Diuresis In Rats Research Articles

Glucocorticoid-induced acute diuresis in rats in relation to the reduced renal expression of sodium-dependent cotransporter genes

Although several studies have shown that glucocorticoids exert diuretic effects in animals and humans, the underlying mechanism responsible for the acute diuretic effect remains obscure. Here we examined the mechanism in terms of gene-expression. We observed that glucocorticoids, including dexamethasone (Dex) and prednisolone (PSL), acutely induced diuresis in rats in a dose-dependent manner. Free water clearance values were negative after Dex or PSL treatment, similar to those observed after treatment with osmotic diuretics (furosemide and acetazolamide). Dex significantly increased the urinary excretion of sodium, potassium, chloride, glucose, and inorganic phosphorus. Renal microarray analysis revealed that Dex significantly altered the renal expression of genes related to transmembrane transport activity. The mRNA levels of sodium/phosphate (NaPi-2a/Slc34a1, NaPi-2b/Slc34a2, and NaPi-2c/Slc34a3) and sodium/glucose cotransporters (Sglt2/Slc5a2) were significantly reduced in the Dex-treated kidney, being negatively correlated with the urinary excretion of their corresponding solutes. Dex did not affect renal expression of the natriuretic peptide receptor 1 (Npr1) gene, or the expression, localization, and phosphorylation of aquaporin-2 (AQP2), a water channel protein. These findings suggest that the acute diuretic effects of glucocorticoids might be mediated by reduced expression of sodium-dependent cotransporter genes.

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.

Acute over-additive natriuretic effects by a combination of finerenone and SGLT2 inhibition in rats with an activated renin-angiotensin-aldosterone system: a mechanistic basis for clinical outcomes?

Abstract Background Recent preclinical studies suggested an independent benefit of non-steroidal mineralocorticoid receptor (MR) antagonism by finerenone and SGLT2 inhibition in cardiorenal diseases, with a potential for combination therapy. Chronic low-dose combination of finerenone and empagliflozin in hypertensive rats revealed an early, sustained and over-additive reduction in proteinuria but the underlying mechanism(s) are not fully understood. Purpose To compare the acute glucosuric, natriuretic, kaliuretic and diuretic efficacy of individual dosages of finerenone and SGLT2 inhibitors (empagliflozin, canagliflozin or dapagliflozin) with the combined administration of both drug classes in conscious rats with an activated renin-angiotensin-aldosterone system (RAAS). Methods The RAAS was activated in male Wistar rats (body mass 250 to 500 g) by placing them on a low-salt diet containing 0.02% sodium chloride for 72 hours. In a series of three independent experiments, finerenone (1 mg/kg), SGLT2 inhibitor (3 mg/kg; either empagliflozin, canagliflozin or dapagliflozin) alone and the respective combinations were administered in 2-3 ml/kg of solvent (PEG400) by oral gavage and the animals (n=6-10 / group) were individually placed in metabolic cages on water ad libitum. The individual urine was collected for 24 hours and the concentration of glucose, sodium and potassium excreted in the urine was measured by a clinical-chemical analyzer system (ADVIA 2400). Results Administration of 1 mg/kg finerenone had no influence on urinary glucose, urinary volume and urinary potassium but caused an increase in urinary sodium excretion at least by trend. At a dose of 3 mg/kg, all SGLT2 inhibitors induced a strong increase in urinary glucose excretion but had no significant influence on urinary potassium and urinary sodium, while only dapagliflozin caused an increase in urinary volume at the tested dose. Administration of a combination of 1 mg/kg finerenone and 3 mg/kg SGLT2 inhibitor did not significantly modify urinary glucose and urinary potassium in comparison to the respective individual finerenone and SGLT2 inhibitor dosages and only the combination with empagliflozin increased urinary volume vs the respective monotherapies. Surprisingly, combination of finerenone with SGLT2 inhibition over-additively induced sodium excretion consistently in all three experiments (finerenone+empagliflozin: 171,4%; finerenone+canagliflozin: 139,6%; finerenone+dapagliflozin: 133,9%) in comparison to the calculated combination (set to 100%) of the respective individual finerenone and SGLT2 inhibitor groups. Conclusion Combination of MR antagonism by finerenone and SGLT2 inhibition revealed an acute over-additive natriuresis in a rat diuresis model. This might provide an additional mechanistic basis for near-term (e.g. hospitalization for heart failure) and long-term outcomes (e.g. blockade of the progression of kidney failure) in cardiorenal patient populations.

