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We have previously observed that prolonged administration of rapamycin, an inhibitor targeting the mammalian target of rapamycin complex (mTORC)1, partially reduced hypertension and alleviated kidney inflammation in Dahl salt-sensitive (SS) rats. In contrast, treatment with PP242, an inhibitor affecting both mTORC1/mTORC2, not only completely prevented hypertension but also provided substantial protection against kidney injury. Notably, PP242 exhibited potent natriuretic effects that were not evident with rapamycin. The primary objective of this study was to pinpoint the specific tubular sites responsible for the natriuretic effect of PP242 in SS rats subjected to either 0.4% NaCl (normal salt) or 4.0% NaCl (high salt) diet. Acute effects of PP242 on natriuretic, diuretic, and kaliuretic responses were determined in unanesthetized SS rats utilizing benzamil, furosemide, or hydrochlorothiazide [inhibitors of epithelial Na+ channel (ENaC), Na-K-2Cl cotransporter (NKCC2), or Na-Cl cotransporter (NCC), respectively] either administered alone or in combination. The findings indicate that the natriuretic effects of PP242 in SS rats stem predominantly from the inhibition of NCC and a reduction of ENaC open probability. Molecular analysis revealed that mTORC2 regulates NCC activity through protein phosphorylation and ENaC activity through proteolytic cleavage in vivo. Evidence also indicated that PP242 also prevents the loss of K+ associated with the inhibition of NCC. These findings suggest that PP242 may represent an improved therapeutic approach for antihypertensive intervention, potentially controlling blood pressure and mitigating kidney injury in salt-sensitive human subjects. NEW & NOTEWORTHY: This study explored mechanisms underlying the natriuretic effects of mammalian target of rapamycin protein complex 2 inhibition using PP242 and revealed both epithelial Na+ channel and Na-Cl cotransporter in the distal tubular segments were potentially inhibited. These observations, with prior lab evidence, indicate that PP242 prevents hypertension via its potent inhibitory effects on these specific sodium transporters and by reducing renal immune responses. This dual action, coupled with potassium sparing effects, suggests an improved approach for managing hypertension and associated kidney damage. [ABSTRACT FROM AUTHOR]

The Ca2+-permeable transient receptor potential vanilloid type 4 (TRPV4) channel serves as the sensor of tubular flow, thus being well suited to govern mechanosensitive K+ transport in the distal renal tubule. Here, we directly tested whether the TRPV4 function is significant in affecting K+ balance. We used balance metabolic cage experiments and systemic measurements with different K+ feeding regimens [high (5% K+), regular (0.9% K+), and low (<0.01% K+)] in newly created transgenic mice with selective TRPV4 deletion in the renal tubule (TRPV4fl/fl-Pax8Cre) and their littermate controls (TRPV4fl/fl). Deletion was verified by the absence of TRPV4 protein expression and lack of TRPV4-dependent Ca2+ influx. There were no differences in plasma electrolytes, urinary volume, and K+ levels at baseline. In contrast, plasma K+ levels were significantly elevated in TRPV4fl/fl-Pax8Cre mice on high K+ intake. K+-loaded knockout mice exhibited lower urinary K+ levels than TRPV4fl/fl mice, which was accompanied by higher aldosterone levels by day 7. Moreover, TRPV4fl/fl-Pax8Cre mice had more efficient renal K+ conservation and higher plasma K+ levels in the state of dietary K+ deficiency. H+-K+-ATPase levels were significantly increased in TRPV4fl/fl-Pax8Cre mice on a regular diet and especially on a low-K+ diet, pointing to augmented K+ reabsorption in the collecting duct. Consistently, we found a significantly faster intracellular pH recovery after intracellular acidification, as an index of H+-K+-ATPase activity, in split-opened collecting ducts from TRPV4fl/fl-Pax8Cre mice. In summary, our results demonstrate an indispensable prokaliuretic role of TRPV4 in the renal tubule in controlling K+ balance and urinary K+ excretion during variations in dietary K+ intake. NEW & NOTEWORTHY The mechanoactivated transient receptor potential vanilloid type 4 (TRPV4) channel is expressed in distal tubule segments, where it controls flow-dependent K+ transport. Global TRPV4 deficiency causes impaired adaptation to variations in dietary K+ intake. Here, we demonstrate that renal tubule-specific TRPV4 deletion is sufficient to recapitulate the phenotype by causing antikaliuresis and higher plasma K+ levels in both states of K+ load and deficiency. [ABSTRACT FROM AUTHOR]

The hypokalemic response to alkali infusion has been attributed to the resulting extracellular fluid (ECF) expansion, urinary potassium excretion, and internal potassium shifts, but the dominant mechanism remains uncertain. Hypertonic NaHCO3 infusion (1 N, 5 mmol/kg) to unanesthetized dogs with normal acid-base status or one of the four chronic acid-base disorders decreased plasma potassium concentration ([K+]p) at 30 min in all study groups (Δ[K+]p, − 0.16 to − 0.73 mmol/L), which remained essentially unaltered up to 90-min postinfusion. ECF expansion accounted for only a small fraction of the decrease in ECF potassium content, (K+)e. Urinary potassium losses were large in normals and chronic respiratory acid-base disorders, limited in chronic metabolic alkalosis, and minimal in chronic metabolic acidosis, yet, ongoing kaliuresis did not impact the stability of [K+]p. All five groups experienced a reduction in (K+)e at 30-min postinfusion, Δ(K+)e remaining unchanged thereafter. Intracellular fluid (ICF) potassium content, (K+)i, decreased progressively postinfusion in all groups excluding chronic metabolic acidosis, in which a reduction in (K+)e was accompanied by an increase in (K+)i. We demonstrate that hypokalemia following hypertonic NaHCO3 infusion in intact animals with acidemia, alkalemia, or normal acid-base status and intact or depleted potassium stores is critically dependent on mechanisms of internal potassium balance and not ECF volume expansion or kaliuresis. We envision that the acute NaHCO3 infusion elicits immediate ionic shifts between ECF and ICF leading to hypokalemia. Thereafter, maintenance of a relatively stable, although depressed, [K+]e requires that cells release potassium to counterbalance ongoing urinary potassium losses. [ABSTRACT FROM AUTHOR]

Abstract Urinary K+ potassium excretion rapidly increases after a potassium‐rich meal. The early aldosterone‐induced sgk1 gene (encoding serum and glucocorticoid‐induced kinase 1), activates potassium clearance, but the role of this kinase in the early activation of K+ secretion has not been clearly defined. Here, we challenged inducible renal‐tubule‐specific Sgk1Pax8/LC1 knockout mice with an acute high‐potassium load (HK:5%K+) and compared the physiological and molecular responses to control mice. We observe that urinary excretion after a K+ load over the first 3 h is not dependent on SGK1 but is coincident with the rapid dephosphorylation of the Na+,Cl−‐cotransporter (NCC) to increase distal salt delivery. Molecular analyses indicate that whereas SGK1‐mediated phosphorylation of the ubiquitin‐protein ligase NEDD4‐2 begins to increase by 3h, SGK1‐dependent proteolytic activation of ENaC only becomes detectable after 6 h of HK intake. Consistent with SGK1‐dependent ENaC activation via inhibition of NEDD4‐2‐mediated ubiquitylation, Sgk1Pax8/LC1 mice are unable to efficiently inhibit NEDD4‐2 or increase ENaC cleavage after 6 h of HK. Nevertheless, no defect in acute K+ balance was detected in the mutant mice after 6 h of HK. Moreover, we found that Sgk1Pax8/LC1 mice reduce NCC phosphorylation and NCC‐mediated salt absorption to a greater extent than control mice after a K+ load, promoting increased amiloride‐sensitive Na+‐reabsorption via ENaC to maintain adequate kaliuresis. Together, these data indicate that: (a) during the early 3 h of HK intake, K+ excretion is SGK1‐independent even under an extreme K+ challenge, (b) shortly after, SGK1 inhibits NEDD4‐2 and activates ENaC to stimulate K+‐secretion, (c) SGK1‐dependent phosphorylation of NCC occurs, acting more likely as a brake pedal to prevent excessive K+ loss.

The kidney plays an essential role in homeostasis, accomplished through the regulation of pH, electrolytes and fluids, by the building blocks of the kidney, the nephrons. One of the important markers of the proper functioning of a kidney is the glomerular filtration rate. Diabetes is characterized by an enlargement of the glomerular and tubular size of the kidney, affecting the afferent and efferent arteriole resistance and hemodynamics, ultimately leading to chronic kidney disease. We postulate that the diabetes-induced changes in kidney may exhibit significant sex differences as the distribution of renal transporters along the nephron may be markedly different between women and men, as recently shown in rodents. The goals of this study are to (i) analyze how kidney function is altered in male and female patients with diabetes, and (ii) assess the renal effects, in women and men, of an anti-hyperglycemic therapy that inhibits the sodium-glucose cotransporter 2 (SGLT2) in the proximal convoluted tubules. To accomplish these goals, we have developed computational models of kidney function, separate for male and female patients with diabetes. The simulation results indicate that diabetes enhances Na+ transport, especially along the proximal tubules and thick ascending limbs, to similar extents in male and female patients, which can be explained by the diabetes-induced increase in glomerular filtration rate. Additionally, we conducted simulations to study the effects of diabetes and SGLT2 inhibition on solute and water transport along the nephrons. Model simulations also suggest that SGLT2 inhibition raises luminal [Cl–] at the macula densa, twice as much in males as in females, and could indicate activation of the tubuloglomerular feedback signal. By inducing osmotic diuresis in the proximal tubules, SGLT2 inhibition reduces paracellular transport, eventually leading to diuresis and natriuresis. Those effects on urinary excretion are blunted in women, in part due to their higher distal transport capacity.

