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.

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.

Organ protection by SGLT2 inhibitors: role of metabolic energy and water conservation.

Therapeutic inhibition of the sodium-glucose co-transporter 2 (SGLT2) leads to substantial loss of energy (in the form of glucose) and additional solutes (in the form of Na+ and its accompanying anions) in urine. However, despite the continuously elevated solute excretion, long-term osmotic diuresis does not occur in humans with SGLT2 inhibition. Rather, patients on SGLT2 inhibitor therapy adjust to the reduction in energy availability and conserve water. The metabolic adaptations that are induced by SGLT2 inhibition are similar to those observed in aestivation - an evolutionarily conserved survival strategy that enables physiological adaptation to energy and water shortage. Aestivators exploit amino acids from muscle to produce glucose and fatty acid fuels. This endogenous energy supply chain is coupled with nitrogen transfer for organic osmolyte production, which allows parallel water conservation. Moreover, this process is often accompanied by a reduction in metabolic rate. By comparing aestivation metabolism with the fuel switches that occur during therapeutic SGLT2 inhibition, we suggest that SGLT2 inhibitors induce aestivation-like metabolic patterns, which may contribute to the improvements in cardiac and renal function observed with this class of therapeutics.

Evaluation of diuretic efficacy and antiurolithiatic potential of ethanolic leaf extract of Annona squamosa Linn. in experimental animal models.

OBJECTIVE: The study is to investigate the diuretic and antiurolithiatic activities of ethanolic leaf extract of Annona squamosa Linn. in experimental animals. MATERIALS AND METHODS: For both studies, Wistar albino rats and two doses of extract (250 and 500 mg/kg) were used. Diuretic activity was evaluated by Lipschitz model. Urine volume and urine pH were noted, the concentration of sodium and potassium was estimated by flame photometry, and diuretic index, natriuretic index, and Lipschitz values were calculated from the results. Furosemide was used as a positive control. Ethylene glycol-induced urolithiasis model was used for antiurolithiatic study. Urine volume, urine pH, body weight, and biochemical parameters such as calcium, urea, uric acid, and creatine both from serum and urine were estimated. Antioxidant parameters and histopathological analysis of the kidney were evaluated. Cystone was used as a positive control in this study. Results were expressed as mean ± standard error of mean. Statistical analysis was carried out using one-way analysis of variance, followed by Dunnett's multiple comparison tests. RESULTS: In both diuretic and antiurolithiatic studies, both doses of the extract showed efficacy, and the dose of 500 mg/kg has shown a significant effect compared to positive control and negative control. CONCLUSION: The dose of 500 mg/kg showed a promising diuretic and antiurolithiatic activity.

Geniposide in Gardenia jasminoides var. radicans Makino modulates blood pressure via inhibiting WNK pathway mediated by the estrogen receptors.

OBJECTIVES: To investigate the effects of geniposide in an iridoid found in Gardenia jasminoides var. radicans Makino (GJRM) in spontaneous hypertensive rat (SHR) and explore the possible mechanisms. METHODS: In this study, we detected the content of geniposide in GJRM by high-performance liquid chromatography (HPLC). Then, we used acute diuretic experiments to determine whether geniposide has diuretic effect. Moreover, we carried out experiments on SHR to further study the mechanism of hypertension, while real-time PCR, Western blot and immunohistochemistry were used for the experiments in vivo test. Hypotonic model was used for in vitro test. KEY FINDINGS: Our data showed that the content of geniposide in the extract of GJRM is 27.54%. Meanwhile, 50 mg/kg geniposide showed the strongest effect on promoting urine volume. Further study indicated that the extract of GJRM and geniposide could significantly reduce blood pressure and promote the excretion of urine and Na+ in SHR. In addition, geniposide significantly inhibited the activation of the with-no-lysine kinase (WNK) signalling pathway and significantly increases the protein expressions of estrogen receptor α (ERα), estrogen receptor ß (ERß) and G protein-coupled receptor 30 (GPR30) in SHR. In hypotonic model, geniposide significantly inhibits the phosphorylation of NKCC and NCC and could be antagonistic to estrogen receptor antagonists. CONCLUSIONS: Collectively, we would suggest that geniposide may potentially be utilized as an adjunct to existing thiazide and thiazide-like diuretics to control hypertension, mainly through inhibiting the activation of the WNK signalling pathway mediated by the estrogen receptor.