Antioxidant and diuretic effects of flower extract of Laurus nobilis

Diuretic medications are widely used and can come with negative effects. Because they are effective and have fewer adverse effects than other treatments for renal illness, medicinal plants have become increasingly important. This study aimed to investigate the antioxidant ability and the impact of Laurus nobilis extract (flower) on diuresis in rats. Two doses of 200 mg and 400 mg of Laurus nobilis extract were used to treat rats for thirty days. Then, we assessed all changes induced in urine and plasma parameters of rats, using furosemide as a standard drug. Further, we evaluated the total phenolic content (TPC), total flavonoid content (TFC), and antioxidant ability (DPPH and FRAP) of the tested extract. The results obtained show that the administration of a single dose of Laurus nobilis extract improved the urine flow significantly after 4 h of treatment. Similarly, both doses of the tested extract enhanced sodium, potassium, and chloride excretion without inducing hypokalemia. A similar tendency was recorded for both urine and creatinine, while the results of the furosemide group revealed a significant hypokalemia effect of the standard drug. Laurus nobilis demonstrated superior antioxidant and diuretic effects without inducing hypokalemia due to the higher content of phenolic and flavonoid content. However, more advanced studies are required to explore the constituents of Laurus nobilis extracts and essential oils, as well as to test their pertinent biological activities.

Acute Toxicity and Effect of an Aqueous Extract of Saccahrum officinarum (Poaceae) on Diuresis in Rat

Saccharum officinarum L (Poaceae) is a plant used as a diuretic and in the traditional treatment of arterial hypertension. This study aims to evaluate the acute toxicity and the diuretic potential of the aqueous extract of Saccharum officinarum (Esol) leaves on the diuresis of rats subjected to water overload. The toxicity results show that Esol is non-toxic at a dose of 2000 mg/Kg B.W. and that the LD50 is greater than this dose. The aqueous extract of Saccharum officinarum has many chemical compounds with diuretic and antihypertensive properties such as polyphenols, flavonoids, sterols and polyterpenes and saponosides. Esol acts effectively on diuresis with 24-hour urine volumes of 12.4 ± 0.74 mL; 11.3 ± 0.72 mL for the doses of 1000 and 1300 mg/kg B.W. whose volumetric urinary excretion (VUE) is greater than 150 %. The Time to First Micturition (TFM) of 41.7 ± 6.2 min and 41.2 ± 3.8 min respectively for these 2 doses. The pH of the urine of rats treated with the extract is more alkaline between 7 and 7.35. These results therefore indicate that the aqueous extract of Saccharum officinarum has a diuretic potential, thus justifying its use in traditional medicine.

Diuretic and Antiurolithic Effect of Garcinia humilis (Vahl) C.D. Adams Leaves, a Medicinal Plant Native to South American Countries.

This study evaluated the diuretic and antiurolithic effect of methanolic extract (MEGHL), dichloromethane (DCM), and ethyl acetate (EtA) fractions obtained from the leaves of Garcinia humilis, a medicinal plant known as achachairu and native to South American countries such as Bolivia, Peru, and Brazil. For the analysis of diuretic effect, the female rats received the treatment with MEGHL (3, 10, and 30 mg/kg), DCM (1, 3 and 10 mg/kg), EtA (1, 3, and 10 mg/kg), hydrochlorothiazide (HCTZ; 10 mg/kg), or vehicle (VEH) after an overload of saline solution. At the end 8 h of the experiment, the urinary parameters were measured. Additionally, the antiurolithic effect was analyzed, in which sodium oxalate was added in synthetic urine in the presence or absence of MEGHL, DCM, and EtA in different concentrations (0.1, 0.3, and 1 mg/mL). MEGHL, DCM, and EtA were able to promote 8-h diuresis in rats. MEGHL treatment at dose 30 mg/kg was accompanied by increased urinary Na+ , K+ and Cl- excretion. Moreover, the DCM and EtA fractions treatment increased K+ and Cl- excretion in the urine, although it does not cause any change in Na+ elimination. All the preparations were able to exert an antiurolithic effect in vitro, decreasing the number of calcium oxalate crystals of the monohydrate and dihydrate types. Taking together, the results presented herein showed that the preparations of G. humilis leaves are promising strategies to induce diuresis and antiurolithic effects.