The kidney plays an essential role in homeostasis, accomplished through the regulation of pH, electrolytes and fluids, by the building blocks of the kidney, the nephrons. One of the important markers of the proper functioning of a kidney is the glomerular filtration rate. Diabetes is characterized by an enlargement of the glomerular and tubular size of the kidney, affecting the afferent and efferent arteriole resistance and hemodynamics, ultimately leading to chronic kidney disease. We postulate that the diabetes-induced changes in kidney may exhibit significant sex differences as the distribution of renal transporters along the nephron may be markedly different between women and men, as recently shown in rodents. The goals of this study are to (i) analyze how kidney function is altered in male and female patients with diabetes, and (ii) assess the renal effects, in women and men, of an anti-hyperglycemic therapy that inhibits the sodium-glucose cotransporter 2 (SGLT2) in the proximal convoluted tubules. To accomplish these goals, we have developed computational models of kidney function, separate for male and female patients with diabetes. The simulation results indicate that diabetes enhances Na+ transport, especially along the proximal tubules and thick ascending limbs, to similar extents in male and female patients, which can be explained by the diabetes-induced increase in glomerular filtration rate. Additionally, we conducted simulations to study the effects of diabetes and SGLT2 inhibition on solute and water transport along the nephrons. Model simulations also suggest that SGLT2 inhibition raises luminal [Cl–] at the macula densa, twice as much in males as in females, and could indicate activation of the tubuloglomerular feedback signal. By inducing osmotic diuresis in the proximal tubules, SGLT2 inhibition reduces paracellular transport, eventually leading to diuresis and natriuresis. Those effects on urinary excretion are blunted in women, in part due to their higher distal transport capacity. [ABSTRACT FROM AUTHOR]

Aim. To assess the effect of electrolyte changes on the prognosis of long-term cardiovascular events after acute coronary syndrome (ACS).Material and methods. The study included 105 patients with ACS who underwent coronary angiography (CA) with coronary stenting. At the study inclusion (before CA with coronary stenting), we collected data on traditional risk factors, analyzed levels of urinary sodium and potassium, kaliuresis and natriuresis. Free water clearance (FWC) and electrolyte free water clearance (EFWC), as well as fluid balance using bioelectrical impedance analysis were determined. Study endpoints (fatal and nonfatal cardiovascular events) were determined 6,2±0,2 months after CA with coronary stenting.Results. It was found that a decrease in urinary sodium (χ2=5,64, p=0,02, Constanta B0 =-0,62, Estimate =-16,5) and natriuresis (χ2=4,1, р=0,044, Constanta B0 =-1,38, Estimate =-5,2) increase the death risk. Urinary sodium of 0,2 mol/L and natriuresis of 0,5 mol are threshold levels of increased risk of death. Urinary potassium decrease was associated with an increase in death risk (threshold level — 0,5 mol/L, χ2=4,99, р=0,025, Constanta B0 =-0,63, Estimate =-70,4) and acute myocardial infarction (threshold level — 0,06 mol/L, χ2=3,93, р=0,04, Constanta B0 =-0,99, Estimate =-58,0) in the long-term period. Increase in EFWC increased the likelihood of long-term transient ischemic attack after ACS (χ2=4,61, р=0,03, Constanta B0 =-2,95, Estimate =-1,0). There were no significant relationships in the matter of FWC (p>0,05). However, with a decrease in intracellular fluid volume compared to normal values and a decrease in FWC or an increase in EFWC, the likelihood of longterm composite endpoints after ACS increases.Conclusion. As a result of the study, risk markers for long-term fatal and non-fatal cardiovascular events after ACS were established: decrease in urinary sodium

Objective: This study was undertaken to justify and validate a very frequent traditional use of a very well-known and widely used plant by a large part of the Moroccan population. It's about Corrigiola telephiifolia, and the activity in question is the diuretic activity. Methods: The aqueous ethanol root extract of corrigiola telephiifolia (200 mg/kg, 400 mg/kg, and 700 mg/kg) was orally administered to rats. The urinary excretion rate and pH, and electrolyte excretion were measured in the urine of saline-loaded rats. Negative control group received only an equivalent volume of distilled water, while the positive control groups received the diuretic drugs hydrochlorothiazide at dose 10 mg/kg. Results: The results showed that hydrochlorothiazide induced significant diuresis and electrolytes excretion at 1, 6 and 24 h after the treatment. Both the higher doses of the extract produced a significant increase in urine volume than the control from the first hour until the end of observation. However, the lowest dose increased significantly only at 24 h after the treatment. With regard to the electrolyte excretion, the tested doses of CTRE which have shown a significant increase in Na+, K+ and Clexcretion in comparison to normal control rats, are 400 and 700 mg/kg bw. Conclusion: These findings collectively indicate that the extracts of C. telephiifolia have a potential to induce diuresis markedly, and providing evidence, for its traditional use. [ABSTRACT FROM AUTHOR]

We hypothesized that torsemide and furosemide, at approximately equipotent dosages (similar diuresis), would have comparable effects on the circulating renin-angiotensin-aldosterone system. Six, healthy, middle-aged, male Beagles were randomized to receive torsemide (0.1 mg/kg PO q 12 h), furosemide (2.0 mg/kg PO q 12 h), or placebo for 10 days during three separate periods, separated by a 10-day washout period, in a crossover design. Blood was collected on days 1, 5, and 9 and 24-h urine collection ended on days 2, 6, and 10. After repeated measures analysis and Bonferonni correction, variables with an adjusted p <0.05 were investigated further, using Tukey's method. Twenty-four-hour urine production differed significantly between the diuretics only on day 10, with torsemide causing a 38% greater diuresis than furosemide. There was, however, no significant difference in average 3-day diuresis. There were no significant differences between diuretics in the 24-h urinary excretion of sodium, chloride, or potassium, though furosemide caused less kaliuresis than torsemide. Serum renin, angiotensin II, and aldosterone and the urine aldosterone-to-creatinine ratio were significantly increased in the diuretic groups, as compared to placebo on days 5/6 and 9/10. There were no significant differences in these values between diuretics. Creatinine and blood urea nitrogen concentrations rose comparably in the diuretic groups, remaining within reference intervals in all dogs. At approximately equipotent dosages (20:1), torsemide and furosemide produced comparable renin-angiotensin-aldosterone system activation. Torsemide's similar potassium excretion profile to furosemide decreases support for a hypothesized mineralocorticoid-receptor blocking capability. [ABSTRACT FROM AUTHOR]

Chronic lithium administration for the treatment of bipolar disorder leads to nephrogenic diabetes insipidus (NDI), characterized by polyuria, natriuresis, kaliuresis, and collecting duct remodeling and cell proliferation among other features. Previously, using a 2-week lithium-induced NDI model, we reported that P2Y2 receptor (R) knockout mice are significantly resistant to polyuria, natriuresis, kaliuresis, and decrease in AQP2 protein abundance in the kidney relative to wild type mice. Here we show this protection is long-lasting, and is also associated with significant amelioration of lithium-induced collecting duct remodeling and cell proliferation. Age-matched wild type and knockout mice were fed regular (n = 5/genotype) or lithium-added (40 mmol/kg chow; n = 10/genotype) diet for 5 months and euthanized. Water intake, urine output and osmolality were monitored once in every month. Salt blocks were provided to mice on lithium-diet to prevent sodium loss. At the end of 5 months mice were euthanized and serum and kidney samples were analyzed. There was a steady increase in lithium-induced polyuria, natriuresis and kaliuresis in wild type mice over the 5-month period. Increases in these urinary parameters were very low in lithium-fed knockout mice, resulting in significantly widening differences between the wild type and knockout mice. Terminal AQP2 and NKCC2 protein abundances in the kidney were significantly higher in lithium-fed knockout vs. wild type mice. There were no significant differences in terminal serum lithium or sodium levels between the wild type and knockout mice. Confocal immunofluorescence microscopy revealed that lithium-induced marked remodeling of collecting duct with significantly increased proportion of [H+]-ATPase-positive intercalated cells and decreased proportion of AQP2-positive principal cells in the wild type, but not in knockout mice. Lithium-induced collecting duct cell proliferation (indicated by Ki67 labeling), was significantly lower in knockout vs. wild type mice. This is the first piece of evidence that purinergic signaling is potentially involved in lithium-induced collecting duct remodeling and cell proliferation. Our results demonstrate that genetic deletion of P2Y2-R protects against the key structural and functional alterations in Li-induced NDI, and underscore the potential utility of targeting this receptor for the treatment of NDI in bipolar patients on chronic lithium therapy.