TMAO, a seafood-derived molecule, produces diuresis and reduces mortality in heart failure rats.

Trimethylamine-oxide (TMAO) is present in seafood which is considered to be beneficial for health. Deep-water animals accumulate TMAO to protect proteins, such as lactate dehydrogenase (LDH), against hydrostatic pressure stress (HPS). We hypothesized that TMAO exerts beneficial effects on the circulatory system and protects cardiac LDH exposed to HPS produced by the contracting heart. Male, Sprague-Dawley and Spontaneously-Hypertensive-Heart-Failure (SHHF) rats were treated orally with either water (control) or TMAO. In vitro, LDH with or without TMAO was exposed to HPS and was evaluated using fluorescence correlation spectroscopy. TMAO-treated rats showed higher diuresis and natriuresis, lower arterial pressure and plasma NT-proBNP. Survival in SHHF-control was 66% vs 100% in SHHF-TMAO. In vitro, exposure of LDH to HPS with or without TMAO did not affect protein structure. In conclusion, TMAO reduced mortality in SHHF, which was associated with diuretic, natriuretic and hypotensive effects. HPS and TMAO did not affect LDH protein structure.

Heart failure is a common cause of death in industrialized countries with aging populations. Japan, however, has lower rates of heart failure and fewer deaths linked to this disease than the United States or Europe, despite having the highest proportion of elderly people in the world. Dietary differences between these regions may explain the lower rate of heart failure in Japan. The Japanese diet is rich in seafood, which contains nutrients that promote heart health, such as omega-3 fatty acids. Seafood also contains other compounds, including trimethylamine oxide (TMAO). Fish that live in deep waters undergo high pressures, which can damage their proteins, but TMAO seems to protect the proteins from harm. In humans, eating seafood increases TMAO levels in the blood and urine, but it is unclear what effects this has on heart health. Increased levels of TMAO in the blood are associated with cardiovascular diseases, but scientists are not sure whether TMAO itself harms the heart. A toxic byproduct of gut bacteria called TMA is converted in TMAO in the body, so it is possible that TMA rather than TMAO is to blame. To assess the effects of dietary TMAO on heart failure, Gawrys-Kopczynska et al. fed the compound to healthy rats and rats with heart failure for one year. TMAO had no effects on the healthy rats. Of the rats with heart failure that were fed TMAO, all of them survived the year, while one third of rats with heart failure that were not fed TMAO died. TMAO-treated rats with heart failure had lower blood pressure and urinated more than untreated rats with the condition. The experiments suggest that dietary TMAO may mimic the effects of heart failure treatments, which remove excess water and salt and lower pressure on the heart. More studies are needed to confirm whether TMAO has this same effect on humans.

Contribution of Monocarboxylate Transporter 6 to the Pharmacokinetics and Pharmacodynamics of Bumetanide in Mice.

Bumetanide, a sulfamyl loop diuretic, is used for the treatment of edema in association with congestive heart failure. Being a polar, anionic compound at physiologic pH, bumetanide uptake and efflux into different tissues is largely transporter-mediated. Of note, organic anion transporters (SLC22A) have been extensively studied in terms of their importance in transporting bumetanide to its primary site of action in the kidney. The contribution of one of the less-studied bumetanide transporters, monocarboxylate transporter 6 (MCT6; SLC16A5), to bumetanide pharmacokinetics (PK) and pharmacodynamics (PD) has yet to be characterized. The affinity of bumetanide for murine Mct6 was evaluated using Mct6-transfected Xenopus laevis oocytes. Furthermore, bumetanide was intravenously and orally administered to wild-type mice (Mct6+/+) and homozygous Mct6 knockout mice (Mct6-/-) to elucidate the contribution of Mct6 to bumetanide PK/PD in vivo. We demonstrated that murine Mct6 transports bumetanide at a similar affinity compared with human MCT6 (78 and 84 µM, respectively, at pH 7.4). After bumetanide administration, there were no significant differences in plasma PK. Additionally, diuresis was significantly decreased by ∼55% after intravenous bumetanide administration in Mct6-/- mice. Kidney cortex concentrations of bumetanide were decreased, suggesting decreased Mct6-mediated bumetanide transport to its site of action in the kidney. Overall, these results suggest that Mct6 does not play a major role in the plasma PK of bumetanide in mice; however, it significantly contributes to bumetanide's pharmacodynamics due to changes in kidney concentrations. SIGNIFICANCE STATEMENT: Previous evidence suggested that MCT6 transports bumetanide in vitro; however, no studies to date have evaluated the in vivo contribution of this transporter. In vitro studies indicated that mouse and human MCT6 transport bumetanide with similar affinities. Using Mct6 knockout mice, we demonstrated that murine Mct6 does not play a major role in the plasma pharmacokinetics of bumetanide; however, the pharmacodynamic effect of diuresis was attenuated in the knockout mice, likely because of the decreased bumetanide concentrations in the kidney.