Study of Asphervon Gum Effect on Diuresis, Spermatogenesis and Its Effect on Testosterone Level in Rat Male Blood

The effect of Asphervon resin gum on spermatogenesis, on the level of testosterone in the blood of rats was studied, and the effect of two dosages of the drug on diuresis of rats with an aqueous load was also considered. Data have been obtained on the quantitative change of sperm in the rat ejaculate, on the ability of Asfervon to reduce testosterone levels in the rat’s blood, and also, a pronounced dose has been revealed - the dependent diuretic effect of the drug Asfervon.

Effects of renal denervation on pressure diuresis in rats with myocardial infarction

Effects of renal denervation on pressure diuresis in rats with myocardial infarction

Enhanced diuretic action of furosemide by complexation with β-cyclodextrin in the presence of sodium lauryl sulfate

AbstractPreparation of inclusion complex using cyclodextrins is a well-known formulation strategy to elevate the solubility of drugs. However, often cyclodextrins alone may not bring a considerable improvement in the solubility of low solubility drugs. In this study, the inclusion complexation of furosemide (FSM) was tried with β-cyclodextrin (β-CD) either with the use or without the use of sodium lauryl sulfate (SLS), which is a surfactant. By using the kneading method, the binary complex of FSM/β-CD in the equal molar ratio was used. FSM and β-CD were kneaded continuously until a thick past was achieved, which was evaporated for a period of about 24 h. The solid complexed product was then crushed and stored in airtight container until use. Phase solubility studies confirmed a stoichiometric ratio of 1:1 (FSM/β-CD and FSM/β-CD with SLS). The apparent stability constant and complexation efficiencies of significantly enhanced in the presence of SLS. The prepared complexes were evaluated for DSC, PXRD, 1H NMR, and in vitro release studies. The results exhibited a significant enhancement in diuresis in rats. It is evident that the addition of SLS with β-CD significantly enhances the solubilizing efficiencies and hence bioavailability of FSM.

C‐Fos Responses Produced by the Central Microinjection of Salvinorin B in Conscious Rats

Intracerebroventricular (ICV) injection of kappa opioid agonists produces a marked diuresis in rats via inhibition of vasopressin secretion. Salvinorin B (Sal B) is a plant‐derived high‐affinity ligand for the kappa opioid receptor (KOR). Previous studies have proposed that Sal B has similar potency and efficacy as other synthetic kappa agonists in mediating the CNS effects of KOR activation. The present study examines the effects of Sal B on renal function and the expression of the proto‐oncogene c‐Fos in several hindbrain regions. Sal B effects were compared to either acetonitrile or saline vehicle treated animals. Sal B is a highly lipophilic drug and past studies utilized drug dissolving vehicles (e.g., DMSO) that produced significant cardiovascular and renal effects. In this study, we dissolved Sal B in acetonitrile/saline (1:9 dilution) to minimize solvent viscosity and cardiovascular effects.MethodsAnimals were habituated to a metabolic cage and injected with either Sal B, acetonitrile or saline. Urine samples were collected during the habituation period and used as an additional control. On the day of the experiment, urine was collected during two 15 min control periods followed by six 15 min periods beginning 15 min after the ICV injection into the lateral ventricle. After 90 minutes, animals were perfused with phosphate buffer and PFA. Brains were removed and cut on a cryostat (40 μm thick). Brain sections were processed for c‐Fos using a commercially available antibody. Sections were double labeled with dopamine beta‐hydroxylase (DBH; CY3 Anti‐mouse) to define anatomically specific hindbrain regions.ResultsICV Sal B failed to produce any significant changes to renal function (urine volume, sodium and potassium excretion rate) as compared to control vehicle. Sal B decreased c‐Fos expression in the medial nucleus of the solitary tract (NTS‐m) and rostral ventrolateral medulla (RVLM), and noradrenergic cell group (A5).ConclusionPrevious studies suggested that Sal B has affinity for the KOR; however, our results indicate that Sal B lacks efficacy and does not produce diuretic or anti‐natriuretic effects associated to synthetic kappa opioid agonists. In addition, KOR agonists increase renal sympathetic nerve activity via changes to cardiovascular controlling centers in the brain. Sal B decreased c‐Fos expression in certain hindbrain regions, but further studies are necessary to determine the role Sal B plays in these regions.