Chronic lithium administration for the treatment of bipolar disorder leads to nephrogenic diabetes insipidus (NDI), characterized by polyuria, natriuresis, kaliuresis, and collecting duct remodeling and cell proliferation among other features. Previously, using a 2-week lithium-induced NDI model, we reported that P2Y2 receptor (R) knockout mice are significantly resistant to polyuria, natriuresis, kaliuresis, and decrease in AQP2 protein abundance in the kidney relative to wild type mice. Here we show this protection is long-lasting, and is also associated with significant amelioration of lithium-induced collecting duct remodeling and cell proliferation. Age-matched wild type and knockout mice were fed regular (n = 5/genotype) or lithium-added (40 mmol/kg chow; n = 10/genotype) diet for 5 months and euthanized. Water intake, urine output and osmolality were monitored once in every month. Salt blocks were provided to mice on lithium-diet to prevent sodium loss. At the end of 5 months mice were euthanized and serum and kidney samples were analyzed. There was a steady increase in lithium-induced polyuria, natriuresis and kaliuresis in wild type mice over the 5-month period. Increases in these urinary parameters were very low in lithium-fed knockout mice, resulting in significantly widening differences between the wild type and knockout mice. Terminal AQP2 and NKCC2 protein abundances in the kidney were significantly higher in lithium-fed knockout vs. wild type mice. There were no significant differences in terminal serum lithium or sodium levels between the wild type and knockout mice. Confocal immunofluorescence microscopy revealed that lithium-induced marked remodeling of collecting duct with significantly increased proportion of [H+]-ATPase-positive intercalated cells and decreased proportion of AQP2-positive principal cells in the wild type, but not in knockout mice. Lithium-induced collecting duct cell proliferation (indicated by Ki67 labeling), was significantly lower in knockout vs. wild type mice. This is the first piece of evidence that purinergic signaling is potentially involved in lithium-induced collecting duct remodeling and cell proliferation. Our results demonstrate that genetic deletion of P2Y2-R protects against the key structural and functional alterations in Li-induced NDI, and underscore the potential utility of targeting this receptor for the treatment of NDI in bipolar patients on chronic lithium therapy. [ABSTRACT FROM AUTHOR]

We sought to decipher the mechanisms underlying the kidney’s response to changes in K+ load and intake, under physiological and pathophysiological conditions. To accomplish that goal, we applied a published computational model of epithelial transport along rat nephrons in a sham rat, an uninephrectomized (UNX) rat, and a 5/6-nephrectomized (5/6-NX) rat that also considers adaptations in glomerular filtration rate and tubular growth. Model simulations of an acute K+ load indicate that elevated expression levels and activities of Na+/K+-ATPase, epithelial sodium channels, large-conductance Ca2+-activated K+ channels, and renal outer medullary K+ channels, together with downregulation of sodium-chloride cotransporters (NCC), increase K+ secretion along the connecting tubule, resulting in a >6-fold increase in urinary K+ excretion in sham rats, which substantially exceeds the filtered K+ load. In the UNX and 5/6-NX models, the acute K+ load is predicted to increase K+ excretion, but at significantly reduced levels compared with sham. Acute K+ load is accompanied by natriuresis in sham rats. Model simulations suggest that the lesser natriuretic effect observed in the nephrectomized groups may be explained by impaired NCC downregulation in these kidneys. At a single-nephron level, a high K+ intake raises K+ secretion along the connecting tubule and reabsorption along the collecting duct in sham, and even more in UNX and 5/6-NX. However, the increased K+ secretion per tubule fails to sufficiently compensate for the reduction in nephron number, such that nephrectomized rats have an impaired ability to excrete an acute or chronic K+ load. [ABSTRACT FROM AUTHOR]

Objectives Some species of the genus Mimosa showed promising results in previous investigations, which include diuretic effect; however, no chemical analyses or animal model has been conducted so far to evaluate the biological properties of M. bimucronata. Methods Male Wistar rats received the oral treatment with vehicle; hydrochlorothiazide; methanolic extract from M. bimucronata ( MEMB), dichloromethane ( DCM) and ethyl acetate ( EA) fractions or methyl gallate ( MG). The cumulative urine volume, electrolytes excretion, p H and osmolality were determined at the end of the experiment. Key findings The chemical studies demonstrated that the phenolic compounds are the majorities in the plant, with the MG being the main substance identified. We showed that MEMB and EA fraction, but not DCM, exhibited diuretic and saluretic effects. Similarly, the MG also revealed diuretic, natriuretic and kaliuretic properties to both normotensive and spontaneously hypertensive rats. Atropine, a muscarinic receptor antagonist, fully prevented MG-induced diuresis and saluresis. In addition, MG did not alter the viability of A7r5 and L929 cell lines and neither stimulated nitric oxide generation. Conclusions These findings suggest that M. bimucronata extracts and its majority compound MG present diuretic, natriuretic and kaliuretic properties, which was dependent on the activation of muscarinic acetylcholine receptor. [ABSTRACT FROM AUTHOR]

Dry immersion (DI) is a Russian-developed, ground-based model to study the physiological effects of microgravity. It accurately reproduces environmental conditions of weightlessness, such as enhanced physical inactivity, suppression of hydrostatic pressure and supportlessness. We aimed to study the integrative physiological responses to a 3-day strict DI protocol in 12 healthy men, and to assess the extent of multi-system deconditioning. We recorded general clinical data, biological data and evaluated body fluid changes. Cardiovascular deconditioning was evaluated using orthostatic tolerance tests (Lower Body Negative Pressure + tilt and progressive tilt). Metabolic state was tested with oral glucose tolerance test. Muscular deconditioning was assessed via muscle tone measurement. Results: Orthostatic tolerance time dropped from 27 ± 1 to 9 ± 2min after DI. Significant impairment in glucose tolerance was observed. Net insulin response increased by 72 ± 23% on the third day of DI compared to baseline. Global leg muscle tone was approximately 10% reduced under immersion. Day-night changes in temperature, heart rate and blood pressure were preserved on the third day of DI. Day-night variations of urinary K+ diminished, beginning at the second day of immersion, while 24-h K+ excretion remained stable throughout. Urinary cortisol and melatonin metabolite increased with DI, although within normal limits. A positive correlation was observed between lumbar pain intensity, estimated on the second day of DI, and mean 24-h urinary cortisol under DI. In conclusion, DI represents an accurate and rapid model of gravitational deconditioning. The extent of glucose tolerance impairment may be linked to constant enhanced muscle inactivity. Muscle tone reduction may reflect the reaction of postural muscles to withdrawal of support. Relatively modest increases in cortisol suggest that DI induces a moderate stress effect. In prospect, this advanced ground-based model is extremely suited to test countermeasures for microgravity-induced deconditioning and physical inactivity-related pathologies. [ABSTRACT FROM AUTHOR]

Angiotensin II (AngII) hypertension increases distal tubule Na-Cl cotransporter (NCC) abundance and phosphorylation (NCCp), as well as epithelial Na(+) channel abundance and activating cleavage. Acutely raising plasma [K(+)] by infusion or ingestion provokes a rapid decrease in NCCp that drives a compensatory kaliuresis. The first aim tested whether acutely raising plasma [K(+)] with a single 3-hour 2% potassium meal would lower NCCp in Sprague-Dawley rats after 14 days of AngII (400 ng/kg per minute). The potassium-rich meal neither decreased NCCp nor increased K(+) excretion. AngII-infused rats exhibited lower plasma [K(+)] versus controls (3.6±0.2 versus 4.5±0.1 mmol/L; P<0.05), suggesting that AngII-mediated epithelial Na(+) channel activation provokes K(+) depletion. The second aim tested whether doubling dietary potassium intake from 1% (A1K) to 2% (A2K) would prevent K(+) depletion during AngII infusion and, thus, prevent NCC accumulation. A2K-fed rats exhibited normal plasma [K(+)] and 2-fold higher K(+) excretion and plasma [aldosterone] versus A1K. In A1K rats, NCC, NCCpS71, and NCCpT53 abundance increased 1.5- to 3-fold versus controls (P<0.05). The rise in NCC and NCCp abundance was prevented in the A2K rats, yet blood pressure did not significantly decrease. Epithelial Na(+) channel subunit abundance and cleavage increased 1.5- to 3-fold in both A1K and A2K; ROMK (renal outer medulla K(+) channel abundance) abundance was unaffected by AngII or dietary K(+) In summary, the accumulation and phosphorylation of NCC seen during chronic AngII infusion hypertension is likely secondary to potassium deficiency driven by epithelial Na(+) channel stimulation. [ABSTRACT FROM AUTHOR]