[Clinical value of Canephron N after surgical treatment of urinary stone disease].

BACKGROUND: The drug Canephron N is a combination of extracts of centaury, lovage and rosemary. Moderate antispasmoic, anti-inflammatory, antioxidant, diuretic and antimicrobial effects are of great interest for urological practice. The optimal combination of components that were made of herbal medicine allows to use their synergistic effect for prevention of recurrence of urinary stone disease. The experience of using the drug Canephron in clinical practice is of great interest. AIM: to clarify the clinical efficiency of Canephron N in patients with urinary stone disease after surgical treatment and to evaluate the changes in diuresis and calcium excretion. MATERIALS AND METHODS: The results of using the drug Canephron after surgical treatment of urinary stone disease are provided. The changes in diuresis and calcium excretion in 75 patients undergone surgical treatment of urinary stone disease were studied. Patients after ureteroscopy, percutaneous nephrolithotomy and extracorporeal shock-wave lithotripsy were prescribed treatment to prevent stone formation including herbal drug Canephron N. RESULTS: At baseline, there was negative correlation between 24-hours diuresis and calcium excretion in all groups. During follow-up, a positive correlation between 24-hours diuresis and calcium excretion was found in patients receiving Canephron N and other types of treatment. The average follow-up was 390 days. During this period, recurrence was noted in 1 patient receiving Canephron, 4 patients in patients who took other drugs and in 5 patients who didnt receive any treatment. CONCLUSION: Risk factors of stone formation persist after surgical treatment of urinary stone disease. This is reflected in a negative correlation between 24-hour diuresis and calcium excretion. During treatment, a positive correlation between diuresis and calcium excretion was noted in patients with urinary stone disease. The use of drugs that affect stone formation as well as herbal medicine Canephron N allow to obtain comparable ratio of diuresis and calcium excretion.

Ethnopharmacological approaches to Talinum paniculatum (Jacq.) Gaertn. - Exploring cardiorenal effects from the Brazilian Cerrado.

ETHNOPHARMACOLOGICAL RELEVANCE: Talinum paniculatum (Jacq.) Gaertn. (Talinaceae), popularly known as "major gomes" and "erva gorda", is a non-conventional food plant extensively distributed throughout the Brazilian territory. In Brazilian folk medicine, this species is used as aphrodisiac, to treat gastrointestinal problems, and as a cardioprotective agent. However, there are no reports in the literature proving its cardiovascular effects. AIM: To perform a whole-ethnopharmacological investigation of the cardiorenal properties of the ethanol soluble fraction from T. paniculatum (ESTP) in Wistar rats. MATERIAL AND METHODS: First, plant samples were collected, properly identified and a morpho-anatomical characterization was carried out to provide quality control parameters. Then, ESTP was obtained and its chemical profile was determined by LC-DAD-MS. In addition, an acute toxicity assay was conducted in female Wistar rats in order to observe any toxic effects after one single administration. Finally, the diuretic and hypotensive potential of ESTP (30, 100 and 300 mg/kg) were investigated in male rats followed by the evaluation of its possible effects on peripheral vascular resistance. RESULTS: Chemical compounds identified from ESTP were chlorogenic acids, amino acids, nucleosides, O-glycosylated flavones and organic acids. No signs of toxicity as well as no changes in urine volume or electrolyte elimination were observed after ESTP acute treatment. On the other hand, prolonged treatment with all doses of ESTP significantly increased urine volume and electrolyte excretion (Na+, K+ and Cl-) without affecting blood pressure or heart rate. Apparently, these effects are involved with the activation of the small conductance calcium-activated potassium channels contributing to the increase of renal blood flow and glomerular filtration rate. CONCLUSION: Data presented show important information about the ethnomedicinal properties of T. paniculatum. In addition, the study presents the ESTP as a possible herbal medicine, especially when a sustained diuretic effect is required.

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

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

[NefroCAPS phytolysin in complex management of women with chronic recurrent cystitis].