Norvaline Reduces Blood Pressure and Induces Diuresis in Rats with Inherited Stress-Induced Arterial Hypertension.

Growing evidence suggests that increased arginase activity affects vital bioprocesses in various systems and universally mediates the pathogenesis of numerous metabolic diseases. The adverse effects of arginase are associated with a severe decline in L-arginine bioavailability, which leads to nitric oxide synthase substrate insufficiency, uncoupling, and, eventually, superoxide anion generation and substantial reduction of nitric oxide (NO) synthesis. In cooperation, it contributes to chronic oxidative stress and endothelial dysfunction, which might lead to hypertension and atherosclerosis. Recent preclinical investigations point arginase as a promising therapeutic target in ameliorating metabolic and vascular dysfunctions. In the present study, adult rats with inherited stress-induced arterial hypertension (ISIAH) were used as a model of hypertension. Wistar rats served as normotensive controls. Experimental animals were intraperitoneally administered for seven days with nonproteinogenic amino acid L-norvaline (30 mg/kg/day), which is a potent arginase inhibitor, or with the vehicle. Blood pressure (BP), body weight, and diuresis were monitored. The changes in blood and urine levels of creatinine, urea, and NO metabolites were analyzed. We observed a significant decline in BP and induced diuresis in ISIAH rats following the treatment. The same procedure did not affect the BP of control animals. Remarkably, the treatment had no influence upon glomerular filtration rate in two experimental groups, just like the daily excretion of creatinine and urea. Conversely, NO metabolite levels were amplified in normotonic but not in hypertensive rats following the treatment. The data indicate that L-norvaline is a potential antihypertensive agent and deserves to be clinically investigated. Moreover, we suggest that changes in blood and urine are causally related to the effect of L-norvaline upon BP regulation.

Effects of myricetin-3-O-α-rhamnoside (myricitrin) treatment on urinary parameters of Wistar rats.

This study aimed to investigate the diuretic efficacy of myricetin-3-O-α-rhamnoside (myricitrin), a common naturally occurring plant-derived flavonoid, obtained from Marlierea eugeniopsoides (D.Legrand & Kausel) D.Legrand leaves in rats. For that, female Wistar rats were treated by oral route with the different treatments and kept in metaboloic cages for 8-h or 24-h experiment. The volume and urinary parameters were measured at the end of the period and compared between groups. When orally given to rats and compared to the vehicle-treated group, myricitrin (0.3 and 1mg/kg) was able to stimulate rat diuresis, natriuresis and kaliuresis. The combination myricitrin plus hydrochlorothiazide, but not plus furosemide or amiloride, potentiated the urinary volume when compared to the effects of drugs alone. Besides, the 8-h renal effects of myricitrin were prevented in the presence of a cyclooxygenase inhibitor and a muscarinic receptor antagonist. However, all groups treated with myricitrin showed a significant reduction in Cl- excretion. In addition, a reduction in the urinary excretion of Cl- and was detected on 24-h analysis, a result that showed to be associated with an increase of these anions in the blood samples from the myricitrin-treated group. Despite these alterations, no changes in urinary or blood pH were detected. Taking together, although the results of this study point to the diuretic potential of myricitrin, the reduction in urinary Cl- and excretion should be considered in future approaches, as well as for therapeutic applicability.