Aim High dietary K+ intake is associated with protection against hypertension. In mammals, acute K+ intake induces natriuresis and kaliuresis, associated with a marked dephosphorylation of the renal Na+/Cl− cotransporter ( NCC). It has been suggested that reduced activity of NCC increases the driving force for more distal tubular epithelial Na+ channel ( ENaC)-dependent K+ secretion. This study investigated the ENaC dependence of urinary K+ and Na+ excretion following acute K+ loading. Methods Mice were fed low (0.03%), control (0.2%) or high (2%) Na+ diets for 25 days to preserve or promote Na+ loss and thus ENaC activity. Once a week, the mice received either K+-containing gavage or a control gavage. Following the gavage treatment, the mice were placed in metabolic cages and urine was collected in real time. ENaC dependence of kaliuresis was assessed by benzamil injections prior to gavage. Results We confirmed that dietary Na+ content is inversely related to plasma aldosterone, NCC phosphorylation and ENaC cleavage products. The novel findings were as follows: (i) acute K+ feeding caused NCC dephosphorylation in all dietary groups; (ii) under all dietary conditions, K+ loading induced natriuresis; (iii) high Na+ diet markedly reduced the K+ excretion following K+ gavage; (iv) benzamil injection prior to K+ loading increased natriuresis, decreased kaliuresis and eliminated the differences between the dietary groups. Conclusion These data indicate that acute K+-induced kaliuresis is ENaC dependent. Maximal K+ excretion rates are attenuated when ENaC is physiologically down-regulated or pharmacologically blocked. NCC is dephosphorylated following acute K+ loading under all dietary Na+ regimens. This leads to natriuresis, even in severely Na+-restricted animals. [ABSTRACT FROM AUTHOR]

Cherula and sticklewort tinctures exhibit rapid and short-lasting diuretic effect. Tinctures of tansy and immortelle are featured by rapid onset of the effect and prolonged action, while the tincture of common bearberry has a long latency period and prolonged action. Under normal conditions of gravity, flavonoid rutin stimulates diuresis only through tubular component; under hypergravity, simultaneously via glomerular and tubular components. [ABSTRACT FROM AUTHOR]

Oxytocin (OT), a neurohormone, has been related to natriuretic and diuretic effects and also to water intake and sodium appetite. The objective of the present study was to determine the effect of subcutaneous OT administration on water intake and urine-related measures induced by the administration of hypertonic NaCl (experiment 1) or polyethylene glycol (PEG) (experiment 2). Experiment 1 showed that OT administration increases the urine volume, urinary sodium concentration, and natriuresis and reduces the water intake, water and sodium balances, and estimated plasma sodium concentration induced by hypertonic NaCl administration. Conversely, experiment 2 showed that OT administration increases the water intake and the antidiuretic response induced by PEG administration. These results show that the opposite effects of OT on the water intake induced by hypertonic NaCl or PEG administration are accompanied by differential regulatory effects, enhancing a natriuretic response in the first experiment and generating an antidiuretic reaction in the second experiment. This study suggests a differential regulatory effect of OT during states of intra- and extracellular thirst. [ABSTRACT FROM AUTHOR]

Despite similar stimulatory actions on the epithelial sodium channel (ENaC)-mediated sodium reabsorption in the distal tubule, insulin promotes kaliuresis, whereas insulin-like growth factor-1 (IGF-1) causes a reduction in urinary potassium levels. The factors contributing to this phenomenon remain elusive. Electrogenic distal nephron ENaC-mediated Na+ transport establishes driving force for Cl- reabsorption and K+ secretion. Using patch-clamp electrophysiology, we document that a Cl- channel is highly abundant on the basolateral plasma membrane of intercalated cells in freshly isolated mouse cortical collecting duct (CCD) cells. The channel has characteristics attributable to the ClC-K2: slow gating kinetics, conductance ~10 pS, voltage independence, Cl->NO3- anion selectivity, and inhibition/ activation by low/high pH, respectively. IGF-1 (100 and 500 nM) acutely stimulates ClC-K2 activity in a reversible manner. Inhibition of PI3-kinase (PI3-K) with LY294002 (20 μM) abrogates activation of ClC-K2 by IGF-1. Interestingly, insulin (100 nM) reversibly decreases ClC-K2 activity in CCD cells. This inhibitory action is independent of PI3-K and is mediated by stimulation of a mitogenactivated protein kinase-dependent cascade. We propose that IGF-1, by stimulating ClC-K2 channels, promotes net Na+ and Cl- reabsorption, thus reducing driving force for potassium secretion by the CCD. In contrast, inhibition of ClC-K2 by insulin favors coupling of Na+ reabsorption with K+ secretion at the apical membrane contributing to kaliuresis. [ABSTRACT FROM AUTHOR]

Dietary potassium loading results in rapid kaliuresis, natriuresis, and diuresis associated with reduced phosphorylation (p) of the distal tubule Na+-Cl- cotransporter (NCC). Decreased NCC-p inhibits NCC-mediated Na+ reabsorption and shifts Na+ downstream for reabsorption by epithelial Na+ channels (ENaC), which can drive K+ secretion. Whether the signal is initiated by ingesting potassium or a rise in plasma K+ concentration ([K+]) is not understood. We tested the hypothesis, in male rats, that an increase in plasma [K+] is sufficient to reduce NCC-p and drive kaliuresis. After an overnight fast, a single 3-h 2% potassium (2%K) containing meal increased plasma [K+] from 4.0 ± 0.1 to 5.2 ± 0.2 mM; increased urinary K+, Na+, and volume excretion; decreased NCC-p by 60%; and marginally reduced cortical Na+-K+-2Cl- cotransporter (NKCC) phosphorylation 25% (P = 0.055). When plasma [K+] was increased by tail vein infusion of KCl to 5.5 ± 0.1 mM over 3 h, significant kaliuresis and natriuresis ensued, NCC-p decreased by 60%, and STE20/SPS1- related proline alanine-rich kinase (SPAK) phosphorylation was marginally reduced 35% (P = 0.052). The following were unchanged at 3 h by either the potassium-rich meal or KCl infusion: Na+/H+ exchanger 3 (NHE3), NHE3-p, NKCC, ENaC subunits, and renal outer medullary K+ channel. In summary, raising plasma [K+] by intravenous infusion to a level equivalent to that observed after a single potassium-rich meal triggers renal kaliuretic and natriuretic responses, independent of K+ ingestion, likely driven by decreased NCC-p and activity sufficient to shift sodium reabsorption downstream to where Na+ reabsorption and flow drive K+ secretion. [ABSTRACT FROM AUTHOR]

Background In the Ethiopian traditional medicine, the leaves of Ajuga remota B. (Local name, Armagusa) is used in the treatment of hypertension. Since this claim has not been investigated scientifically, the aim of the present study was to evaluate the diuretic potential of the aqueous and 80% methanolic extracts of the leaves of Ajuga remota in mice after acute oral administration. Methods Adult mice were administered orally either aqueous (250 mg/kg, AA250; 500 mg/kg, AA500 and 1000 mg/kg, AA1000) or 80% methanolic (250 mg/kg, AM250; 500 mg/kg, AM500 and 750 mg/kg, AM750) extract. Urine output and electrolyte contents were then quantified up to 5 h and compared with those administered with furosemide 10 mg/kg (F10) and distilled water (CON). Results The larger dose of 80% methanolic extract produced significant diuresis (p < 0.01), while the aqueous extract had shown diuresis both at the middle (p < 0.01) and higher (p < 0.01) doses by the end of the fifth hour compared to CON mice. Regarding electrolyte excretion, larger doses of both extracts had increased natriuresis (p < 0.001 for AA1000 and p < 0.01 for AM1000), while the effect on kaliuresis were smaller when compared with the standard, suggesting the plant could possibly have a potassium-sparing effect. Phytochemical screening revealed the presence of secondary metabolites like phenolic compounds, tannins, saponins, flavonoids, terpenoids, steroids, and cardiac glycosides, which might account for the diuretic activity. Conclusions The results indicate that the plant is endowed with significant diuretic activity at various doses, providing evidence for its folkloric use. The major components like flavonoids, tannins, terpenoids and alkaloids found in the plant might have contributed to the observed diuretic activity. [ABSTRACT FROM AUTHOR]

Na+ reabsorption from the distal renal tubule involves electroneutral and electrogenic pathways, with the latter promoting K+ excretion. The relative activities of these two pathways are tightly controlled, participating in the minute-to-minute regulation of systemic K+ balance. The pathways are interdependent: the activity of the NaCl cotransporter (NCC) in the distal convoluted tubule influences the activity of the epithelial Na+ channel (ENaC) downstream. This effect might be mediated by changes in distal Na+ delivery per se or by molecular and structural adaptations in the connecting tubule and collecting ducts. We hypothesized that acute inhibition of NCC activity would cause an immediate increase in Na+ flux through ENaC, with a concomitant increase in renal K+ excretion. We tested this using renal clearance methodology in anesthetized mice, by the administration of hydrochlorothiazide (HCTZ) and/or benzamil (BZM) to exert specific blockade of NCC and ENaC, respectively. Bolus HCTZ elicited a natriuresis that was sustained for up to 110 min; urinary K+ excretion was not affected. Furthermore, the magnitude of the natriuresis was no greater during concomitant BZM administration. This suggests that ENaC-mediated Na+ reabsorption was not normally limited by Na+ delivery, accounting for the absence of thiazide-induced kaliuresis. After dietary Na+ restriction, HCTZ elicited a kaliuresis, but the natiuretic effect of HCTZ was not enhanced by BZM. Our findings support a model in which inhibition of NCC activity does not increase Na+ reabsorption through ENaC solely by increasing distal Na+ delivery but rather by inducing a molecular and structural adaptation in downstream nephron segments. [ABSTRACT FROM AUTHOR]