RELEVANCE: Recurrent lower urinary tract infections (UTI) in women are one of the most challenging problems of modern urology, which is associated both with their high incidence and increasing resistance of uropathogens to antibacterial drugs. Due to this fact, the phytotherapy of infectious and inflammatory diseases of the urinary tract has received increased attention. AIM: To investigate the effectiveness of Phytolysin nefroCAPS in the complex management of women with chronic recurrent cystitis. MATERIALS AND METHODS: 50 women with chronic recurrent cystitis underwent a complex examination. They were divided into two groups depending on the treatment they received. Patients of the 1st group (n=27) received a combination therapy: fosfomycin (monural) 3 g (single dose) and Phytolysin nefroCAPS one capsule three times daily for three months. Patients of the 2nd group (n=23) were administered a single 3-g dose of fosfomycin (monural). RESULTS: Follow-up examinations were performed 1, 3 and six months after initiation of the treatment. In patients of the 1st group, clinical manifestations of the disease disappeared earlier, and they had fewer recurrences than the patients of the 2nd group. Also, bacteriological study of urine showed a more persistent antimicrobial effect among patients of the 1st group. CONCLUSION: In patients with chronic recurrent cystitis, plant-based preparation Phytolysin nefroCAPS administered concurrently with an antibacterial drug is more effective than antibiotic monotherapy.

Worsening Renal Function in Patients With Acute Heart Failure Undergoing Aggressive Diuresis Is Not Associated With Tubular Injury.

BACKGROUND: Worsening renal function (WRF) in the setting of aggressive diuresis for acute heart failure treatment may reflect renal tubular injury or simply indicate a hemodynamic or functional change in glomerular filtration. Well-validated tubular injury biomarkers, N-acetyl-ß-d-glucosaminidase, neutrophil gelatinase-associated lipocalin, and kidney injury molecule 1, are now available that can quantify the degree of renal tubular injury. The ROSE-AHF trial (Renal Optimization Strategies Evaluation-Acute Heart Failure) provides an experimental platform for the study of mechanisms of WRF during aggressive diuresis for acute heart failure because the ROSE-AHF protocol dictated high-dose loop diuretic therapy in all patients. We sought to determine whether tubular injury biomarkers are associated with WRF in the setting of aggressive diuresis and its association with prognosis. METHODS: Patients in the multicenter ROSE-AHF trial with baseline and 72-hour urine tubular injury biomarkers were analyzed (n=283). WRF was defined as a ≥20% decrease in glomerular filtration rate estimated with cystatin C. RESULTS: Consistent with protocol-driven aggressive dosing of loop diuretics, participants received a median 560 mg IV furosemide equivalents (interquartile range, 300-815 mg), which induced a urine output of 8425 mL (interquartile range, 6341-10 528 mL) over the 72-hour intervention period. Levels of N-acetyl-ß-d-glucosaminidase and kidney injury molecule 1 did not change with aggressive diuresis (both P>0.59), whereas levels of neutrophil gelatinase-associated lipocalin decreased slightly (-8.7 ng/mg; interquartile range, -169 to 35 ng/mg; P<0.001). WRF occurred in 21.2% of the population and was not associated with an increase in any marker of renal tubular injury: neutrophil gelatinase-associated lipocalin (P=0.21), N-acetyl-ß-d-glucosaminidase (P=0.46), or kidney injury molecule 1 (P=0.22). Increases in neutrophil gelatinase-associated lipocalin, N-acetyl-ß-d-glucosaminidase, and kidney injury molecule 1 were paradoxically associated with improved survival (adjusted hazard ratio, 0.80 per 10 percentile increase; 95% confidence interval, 0.69-0.91; P=0.001). CONCLUSIONS: Kidney tubular injury does not appear to have an association with WRF in the context of aggressive diuresis of patients with acute heart failure. These findings reinforce the notion that the small to moderate deteriorations in renal function commonly encountered with aggressive diuresis are dissimilar from traditional causes of acute kidney injury.

Divergent profile between hypothalamic and plasmatic aminopeptidase activities in WKY and SHR. Influence of beta-adrenergic blockade.