Дослідження впливу екстрактів листя шавлії лікарської на діурез у щурів

Відомо, що шавлія лікарська (ШЛ) має виражений протизапальний ефект, який можна порівняти з таким у нестероїдних протизапальних препаратів. Доцільним є з’ясування впливу екстрактів ШЛ на сечовидільну функцію нирок. Мета дослідження – вивчення впливу 11 різних екстрактів ШЛ на діурез у щурів за умов водного навантаження. Дослідження виконано за стандартною методикою Є. Б. Берхіна. Досліджувані екстракти вводили внутрішньошлунково (в/ш) в дозах 10, 15, 20, 50, 70 мг/кг (екстракти № 1, 2 і 3) і 10, 20, 50, 70 мг/ кг (екстракти № 4, 5, 6, 7, 8, 9, 10 і 11). Препарати порівняння – фуросемід (10 мг/кг, в/ш), гідрохлортіазид (50 мг/кг, в/ш), адіурекрин (2 ОД, підшкірно). Білих нелінійних щурів розподіляли в групи по 6 тварин. Діурез реєстрували через 2 і 4 год після водного навантаження. За результатами дослідження встановлено, що 10 з 11 екстрактів ШЛ виявляють антидіуретичні властивості. Досліджувані сполуки статистично значущо зменшували об’єм виведеної сечі на 15,7– 58,3 % порівняно з показником контрольних тварин (р < 0,05). Для екстрактів № 1, 2, 3, 6, 8, 9, 10 і 11 встановлено зворотний дозозалежний ефект, тобто, у разі зменшення дози (до 10–20 мг/кг) посилювалась антидіуретична дія. На відміну від цих екстрактів, екстракти № 4 і 5 виявляли антидіуретичну активність у всьому діапазоні досліджуваних доз (10–70 мг/кг). Екстракт № 7 у жодній з досліджуваних доз не чинив антидіуретичного ефекту. Зважаючи на те, що основним компонентом екстрактів ШЛ є фенольні сполуки, зокрема, гідроксикоричні кислоти, зроблено припущення, що в основі антидіуретичного ефекту є їхня здатність зменшувати синтез простагландинів. Амінокислоти L-лізин і L-аргінін у цьому випадку проявили потенціювальний ефект.

C‐Fos Responses Produced by the Central Microinjection of Salvinorin A in Conscious Rats

Intracerebroventricular (ICV) injection of the kappa opioid agonists produces a marked diuresis in rats via inhibition of vasopressin secretion. Salvinorin A (SalA) is a plant‐derived high affinity agonist for the kappa opioid receptor (KOR). Previous studies have proposed that SalA has similar potency and efficacy as other synthetic kappa agonists in mediating the CNS effects of KOR activation. The present study examines the expression of the proto‐oncogene c‐fos in several forebrain regions of rats treated with SalA as compared to either acetonitrile or saline vehicle treated animals. SalA is a highly lipophilic drug and past studies utilized drug dissolving vehicles (e.g., DMSO) that produced significant cardiovascular and renal effects. In this study, we dissolved SalA in acetonitrile/saline (1:9 dilution) to minimize solvent viscosity and cardiovascular effects.MethodsAnimals were habituated to a metabolic cage and injected with either SalA, acetonitrile or saline. Urine samples were collected during two 15 min control periods and six 15 min periods beginning 15 min after injection into the lateral ventricle. After 90 minutes, animals were perfused with a phosphate buffer and PFA. Brains were removed and cut on a cryostat (40 μm thick). Brain sections were processed for c‐fos using a commercially available antibody. Sections were also double labeled with oxytocin to define anatomically specific forebrain regions.ResultsSalA decreased c‐fos expression in the parvocellular PVN, magnocellular PVN, supraoptic (SON) and median pre‐optic (MnPO) nucleus relative to the acetonitrile group. However, only in the parvocellular PVN was the decrease in c‐fos expression statistically significant (p<0.001). In contrast, there was no difference in c‐fos expression between SalA and saline vehicle treated rats, with the exception of the MnPO in which c‐fos expression was markedly increased (P<0.001).ConclusionThe ability of kappa opioid receptor agonists to increase diuresis and decrease osmolality may be associated with changes in c‐fos expression in the PVN and lamina terminalis. Previous studies in our lab, demonstrated a small increase in urine excretion rate following ICV administration of SalA and is consistent with the present findings in which there is a concomitant decrease in c‐fos expression in the magnocellular PVN and SON forebrain regions in SalA treated animals. However, the decrease was not a prominent as observed with U50488H, a synthetic KOR agonist. These results support the findings that the diuretic effects of SalA are not as potent as synthetic kappa opioid agonists.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sodium Dichloroacetate Pharmacological Effect as Related to Na-K-2Cl Cotransporter Inhibition in Rats.