Abstract: The aim of the present study was an investigation of mechanisms mediating selective effect of vasotocin analogues on water, sodium, and potassium excretion. We tested vasotocin analogues: Mpa1-vasotocin (dAVT), Mpa1-Arg4-vasotocin (dAAVT) and Mpa1-DArg8-vasotocin (dDAVT). The effects on water, sodium, and potassium transport were evaluated in experiments using normal and water-loaded Wistar rats. It was shown that all tested peptides exerted antidiuretic activity. Vasotocin and dAVT induced natriuresis and kaliuresis in rats. V1a agonist (Phe2-Ile3-Orn8-vasopressin) reproduced the renal effects of dAVT on sodium and potassium excretion but not on water reabsorption. dAAVT, dDAVT and V2 agonist (desmopressin) induced kaliuresis without any effect on sodium excretion. Natriuresis was associated with increase in cGMP excretion, whereas kaliuresis was correlated with rise of cAMP excretion. V1a antagonist (Pmp1-Tyr(Me)2-vasopressin) significantly reduced the dAVT-stimulated natriuresis and did not influence on urinary potassium excretion. V2 antagonist (Pmp1-DIle2-Ile4-vasopressin) significantly reduced the dAVT- and dAAVT-induced kaliuresis. It is assumed that effects of the nonapeptides on sodium and potassium transport are independent of their antidiuretic activity and mediated by different subtypes of V receptors (the V1a or V1a-like receptor for natriuretic effect and V2 or V2-like one for kaliuretic). In accordance to the data obtained, there is a possibility of selective regulation of renal water reabsorption and urinary sodium and potassium excretion with involvement of neurohypophysial hormones. [Copyright &y& Elsevier]

Whole body knockout (KO) of the P2Y2 receptor (P2Y2R) results in enhanced vasopressin V2 receptor activity and increased renal Na+ conservation. We hypothesized that P2Y2R KO mice would be less sensitive to lithiuminduced natriuresis and kaliuresis due to attenuated downregulation of one or more of the major renal Na+ or K+ transporter/channel proteins. KO and wild-type (WT) mice were fed a control or lithiumadded diet (40 mmol/kg food) for 14 days. Lithium-induced natriuresis and kaliuresis were significantly (~25%) attenuated in KO mice. The subunits of the epithelial Na+ channel (ENaC) were variably affected by lithium and genotype, but, overall, medullary levels were decreased substantially by lithium (15-60%) in both genotypes. In contrast, cortical, β-, and γ-ENaC were increased by lithium (~50%), but only in WT mice. Moreover, an assessment of ENaC activity by benzamil sensitivity suggested that lithium increased ENaC activity in WT mice but in not KO mice. In contrast, medullary levels of Na+-K+-2Cl- cotransporter 2 and cortical levels of the renal outer medullary K+ channel were not downregulated by lithium and were significantly (15-76%) higher in KO mice under both dietary conditions. In addition, under control conditions, tissue osmolality of the inner medulla as well as furosemide sensitivity were significantly higher in KO mice versus WT mice. Therefore, we suggest that increased expression of these proteins, particularly in the control state, reduces Na+ delivery to the distal nephron and provides a buffer to attenuate collecting duct-mediated natriuresis and kaliuresis. Additional studies are warranted to explore the potential therapeutic benefits of purinergic antagonism. [ABSTRACT FROM AUTHOR]

A dietary potassium load induces a rapid kaliuresis and natriuresis, which may occur even before plasma potassium and aldosterone (aldo) levels increase. Here we sought to gain insight into underlying molecular mechanisms contributing to this response. After gastric gavage of 2% potassium, the plasma potassium concentrations rose rapidly (0.25 h), followed by a significant rise of plasma aldo (0.5 h) in mice. Enhanced urinary potassium and sodium excretion was detectable as early as spot urines could be collected (about 0.5 h). The functional changes were accompanied by a rapid and sustained (0.25-6 h) dephosphorylation of the NaCl cotransporter (NCC) and a late (6 h) upregulation of proteolytically activated epithelial sodium channels. The rapid effects on NCC were independent from the coadministered anion. NCC dephosphorylation was also aldo-independent, as indicated by experiments in aldo-deficient mice. The observed urinary sodium loss relates to NCC, as it was markedly diminished in NCC-deficient mice. Thus, downregulation of NCC likely explains the natriuretic effect of an acute oral potassium load in mice. This may improve renal potassium excretion by increasing the amount of intraluminal sodium that can be exchanged against potassium in the aldo-sensitive distal nephron. [ABSTRACT FROM AUTHOR]

Summary: A new understanding of renal potassium balance has emerged as the molecular underpinnings of potassium secretion have become illuminated, highlighting the key roles of apical potassium channels, renal outer medullary potassium channel (ROMK) and Big Potassium (BK), in the aldosterone-sensitive distal nephron and collecting duct. These channels act as the final-regulated components of the renal potassium secretory machinery. Their activity, number, and driving forces are precisely modulated to ensure potassium excretion matches dietary potassium intake. Recent identification of the underlying regulatory mechanisms at the molecular level provides a new appreciation of the physiology and reveals a molecular insight to explain the paradoxic actions of aldosterone on potassium secretion. Here, we review the current state of knowledge in the field. [Copyright &y& Elsevier]

Vasopressin and nonmammalian hormone vasotocin are known to increase the water permeability of mammalian collecting ducts, frog skin and the urinary bladder. Neurohypophysial nonapeptides have also been shown to interfere with the regulation of renal ion transport. The subject of this study was a search for vasopressin and vasotocin analogues with selective effects on renal water, sodium and potassium excretion. During this study, we synthesised the following peptides: 13 vasotocin analogues modified at positions 4 (Thr or Arg), 7 (Gly or Leu) and 8 ( d-Arg, Lys or Glu); 4 vasopressin analogues modified at positions 4 and 8; and 9 peptides shortened or extended at the C-terminal or with substitutions for Gly-NH2. Most of these peptides had mercaptopropionic acid (Mpa) instead of Cys in position 1. The effects of these nonapeptides on renal water, sodium and potassium transport were evaluated in in vivo experiments using Wistar rats. Some nonapeptides possessed antidiuretic, natriuretic and kaliuretic activities ([Mpa1]-arginine vasotocin, [Mpa1, homoArg8]-vasotocin, [Mpa1, Thr4]-arginine vasotocin and [Mpa1, Arg4]-arginine vasopressin). Substitutions at positions 4 and 8 increased the selectivity of peptide actions. The antidiuretic [ d-Arg8]-vasotocin analogues had no effects on sodium excretion. [Mpa1, Arg4]-arginine vasotocin was antidiuretic and kaliuretic but not natriuretic. [Mpa1, Glu8]-oxytocin had weak natriuretic activity without any effects on water and potassium transport. In accordance with the data obtained, synthesised vasotocin analogues could be good candidates for pharmaceuticals selectively regulating renal sodium and potassium transport, which is of clinical importance. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

We report a 46-year-old male who presented with fever and flaccid weakness of all four limbs due to Leptospirosis associated hypokalemia. Acute hypokalemic quadriparesis is an uncommon presentation of leptospirosis, not yet widely recognised. Renal potassium wasting occurs in Leptospirosis and subsequently, the development of hypokalemia leads to paralysis. The patient had kaliuresis due to leptospirosis which improved with antibiotics and potassium replacement.

The 5′-adenosine monophosphate-activated serine/threonine protein kinase (AMPK) is stimulated by energy depletion, increase in cytosolic Ca activity, oxidative stress, and nitric oxide. AMPK participates in the regulation of the epithelial Na channel ENaC and the voltage-gated K channel KCNE1/KCNQ1. It is partially effective by decreasing PIP formation through the PI3K pathway. The present study explored whether AMPK regulates the renal outer medullary K channel ROMK. To this end, cRNA encoding ROMK was injected into Xenopus oocytes with and without additional injection of constitutively active AMPK (AMPK-HA+AMPK-Flag+AMPKγ1), or of inactive AMPK (AMPK+AMPK-Flag+AMPK-HA), and the current determined utilizing two-electrode voltage-clamp and single channel patch clamp. ROMK protein abundance was measured utilizing chemiluminescence in Xenopus oocytes and western blot in whole kidney tissue. Moreover, renal Na and K excretion were determined in AMPK-deficient mice ( ampk) and wild-type mice ( ampk) prior to and following an acute K load (111 mM KCl, 30 mM NaHCO, 4.7 mM NaCl, and 2.25 g/dl BSA) at a rate of 500 μl/h. As a result, coexpression of AMPK but not of AMPK significantly decreased the current in ROMK1-expressing Xenopus oocytes. Injection of phosphatidylinositol PIP significantly increased the current in ROMK1-expressing Xenopus oocytes, an effect reversed in the presence of AMPK. Under control conditions, no significant differences between ampk and ampk mice were observed in glomerular filtration rate (GFR), urinary flow rate, serum aldosterone, plasma Na, and K concentrations as well as absolute and fractional Na and K excretion. Following an acute K load, GFR, urinary flow rate, serum aldosterone, plasma Na, and K concentration were again similar in both genotypes, but renal absolute and fractional Na and K excretion were higher in ampk than in ampk mice. According to micropuncture following a K load, delivery of Na to the early distal tubule but not delivery of K to late proximal and early distal tubules was increased in ampk mice. The upregulation of renal ROMK1 protein expression by acute K load was more pronounced in ampk than in ampk mice. In conclusion, AMPK downregulates ROMK, an effect compromising the ability of the kidney to excrete K following an acute K load. [ABSTRACT FROM AUTHOR]