AIMS: Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) differ in their renin-angiotensin system function and sympathetic tone. The metabolism of angiotensins and vasopressin depends on the action of certain aminopeptidases whose activity may be influenced by the autonomic nervous system. Their regulation may differ between WKY and SHR in hypothalamus and plasma according to the sympathetic tone. We analyzed aminopeptidases responsible for the hydrolysis of certain angiotensins, vasopressin, cholecystokinin or enkephalins in hypothalamus and plasma of WKY and SHR in untreated controls rats and under beta-adrenoceptor blockade. Systolic blood pressure, food intake, water intake and diuresis were measured as parameters modulated by the autonomic nervous system and the above mentioned peptides. MAIN METHODS: Glutamyl-, aspartyl-, cystinyl- and alanyl-aminopeptidase activities were analyzed fluorimetrically in plasma and hypothalamus of control and propranolol-treated (100mg/kg/day administered in drinking water for 1month) WKY and SHR, using arylamide derivatives as substrates. KEY FINDINGS: An opposite response of aminopeptidases to propranolol treatment between plasma and hypothalamus was observed in either WKY and SHR. Furthermore, the behavior of aminopeptidases was inversed between WKY and SHR either in hypothalamus and plasma: while the activity increased in hypothalamus and decreased in plasma of WKY, it decreased in hypothalamus and increased in plasma of SHR. SIGNIFICANCE: These results revealed an inverse response of aminopeptidases between hypothalamus and plasma and also an opposite behavior of these enzymes between WKY and SHR in hypothalamus and plasma. These observations support the involvement of the sympathetic system in the modulation of aminopeptidase activities.

Phytochemical and biological assessments on Lipidium meyenii (maca) and Epimidium sagittatum (horny goat weed).

The effects of Lipidium meyenii (maca, LM) and Epimidium sagittatum (horny goat weed, ES) have been investigated due to their involvement in fertilization. Both of the drugs showed good results before, during and after fertilization in male and female mice. The results revealed that the crude extract of Lipidium meyenii caused a significant decrease in the no. of writhes at 300 and 500mg/kg (p<0.05) as compare to control, Epimidium sagittatum and standard drug. The gross behavioral, open field, exploratory behaviour, forced swimming test for stress, diuretic activity, chronic toxicity with the effect on reproduction of both male and female and change in body weight were also studied. The phytochemical study showed the presence of tannin, alkaloid, carbohydrate, rich protein and absence of sterol in LM, whereas ES shows presence of sterol and less protein. LS improve in muscle activity and exploratory behaviours without any toxic effects on mice and their pups. It does not have diuretic effect for first two hour but act normally after initial phase of drug therapy. Epimidium sagittatum has dual action that is at low dose it has slight stimulation action and at high dose little depressive effect. ES also has some diuretic effect. Overall these results suggest that LM is highly effective remedy for treatment of impotency and reduces stress and depression, because of dual effect ES not only suggested as an anxiolytic medicine but also effective in female hormonal disorder.

Intravenous Chlorothiazide Versus Enteral Metolazone to Augment Loop Diuretic Therapy in the Intensive Care Unit.

BACKGROUND: In cases of loop diuretic resistance in the intensive care unit (ICU), recommendations for a specific second-line thiazide agent are lacking. OBJECTIVE: To compare the effects of intravenous chlorothiazide (CTZ) and enteral metolazone (MET) on urine output (UOP) when added to furosemide monotherapy therapy in critically ill adults. METHODS: This was a retrospective cohort study conducted in the medical, surgical, and cardiothoracic ICUs of a quaternary medical center. The primary outcome was change in UOP induced by the study interventions compared with furosemide alone. Secondary outcomes included onset of diuresis, eventual need for hemodialysis, and incidence of adverse events. RESULTS: A total of 122 patients (58 in CTZ, 64 in MET) were included. When added to furosemide monotherapy, CTZ induced a greater change in UOP at 24 hours compared with MET (2405 vs 1646 mL, respectively; P = 0.01). CTZ also caused a more rapid dieresis: 1463 mL total UOP in the first 6 hours compared with 796 mL in the MET group ( P < 0.01). There were no differences found regarding ICU length of stay, need for renal replacement therapy, or survival to discharge. The CTZ arm required more potassium supplementation to maintain normokalemia (median 100 vs 57 mEq in MET; P = 0.02) and carried a higher cost (mean $97 vs $8, P < 0.01). CONCLUSION: Both CTZ and MET induced significant increases in UOP. CTZ induced a greater and more rapid change and was associated with higher cost and greater need for potassium replacement. Randomized controlled trials are needed to establish whether a preferable thiazide diuretic exists in this setting.

Neural Substrate Essential for Suppression of Vasopressin Secretion and Excretion of a Water Load.