The study objective was to investigate a possible sodium dichloroacetate (DCA) pharmacological mechanism causing an increase in diuresis in rats. The aim was to define characteristics of 24-hour urinary Na+, K+, Cl−, Ca2+, and Mg2+ excretion in Wistar male rats and to evaluate effect of a single-dose DCA and repeated DCA dosage on diuresis. Six control and 6 DCA-treated male rats aged 5 to weeks after a single DCA dose and repeated dosage were tested. The single DCA dose treatment caused a significantly higher 24-hour diuresis when compared to control (P < .05), and it was related to increased Cl−, Na+, and K+ urine excretion and a significant increase in Ca2+ and Mg2+ excretion (P < .05); after the repeated 4-week DCA dosage, the diuresis was not increased, but the excretion of the Na+, Cl−, Ca2+, and Mg2+ ions was significantly higher. Kidney immunohistochemistry has revealed that DCA continuous treatment results in an increase in the size of Henle loop thick ascending limb epithelial cells (P < .001). The study results show a significantly reduced RNA expression of Na-K-2Cl co-transporter (NKCC1) in thymus of 4-week DCA-treated rats (P < .03). The study data have indicated a possible mechanism of such pharmacological effect to be NKCC inhibition.

Signaling Pathways Contributing to Central Kappa Opioid Diuresis

Central activation of alpha‐2 receptors and nociceptin opioid peptide receptors (NOP) produce marked diuresis in rats, which is mediated in part by a downstream G‐alpha z protein signaling pathway that inhibits antidiuretic hormone (ADH) secretion. These studies investigated whether central G‐alpha protein signaling pathways also contribute in producing the diuretic and/or antinatriuretic response to central administration of the kappa opioid agonist, U‐50488H. Sprague Dawley rats were implanted with an intracerebroventricular (i.c.v.) cannula and pretreated with vehicle or pertussis toxin (PTX), which inhibits the Gi/o family of proteins except for Gz. After 48‐hrs pretreatment, rats were instrumented with cannula in the femoral artery, vein, and bladder and infused i.v. with isotonic saline (55 μl/min). After recovery, blood pressure (BP), heart rate (HR), and urine output (V) were collected in conscious rats before (control) and for 90‐min after (10‐min collections) i.c.v. U‐50488H (n=6). In vehicle pretreated rats, i.c.v. U‐50488H produced a marked increase in V (max Δ, 101±8 μl/min) and decrease in urinary sodium excretion (UNaV; max Δ, 5±0.5 μeq/min). The diuretic response produced by U‐50488H was significantly (p&lt;0.05) blunted by pretreatment with PTX (max Δ, 57±3 ul/min). In contrast, PTX did not alter the decrease in UNaV. U‐50488H did not alter BP or HR in either group. To explore which G‐alpha proteins may participate in the kappa opioid mediated diuresis, separate rats were pretreated i.c.v. (24‐hrs) with an oligodeoxynucleotide (ODN), which selectively targeted a specific G‐alpha protein. In these studies, pretreatment of groups of rats (n=6/group) with a single ODN for either Gi1, Gi2, Gi3, Go, or Gz, failed to blunt the maximal diuresis as compared to the increase in V produced by i.c.v. U‐50488H in scrambled ODN treated rats. These results demonstrate that central kappa opioids produce a pertussis toxin sensitive diuresis, but not antinatriuresis. This suggests that a combination of Gi/o proteins may be required to produce the aquaretic effects of kappa opioid agonists.Support or Funding InformationSupported by NIH P30GM106392 to DRKThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Поиск новых мочегонных средств синтетического происхождения