Background. Intrauterine growth restriction (IUGR) is associated with an increased risk of renal diseases in adulthood. However, while low-birth-weight-infants often undergo accelerated postnatal growth, the impact of postnatal environmental factors such as nutrition and early postnatal stressors on renal development and function remains unclear. In this context, Neuropeptide Y (NPY) may act as a critical factor. NPY is a sympathetic coneurotransmitter involved in blood pressure regulation and tubular function. Yet, little is known about the expression and function of endogenous NPY in the kidney and the functional relevance for the transmission of persistent postnatal-induced effects.Methods. (1) IUGR was induced in Wistar rats by isocaloric protein restriction in pregnant dams. (2) Litter size was reduced to 6 (LSR6) or 10 (LSR10) male neonates. To differentiate the effect of postnatal nutrition and stressors, we additionally included home-cage-control animals without any postnatal manipulation. Animals were sacrificed at Day 70.Results. Litter size reduction (LSR) to 6 but not IUGR increased messenger RNA expression of endogenous NPY and down-regulated the NPY-receptors Y1 and Y2. Furthermore, dipeptidylpeptidase IV (DPPIV)—an enzyme that cleaves NPY—was decreased after LSR. Expression and the phosphorylation of mitogen-activated protein kinase 42/44 (intracellular signalling pathway of the receptor Y1) were altered. An impaired renal function with pronounced kaliuresis and natriuresis was observed at Day 70 after LSR.Conclusions. Postnatal nutrition and stressors such as LSR lead to dysregulated signalling of NPY. These data demonstrate that factors in the early postnatal environment exert important changes in the tubular function, which may predispose to corresponding pathology. [ABSTRACT FROM AUTHOR]

The peptide uroguanylin (Ugn) is stored and released as a propeptide (proUgn) by enterochromaffin cells in the intestine, and converted to Ugn and other metabolites in the renal tubules. Both proUgn and Ugn are natriuretic, although the response to proUgn is thought to depend on its conversion to Ugn within nephrons. To assess the efficiency of intrarenal conversion of proUgn to Ugn, we measured urinary Ugn excretion in rats following intravenous infusions of proUgn or Ugn. Infusion of 2 and 10 nmol proUgn/kg body wt increased plasma proUgn concentration from 2.2 ± 0.3 to 5.6 ± 1.3 pmol/ml and to 37 ± 9.6 pmol/ml, respectively. No proUgn was detected in urine before, during, or after proUgn infusions. These two proUgn infusion doses resulted in total Ugn recovery in urine of 162 ± 64 and 206 ± 39 pmol/kg body wt (9 and 2% of the infused amount, respectively). By contrast, the same molar amounts of Ugn resulted in 1,009 ± 477 and 5,352 ± 2,133 pmol/kg body wt of Ugn in urine (recoveries of ∼50%). Unexpectedly, comparisons of natriuretic dose-response curves for each peptide showed proUgn to be about five times more potent than Ugn, despite the relatively modest amount of Ugn generated from infused proUgn. In addition, both peptides were antikaliuretic at low doses, but in this case Ugn showed greater potency than proUgn. These data do not support Ugn as the primary active principle of proUgn for regulation of renal sodium excretion. Instead, an alternative peptide fragment produced from proUgn may be responsible for natriuretic activity in the kidney, whereas Ugn itself may play an antikaliuretic role. [ABSTRACT FROM AUTHOR]

ROMK-deficient (Romk-/-) mice exhibit polyuria, natriuresis, and kaliuresis similar to individuals with type II Bartter's form of hyper-prostaglandin E syndrome (HPS; antenatal Bartter's syndrome). In the present study, we utilized both metabolic and clearance studies to define the contributions of specific distal nephron segments to the renal salt wasting in these mice. The effects of furosemide, hydrochlorothiazide, and benzamil on urinary Na+ and K+ excretion in both wild-type (RomK+/+) and Romk-/- mice were used to assess and compare salt transport by the Na+-K+-2Cl- cotransporter (NKCC2)-expressing thick ascending limb (TAL), the Na+-Cl- cotransporter (NCC)-expressing distal convoluted tubule (DCT1/DCT2), and the epithelial Na+ channel (ENaC)-expressing connecting segment (CNT) and collecting duct (CD), respectively. Whole kidney glomerular filtration rate was reduced by 47% in Romk-/- mice. Furosemide-induced increments in the fractional excretion rate of Na+ and K+ and absolute excretion of Na+ and K+ were significantly blunted in Romk-/- mice, consistent with a major salt transport defect in the TAL. In contrast, hydrochlorothiazide produced an exaggerated natriuresis in RomK-/- mice, indicating upregulation of salt absorption by the DCT. Benzamil resulted in a similar increment in absolute Na excretion in both RomK-/- and RomK+/+, indicating no significant upregulation of Na+ transport by ENaC in ROMK null mice. Moreover, hydrochlorothiazide increased the fractional K+ excretion rate in Romk-/- mice, confirming our recent observation that maxi-K channels contribute to distal K+ secretion in the absence of ROMK. [ABSTRACT FROM AUTHOR]

Abstract: Aim of the study: The present investigation was carried out to evaluate the acute diuretic activity of continuous intravenous infusion of an aqueous extract of the seed of Coriandrum sativum L. Apiaceae (coriander) in rats. Materials and Methods: The aqueous extract of coriander seed was administered by continuous intravenous infusion (120min) at two doses (40 and 100mg/kg) to anesthetized Wistar rats. Furosemide (10mg/kg), a standard diuretic was used as the reference drug. Excretion of water and electrolytes (sodium, potassium and chloride) in urine was measured, and glomerular filtration rate (equal to creatinine clearance) was determined. Results: The crude aqueous extract of coriander seeds increased diuresis, excretion of electrolytes, and glomerular filtration rate in a dose-dependent way; furosemide was more potent as a diuretic and saluretic. The mechanism of action of the plant extract appears to be similar to that of furosemide. Conclusions: The aqueous extract of coriander seed possesses diuretic and saluretic activity, thus, validating the use of coriander as a diuretic plant in Moroccan pharmacopoeia. [Copyright &y& Elsevier]

The present study was carried out to assess the influence of noradrenergic stimulation of the midbrain dorsal (DRN) and median raphe nuclei (MRN) on urinary volume and electrolyte excretion in hydrated rats. Wistar rats were implanted with a guide cannula into the MRN or DRN and then submitted to two intragastric administrations of water in order to attain an increased diuresis. The following treatments were performed. (1) Intra-DRN microinjections of saline (0.2 μl), α1-adrenergic agonist phenylephrine (PHE, 0.49 and 4.9 nmol in 0.2 μl), α2-adrenergic antagonist idazoxan (IDZ, 0.42 and 4.2 nmol in 0.2 μl) or the α1-adrenergic antagonist prazosin (PRZ, 0.24 and 2.4 nmol in 0.2 μl). (2) Intra-MRN microinjections of saline, IDZ (4.2 nmol in 0.2 μl), PHE (4.9 nmol in 0.2 μl) or PRZ (2.4 nmol in 0.2 μl). Urine samples were subsequently collected over 120 min at 20 min intervals for photometric measurement of sodium and potassium. Intra-DRN administration of PHE and IDZ significantly increased the urinary volume, natriuresis and kaliuresis. Intra-DRN microinjection of a higher dose of PRZ reduced the urinary volume and both sodium and potassium excretion. Intra-MRN microinjections of PHE, IDZ or PRZ did not induce any significant effect on urinary volume or electrolyte excretion. These data suggest that the increase of tonic excitatory noradrenergic input conveyed to DRN influences the hydroelectrolyte homeostasis, possibly through 5-HTergic circuitry. [ABSTRACT FROM AUTHOR]

Objective. To investigate whether different types of stroke influence renal excretion of albumin, major electrolytes and water. Material and methods. Timed urine collections were started shortly after admission in 5 patients with haemorrhagic stroke (group A), 5 with ischaemic stroke (group Bx), 6 with presumed ischaemic stroke (groups By/z) and 6 with subarachnoid haemorrhage (group C). Albuminuria was also investigated in four patients undergoing elective abdominal surgery. Results. Increased levels of albuminuria were observed in all patients in groups A and B, but were found to decline with observation time and appeared to be related to outcome in group B. In group C, albuminuria was detected in 4 out of 6 patients. Elective surgery did not affect albumin excretion. In a setting with high urinary osmolality, high excretion rates for creatinine, urea, sodium, potassium and large diuresis were intermittently observed in groups A, B and C. None of these patients was in steady‐state condition. Conclusions. Different types of stroke elicit a complex change in renal function which resembles the response to a hypervolaemic and hyperosmolar signal, possibly mediated by a breakdown of renal autoregulation of blood flow in the presence of high vasopressin activity. Acute changes in excretion of albumin might be an indicator of prognosis in stroke. The findings point to the existence of unrecognized pathways between the central nervous system and the kidneys. Further studies on the mechanisms underlying alterations in renal function in stroke and their implication for treatment and outcome are indicated. [ABSTRACT FROM AUTHOR]