Suppression of vasopressin secretion to very low levels is essential for the excretion of excess water. To investigate a role for the preoptic brain region in the suppression of vasopressin secretion and the excretion of a water load, lesions were made in the vicinity of the lamina terminalis in ewes (LTX-sheep) and responses to water-loading or reduction of cerebrospinal fluid NaCl by i.c.v. isotonic mannitol solution were investigated. In normal conscious sheep, intraruminal water-loading resulted in the urine flow rate increasing and urine osmolality decreasing within 1 h, such that renal free water clearance (CH 2O ) increased from -1.02 ± 0.16 ml/min (mean ± SEM) to a maximum of +4.99 ± 0.62 ml/min at 2.5 h after water-loading (P < 0.05, n = 6). Plasma vasopressin levels fell from 0.88 ± 0.17 pg/ml to undetectable levels (< 0.4 pg/ml, n = 4). In LTX-sheep (n = 6), CH 2O did not change significantly after water-loading (-1.78 ± 0.13 to -2.03 ± 0.49 ml/min at 2.5 h after water-loading). Plasma vasopressin levels were inappropriately elevated in water-loaded LTX-sheep (n = 3). Intracerebroventricular mannitol (1 ml/h for 2 h) resulted in a water diuresis and increase in CH 2O (-1.16 ± 0.12 to +2.81 ± 0.58 ml/min, P < 0.05) after 2 h in normal sheep, and plasma vasopressin levels fell significantly from to 0.88 ± 0.23 pg/ml to < 0.4 pg/ml (P < 0.05, n = 6). However, in LTX-sheep, there was no change in CH 2O (-1.31 ± 0.14 to -1.35 ± 0.12 ml/min) or the plasma vasopressin concentration (1.47 ± 0.18 to 1.60 ± 0.44 pg/ml, not significant) with i.c.v. mannitol. The results suggest that an inhibitory pathway from the vicinity of the median preoptic nucleus to the supraoptic and hypothalamic paraventricular nuclei plays an important role in the suppression of vasopressin secretion and the excretion of excess water.

[Effect of Zhuangyao Jianshen Wan (ZYJCW) on P2X1 and P2X3 mRNA expressions in rats with diuresis caused by kidney deficiency].

To investigate the urination-reducing effect and mechanism of Zhuangyao Jianshen Wan (ZYJCW). In this study, SI rats were subcutaneously injected with 150 mg · kg(-1) dose of D-galactose to prepare the sub-acute aging model and randomly divided into the model group, the Suoquan Wan group (1.17 g · kg(-1) · d(-1)), and ZYJCW high, medium and low dose groups (2.39, 1.20, 0.60 g · kg(-1) · d(-1)) , with normal rats in the blank group. They were continuously administered with drugs for eight weeks. The metabolic cage method was adopted to measure the 24 h urine volume and 5 h water load urine volume in rats. The automatic biochemistry analyzer was adopted to detect urine concentrations of Na+, Cl-, K+. The ELISA method was used to determine serum aldosterone (ALD) and antidiuretic hormone (ADH). The changes in P2X1 and P2X3 mRNA expressions in bladder tissues of rats were detected by RT-PCR. According to the results, both ZYJCW high and medium dose groups showed significant down-regulations in 24 h urine volume and 5 h water load urine volume in (P <0.05, P <0.01), declines in Na+ and Cl- concentrations in urine (P <0.01), notable rises in plasma ALD and ADH contents (P <0.05, P <0.01) and remarkable down-regulations in the P2X1 and P2X3 mRNA expressions in bladder tissues (P <0.01). The ZYJCW low dose group revealed obvious reductions in Na+ and Cl- concentrations in urine (P <0.01). The results indicated that ZYJCW may show the urination-reducing effect by down-regulating the P2X1 and P2X3 mRNA expressions in bladder tissues of rats with diuresis caused by kidney deficiency.

The ethanol metabolite acetaldehyde induces water and salt intake via two distinct pathways in the central nervous system of rats.

