolality (1010 ± 137 mOsm/kg H2O) and the concentration of vasopressin are high, this causes an increase in the reabsorption of solute-free water. Thus, oxytocin increases saluresis, which, against the background of a high level of endogenous vasopressin, increases the water reabsorption in the collecting ducts.

Exploring the mechanisms of action of gliflozines in heart failure and possible implications in pulmonary hypertension.

Although results from two major trials trials have shown a clear benefit of gliflozines in the management of heart failure (HF) irrespective of diabetes status, the mechanism of cardiac benefits remains incompletely understood. Gliflozines have an osmotic diuretic effect that differs from that of other diuretic classes, resulting in greater electrolyte-free water clearance, and clinical studies have shown that intravascular volume depletion is rare and occurs at similar frequency in the gliflozines and placebo groups. As a consequence of the negligible effects on the blood volume and body's fluid balance compared to diuretics, gliflozines may limit the reflex neurohumoral stimulation and activation of renin-angiotensin-aldosterone system (RAAS). Since neurohormonal and RAAS activation in patients with HF reduced or ejection fraction (HFrEF and HFpEF) also leads to systemic and pulmonary arterial stiffening, pulmonary hypertension (PH) and PH-related right ventricular failure, gliflozines may lead to a mitigation of systemic and pulmonary arterial stiffening, which in turn can reduce the degree of PH associated with HFrEF or HFpEF, can improve the ventricular arterial coupling and can reduce the overload of the left and right ventricle, improving their function. The current review discusses the latest findings regarding the effects of SGLT2 inhibitors on heart failure with focus also on pulmonary hypertension, discussing the molecular mechanisms involved.