Abstract: Diuretic and uricosuric properties have traditionally been attributed to corn silk, stigma/style of Zea mays L. Although the diuretic effect was confirmed, studies of the plant''s effects on renal function or solute excretion were lacking. Thus, we studied the effects of corn silk aqueous extract on the urinary excretion of water, Na+, K+, and uric acid. Glomerular and proximal tubular function and Na+ tubular handling were also studied. Conscious, unrestrained adult male rats were housed in individual metabolic cages (IMC) with continuous urine collection for 5 and 3h, following two protocols. The effects of 25, 50, 200, 350, and 500mg/kg body wt. corn silk extract on urine volume plus Na+ and K+ excretions were studied in water-loaded conscious rats (2.5ml/100g body wt.) in the IMC for 5h (Protocol 1). Kaliuresis was observed with doses of 350 (100.42±22.32–120.28±19.70μEq/5h/100g body wt.; ) and 500mg/kg body wt. (94.97±29.30–134.32±39.98μEq/5h/100g body wt.; ; ), and the latter dose resulted in diuresis as well (1.98±0.44–2.41±0.41ml/5h/100g body wt.; ; ). The effects of a 500mg/kg body wt. dose of corn silk extract on urine volume, Na+, K+ and uric acid excretions, and glomerular and proximal tubular function, were measured respectively by creatinine (Clcr) and Li+ (ClLi) clearances and Na+ tubular handling, in water-loaded rats (5ml/100g body wt.) in the IMC for 3h (Protocol 2). Clcr (294.6±73.2, , to 241.7±48.0μl/min/100g body wt.; ; ) and the Na+ filtered load (41.9±10.3, , to 34.3±.8, , ) decreased and ClLi and Na+ excretion were unchanged, while K+ excretion (0.1044±0.0458, , to 0.2289±0.0583μEq/min/100body wt.; ; ) increased. For Na+ tubular handling, the fractional proximal tubular reabsorption (91.5±3.5, , to 87.5±3.4%; ; ) decreased, and both fractional distal reabsorptions — I and II — increased (96.5±1.5, , to 97.8±0.9%; ; ; and 8.2±3.5, , to 12.2±3.4%, , , respectively). To summarize, in water-loaded conscious rats (2.5ml/100 body wt.), corn silk aqueous extract is diuretic at a dose of 500mg/kg body wt. and kaliuretic at doses of 350 and 500mg/kg body wt. In water-loaded conscious rats (5.0ml/100g body wt.), corn silk aqueous extract is kaliuretic at a dose of 500mg/kg body wt., but glomerular filtration and filtered load decrease without affecting proximal tubular function, Na+, or uric acid excretion. [Copyright &y& Elsevier]

Abstract: Isotonic NaCl is ingested in addition to water by cell-dehydrated rats in two-bottle tests. The objective of the present work was to find out whether mineral intake in the cell-dehydrated rat is specific to NaCl in a five-bottle test. Adult male Sprague Dawley rats had distilled water and four mineral solutions at palatable concentrations (0.01 M KCl, 0.05 mM CaCl2, 0.15 M NaHCO3, 0.15 M NaCl) simultaneously available for consumption. Cell-dehydration was produced infusing 1.5 ml of NaCl solution (0.15, 0.25, 0.5, 1.0, 2.0, 4.0 M) intravenously for 10 min and intakes were recorded for the next hour. It was observed a NaCl concentration-dependent increase in 0.01 M KCl intake. The ingestion of the other mineral solutions was not significantly altered compared to infusion of 0.15 M NaCl. The ingestion of KCl was not related to changes in serum potassium concentration. The ingestion of KCl was reduced in half and water was the preferred fluid when the five-bottle test was performed with mineral solutions at isomolar (0.15 M) concentrations. There was no increase in intake of other mineral solution in the isomolar test. No preference was observed for palatable or isomolar solutions during early extracellular dehydration until 4 h after subcutaneous injection of furosemide, in spite of the increase in total volume intake. Therefore, mineral intake induced by cell dehydration is not specific for NaCl solution. The type of mineral solution available influences the choice and KCl is the preferred solution of the cell-dehydrated rat in the conditions of the present study. [Copyright &y& Elsevier]

Large, Ca2+-activated K+ channels (BK), comprised of α- and β-subunits, mediate K+ secretion during high flow rates in distal nephron segments. Because the BK-β1 subunit enhances Ca2+ sensitivity of BK in a variety of cells, we determined its role in flow-induced K+ secretion and its localization in the mammalian nephron. To determine the role of BK-β1 in the kaliuretic response to volume expansion, the rate of K+ excretion (UKV) vs. varied urinary flow rates were determined in wild-type and BK-β1 knockout mice (BK-β1-/-). When flow rate was varied by volume expansion (2 ml·h-1·25 g body wt-1) for 30 to 60 min in wild-type mice, we found that the UKV increased significantly with increasing urine flow rates (r² = 0.50, P < 0.00001, n = 31), as demonstrated previously in distal nephron of rats and rabbits. However, in BK-β1-/- mice, UKV did not vary with changing flow rates (r² = 0.15, P = 0.08, n = 20). Using immunohistochemical techniques, we found that BK-β1 was strongly expressed in the apical membrane of the murine distal nephron and that 98% of BK-β1 protein detected by histochemistry colocalized with NCX, a marker of connecting tubules (CNT). Both BK-β1 and NCX colocalized with BK-α in separate experiments. Furthermore, we confirmed BK-β1 protein expression in the apical membrane of connecting tubules in rabbits. BK-β1 RNA from rabbit CNT was sequenced and was identical to previously published rabbit muscle sequences. These data show that the BK-β1 accessory subunit is present in the CNT segment of the mammalian distal nephron and has a significant role in the kaliuretic response to increased urinary flow induced by volume expansion. [ABSTRACT FROM AUTHOR]

We describe a 21 month old male infant who presented with failure to thrive associated with severe hypokalaemia and metabolic acidosis, together with hypomagnesaemia. Evaluation revealed marked renal and probable faecal potassium wasting, distal renal tubular acidosis, mild urinary magnesium wasting, and a normal gastric pH (gastric H+-K+-ATPase). Hypokalaemic forms of metabolic acidosis, such as diabetic ketoacidosis and proximal renal tubular acidosis were ruled out from the clinical picture. The hypokalaemia of distal renal tubular acidosis usually improves with alkali therapy, but this was not observed: despite correction of acidosis with 5 mmol/kg potassium citrate per day, an additional 5 mmollkg potassium chloride was required to bring serum potassium to 3.5 mmol/l. At 3 years of age potassium was provided in the absence of potential alkali and acidosis ensued; serum bicarbonate fell to 10 mmol/l. Although a specific genetic analysis is not yet possible, the abnormalities are consistent with a novel form of distal renal tubular acidosis. The pathophysiology probably does not stem from defects in the vacuolar H+-ATPase but more likely from deficient activity of the colonic isoform of H+ -K+ -ATPase that is resident in the medullary collecting duct and mediates potassium absorption and proton secretion. [ABSTRACT FROM AUTHOR]

The seminal studies conducted by Giebisch and coworkers in the 1960s paved the way for understanding the renal mechanisms involved in K + homeostasis. It was demonstrated that differential handling of K + in the distal segments of the nephron is crucial for proper K + balance. Although aldosterone had been classically ascribed as the major ion transport regulator in the distal nephron, thereby contributing to K + homeostasis, it became clear that aldosterone per se could not explain the ability of the kidney to modulate kaliuresis in both acute and chronic settings. The existence of alternative kaliuretic and antikaliuretic mechanisms was suggested by physiological studies in the 1980s but only gained form and shape with the advent of molecular biology. It is now established that the kidneys recruit several endocrine and paracrine mechanisms for adequate kaliuretic response. These mechanisms include the direct effects of peritubular K + , a gut-kidney regulatory axis sensing dietary K + levels, the kidney secretion of kallikrein during postprandial periods, the upregulation of angiotensin II receptors in the distal nephron during chronic changes in K + diet, and the local increase of prostaglandins by low-K + diet. This review discusses recent advances in the understanding of endocrine and paracrine mechanisms underlying the modulation of K + secretion and how these mechanisms impact kaliuresis and K + balance. We also highlight important unknowns about the regulation of renal K + excretion under physiological circumstances.