Цель работы — оценка диуретической и салуретической активности синтетического 4-нитрофенил-O-β-D-глюкопиранозида и его агликона (4-нитрофенола). Животные ежедневно получали: 1-я группа — 4-нитрофенил-O-β-D-глюкопиранозид и 2-я группа — 4-нитрофенол в дозе 18 мкмоль/кг с 1 по 7 дни введения и 54 мкмоль/кг с 8 по 14 дни в 2 мл дистиллированной воды внутрижелудочно с помощью зонда. В ходе эксперимента наибольшую мочегонную активность оказывает 4-нитрофенил-O-β-D-глюкопиранозид в дозе 54 мкмоль/кг, увеличивая диурез у крыс в 2,5 раза в сопоставлении с контрольным значением.

Phytochemical and Toxicological Studies of an Extract of the Seeds of Picralima Nitida (Stapf) (Apocynaceae) and Its Pharmacological Effects on the Blood Pressure of Rabbit

The phytochemical screening of the seeds extracts of Picralima nitida has highlighted the presence of alkaloids and terpenes poly sterols in chloroform solutions, methanol and in the aqueous. Unlike chloroform and methanol solutions, the aqueous revealed the presence of saponins. An acute toxicity study in mice showed that the aqueous extract of Picralima nitida would be slightly toxic with a lethal dose (LD) 50 % of 9120.11 mg/kg of body weight (bw). This extract, in rabbits induced a dose-dependent hypotension for the doses between 3.10 -6 g / kg bw and 2.10 -5 g/kg bw with an effective dose 50% (ED50) equal to 4.07×10 -6 g/kg bw. In the presence of atropine (6.10 -9 g/kg), a competitive inhibitor of acetylcholine, the hypotensive effect of aqueous extract of Picralima nitida is reduced, confirming in this extract the presence of cholinomimetics substances of muscarinic type. The results therefore suggest the presence of cholinomimetics substances in the aqueous extract of Picralima nitida seed. These substances could be responsible for the hypotensive effect of this extract. The same extract did not induce diuresis in rats.

Exercise Effects on Circadian Rhythmicity of Urine Osmolality and Diuresis in Rats

Sportsmen have to maintain hydration monitoring for health, but biomarkers are transient during the process of dehydration and rehydration. The aim of this study was to examine the circadian rhythmicity of urine osmolality and diuresis in rats at 4 h intervals, and to determine whether training exercise resulted in changes in this rhythmicity. Rats were trained progressively on a running wheel over four days. Two urine group samples were taken from each animal; the first was taken before the start of the training program and the second was taken at the completion of the last running trial. We found a characteristic circadian rhythmicity in diuresis and in urine osmolality, which was the same for pre- and postexercise patterns. However, post- exercise urine osmolality values were greater than pre-exercise values when the exercise intensity was of sufficient intensity to reduce urine production. The urine osmolality was elevated during the approximately 4 h period after termination of the exercise, and remained high up to 16 h after the termination of exercise, after which osmolality started to normalize. Thus, this study suggests that the urinary measures described herein represent a noninvasive and easy-to-use tool for the characterization of 24 h hydration status.

Discovery of a novel sub-class of ROMK channel inhibitors typified by 5-(2-(4-(2-(4-(1H-Tetrazol-1-yl)phenyl)acetyl)piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one

A sub-class of distinct small molecule ROMK inhibitors were developed from the original lead 1. Medicinal chemistry endeavors led to novel ROMK inhibitors with good ROMK functional potency and improved hERG selectivity. Two of the described ROMK inhibitors were characterized for the first in vivo proof-of-concept biology studies, and results from an acute rat diuresis model confirmed the hypothesis that ROMK inhibitors represent new mechanism diuretic and natriuretic agents.