The sensation of thirst experienced after heavy alcohol drinking is widely regarded as a consequence of ethanol (EtOH)-induced diuresis, but EtOH in high doses actually induces anti-diuresis. The present study was designed to investigate the introduction mechanism of water and salt intake after heavy alcohol drinking, focusing on action of acetaldehyde, a metabolite of EtOH and a toxic substance, using rats. The aldehyde dehydrogenase (ALDH) inhibitor cyanamide was used to mimic the effect of prolonged acetaldehyde exposure because acetaldehyde is quickly degraded by ALDH. Systemic administration of a high-dose of EtOH at 2.5 g/kg induced water and salt intake with anti-diuresis. Cyanamide enhanced the fluid intake following EtOH and acetaldehyde administration. Systemic administration of acetaldehyde with cyanamide suppressed blood pressure and increased plasma renin activity. Blockade of central angiotensin receptor AT1R suppressed the acetaldehyde-induced fluid intake and c-Fos expression in the circumventricular organs (CVOs), which form part of dipsogenic mechanism in the brain. In addition, central administration of acetaldehyde together with cyanamide selectively induced water but not salt intake without changes in blood pressure. In electrophysiological recordings from slice preparations, acetaldehyde specifically excited angiotensin-sensitive neurons in the CVO. These results suggest that acetaldehyde evokes the thirst sensation following heavy alcohol drinking, by two distinct and previously unsuspected mechanisms, independent of diuresis. First acetaldehyde indirectly activates AT1R in the dipsogenic centers via the peripheral renin-angiotensin system following the depressor response and induces both water and salt intake. Secondly acetaldehyde directly activates neurons in the dipsogenic centers and induces only water intake.

Effect of Corticosteroid on Renal Water and Sodium Excretion in Symptomatic Heart Failure: Prednisone for Renal Function Improvement Evaluation Study.

BACKGROUND: Recent evidence indicates that prednisone can potentiate renal responsiveness to diuretics in heart failure (HF). However, the optimal dose of prednisone is not known. METHOD: Thirty-eight patients with symptomatic HF were randomized to receive standard HF care alone (n = 10) or with low-dose (15 mg/d, n = 8), medium-dose (30 mg/d, n = 10), or high-dose prednisone (60 mg/d, n = 10), for 10 days. During this time, we recorded the 24-hour urinary output and the 24-hour urinary sodium excretion, at baseline, on day 5 and day 10. We also monitored the change in the concentration of serum creatinine, angiotensin II, aldosterone, high-sensitive C-reactive protein, tumor necrosis factor-α, interleukin 1ß, and interleukin 6. RESULTS: Low-dose prednisone significantly enhanced urine output. However, the effects of medium- and high-dose prednisone on urine output were less obvious. As for renal sodium excretion, high-dose prednisone induced a more potent natriuresis than low-dose prednisone. Despite the potent diuresis and natriuresis induced by prednisone, serum creatinine, angiotensin II, and aldosterone levels were not elevated. These favorable effects were not associated with an inflammatory suppression by glucocorticoids. CONCLUSIONS: Only low-dose prednisone significantly enhanced urine output. However, high-dose prednisone induced a more potent renal sodium excretion than low-dose prednisone.

Salt-sparing diuretic action of a water-soluble urea analog inhibitor of urea transporters UT-A and UT-B in rats.

Inhibitors of kidney urea transporter (UT) proteins have potential use as salt-sparing diuretics ('urearetics') with a different mechanism of action than diuretics that target salt transporters. To study UT inhibition in rats, we screened about 10,000 drugs, natural products and urea analogs for inhibition of rat UT-A1. Drug and natural product screening found nicotine, sanguinarine and an indolcarbonylchromenone with IC50 of 10-20 µM. Urea analog screening found methylacetamide and dimethylthiourea (DMTU). DMTU fully and reversibly inhibited rat UT-A1 and UT-B by a noncompetitive mechanism with IC50 of 2-3 mM. Homology modeling and docking computations suggested DMTU binding sites on rat UT-A1. Following a single intraperitoneal injection of 500 mg/kg DMTU, peak plasma concentration was 9 mM with t1/2 of about 10 h, and a urine concentration of 20-40 mM. Rats chronically treated with DMTU had a sustained, reversible reduction in urine osmolality from 1800 to 600 mOsm, a 3-fold increase in urine output, and mild hypokalemia. DMTU did not impair urinary concentrating function in rats on a low protein diet. Compared to furosemide-treated rats, the DMTU-treated rats had greater diuresis and reduced urinary salt loss. In a model of syndrome of inappropriate antidiuretic hormone secretion, DMTU treatment prevented hyponatremia and water retention produced by water-loading in dDAVP-treated rats. Thus, our results establish a rat model of UT inhibition and demonstrate the diuretic efficacy of UT inhibition.