Diuretics in current use include early distal tubular (i.e., thiazide-type), loop (i.e., furosemide-type), and potassium-and-hydrogen-retaining substances. Available oral formulations of diuretics differ in terms of their renal excretory potency in man, as formally assessed through the effect of a single dose on 24-hour natriuresis in healthy subjects. The 2.5 mg formulation of the loop diuretic torasemide does not increase mean 24-hour natriuresis, and it is therefore considered a very-low-dose formulation. Amiloride 5 mg and torasemide 5 mg and 10 mg, which increase mean 24-hour natriuresis by less than 40%, are considered low-dose or low-potency diuretic formulations of diuretic substances. Hydrochlorothiazide 25 and 50 mg, furosemide 40 and 80 mg, and torasemide 20 mg, which increase mean 24-hour natriuresis by more than 40%, are considered high-dose or high-potency formulations. A rebound in natriuresis follows the early-after-dosing increase in this variables caused by loop diuretics; hence many oral formulations of loop substances are less potent natriuretics than most oral formulations of thiazide-type diuretics. Hydrochlorothiazide 25 mg and furosemide 80 mg have similar natriuretic potencies. During once-daily administration of diuretic formulations of diuretics to subjects without edema and normal renal function, the increases in 24-hour natriuresis and diuresis that follow the first dose disappear or attenuate markedly. This is due to neuroendocrine reactions to diuretic-induced sodium loss and its attendant hemodynamic shifts. Some of these reactions, e.g. the increase in plasma aldosterone that takes place, account for an elevation in kaliuresis that occurs during once-daily treatment with a high-dose formulation of a thiazide-type diuretic. Common fixed-dose combinations of a thiazide-type or a loop diuretic and a potassium-and-hydrogen-retaining subtance generally do not change kaliuresis, but they increase natriuresis strikingly. Thiazide-type and loop diuretics decrease and increase calciuresis respectively; none of these actions wanes during prolonged administration. Plasma renin activity and aldosterone do not rise in response to very-low-dose formulations of loop diuretics taken once daily. Glomerular filtration rate tends to fall in the course of once-daily administration of high-dose formulations of diuretics, but not during prolonged once-daily treatment with very-low-dose formulations of loop diuretics. [ABSTRACT FROM AUTHOR]

The effect of piretanide on Na and K excretion and on renal haemodynamics has been studied in 14 subjects with a GFR (Inulin clearance) ranging from 140 to 2 ml · min. After a two day fluid and salt balance control period, oral piretanide 6 mg induced a natriuresis and kaliuresis, which was proportional to the GFR of the patients. The ratio of drug-induced K to Na excretion was always 0.13, independent of individual GFR. This was only true for the duration of the action of piretanide, τ, which was 6 h in subjects with normal GFR and 5 h in patients with impaired kidney function. Surprisingly, after τ, i. e. for 24 h after drug administration, less potassium was lost than in the pretreatment period. Neither the GFR nor the renal blood flow (PAH clearance) of the patients were affected by piretanide. In conclusion, piretanide given once a day was an effective natriuresic agent, even in end-stage renal disease, and it produced relatively little K-loss when given once daily. [ABSTRACT FROM AUTHOR]

The effects of oral doses of the dopamine antagonist antiemetics metoclopramide and domperidone on baseline and dopamine stimulated renal function and systemic haemodynamics were assessed in a placebo controlled crossover study in 9 healthy volunteers. Metoclopramide did not change baseline ERPF, GFR or FF over 2 h post dosing but it significantly reduced baseline UV, UV, urine flow, urinary dopamine excretion, supine and erect diastolic blood pressure and supine systolic blood pressure. Domperidone and placebo did not cause these effects. Metoclopramide caused a marked rise and domperidone a small fall in plasma aldosterone concentration (PAC) but placebo was without effect. Neither antiemetic altered plasma renin activity (PRA) but a small fall occurred with placebo. Two hours after pretreatment with placebo dopamine (2 μg/kg/min) increased effective renal plasma flow (ERPF), glomerular filtration rate (GFR), sodium excretion rate (UV), urine flow rate, urinary dopamine excretion rate, supine systolic blood pressure and supine and erect pulse rate and decreased the potassium excretion rate (UV), filtration fraction (FF) and supine diastolic blood pressure. Metoclopramide pretreatment, did not attenuate the dopamine induced rise in ERPF, GFR, urine flow, urinary dopamine excretion or supine systolic blood pressure but it did attenuate the rise in pulse rate, the fall in diastolic pressure, and the antikaliuretic effect of dopamine leading to a net kaliuresis when compared to placebo. Domperidone was similar to placebo. Neither metoclopramide nor domperidone given orally caused clinically important antagonism of the renal haemodynamic effects of dopamine. However the effects of metoclopramide on blood pressure and electrolyte excretion may have clinical importance. Metoclopramide has significant pharmacodynamic effects which are probably not due to DA antagonism but may be mediated by DA antagonism or be non-specific. [ABSTRACT FROM AUTHOR]

The natriuretic effect of the new loop diuretic piretanide was investigated in patients with severe renal insufficiency and was compared with that of furosemide. In the first study 4 hospitalized patients (serum creatinine 407 to 1220 µmol/l) were examined after administration of piretanide (12, 24, 48 and 96 mg to two patients, and 24, 48, 96 and 192 mg to 2 other subjects, given every third day). In the second study 6 hospitalized patients (serum creatinine 194 to 698 µmol/l) were studied after receiving orally 2 different doses of piretanide and 2 different doses of furosemide orally, given every fourth day. The mean natriuretic effect of 48 mg and 96 mg piretanide was 250 and 340% of the control value for the entire group, and 311 to 480% in the subgroup of patients with serum creatinine below 530 µmol/l. For a given dose the natriuresis was inversely correlated with renal function, and at a given serum creatinine level the natriuretic response was dose-dependent. The drug had less effect on water and potassium diuresis than on natriuresis. No significant difference in natriuretic effect was found on comparison with furosemide given in the ratio furosemide: piretanide 3.33:1. The pharmacokinetic data showed a direct correlation between the dose and the mean plasma concentration and also between urinary recovery of the drug and the measured natriuretic response. [ABSTRACT FROM AUTHOR]

Hydrochlorothiazide (hct) was administered orally in four different doses (12.5, 25, 50 and 75 mg), to eight healthy volunteers. Plasma and urine concentrations of hct were determined by GLC. Maximal plasma levels were found at 1.5-5 h, and averaged 70, 142, 260 and 376 ng × ml respectively. The peak plasma levels and AUC of hct were highly correlated (p<0.001) with the dose. The decline in the plasma curve was biphasic in those experiments in which the plasma levels of hct could be determined for at least 24 h. The half life of the slower phase lay between 5.6 and 14.8 h. The urinary recovery of hct, which represented the gastrointestinal absorption, averaged 65 to 72 per cent of the dose. The mean renal plasma clearance did not vary with the dose and averaged 319 to 345 ml × min. The diuresis during the 10 h after hct 12.5 mg exceeded that after placebo by a mean of 800 ml. The diureses was not increased further after higher doses of hct. The maximal natriuretic effect (+ 100 mmol), too, was found after the 12.5 mg dose. The excretion of potassium, however, rose with increasing doses; the maximal increment, after 75 mg hct, averaged 25 mmol. The excretion of calcium was significantly increased after 50 mg hct (+ 0.6 mmol). The maximal effect on magnesium excretion occurred after 25 mg hct (+ 0.5 mmol). In healthy volunteers there was no correlation between peak plasma level of hct or AUC and the renal excretion of water and electrolytes. [ABSTRACT FROM AUTHOR]

The activity of two aldosterone antagonists in reversing the urinary electrolyte changes induced by the mineralocorticoid fludrocortisone was examined in healthy subjects. Between 2-10 h after treatment there were dose-related increases in sodium excretion and the urine log 10 Na/K ratio, but no significant changes in urine volume, potassium concentration, or potassium excretion. Between 12-16 h after treatment there were dose-related increases in urine sodium excretion and the log 10 Na/K ratio. Unexpectedly, there were significant dose-related increases in potassium excretion despite significant dose-related reductions in urinary potassium concentration. The paradoxical increases in potassium excretion were attributed to dose-related increases in urine volume in the same period. These observations may explain the increased potassium excretion occasionally observed during clinical use of aldosterone antagonists and suggest that potassium excretion in man is influenced by the urine flow rate. [ABSTRACT FROM AUTHOR]

The pharmacological activity of single oral doses of a new aldosterone antagonist, prorenoate potassium, has been compared with spironolactone and placebo in a balanced double-blind crossover study in six healthy subjects. Endogenous mineralocorticoids were stimulated by administration of frusemide followed by dietary sodium restriction, and the urinary excretion of electrolytes in response to prorenoate potassium, spironolactone and placebo was measured over a 24 hour period. Significant activity of prorenoate potassium and spironolactone was observed between 2 - 24 hours after medication, with peak activity at 6 - 8 hours. The active drugs significantly increased sodium excretion and the sodium: potassium (Na/K) ratio, but changes in potassium excretion were not significant. The total urine Na/K response to prorenoate potassium 45 mg was significantly greater than to spironolactone 100 mg. [ABSTRACT FROM AUTHOR]

In order to elucidate the effects of angiotensin II on renal function, angiotensin II (AII; 1 ng/kg per min) and the AII antagonist 1-sar-8-ala-angiotensin II (AIIA; 200 ng/kg per min) were infused into the renal artery of anesthetized dogs (pentobarbital), on either a high (8 mmol/kg per day for seven days) or a low sodium intake (0.5 mmol/kg). In sodium replete dogs AII produced renal vasoconstriction with decreased RBF (−28%; P<0.001), but with less decrease of GFR (−14%; P<0.001), leading to an increase of FF (+19%; P<0.01),andantidiuresis(−39%; P<0.001); the antinatriuresis (−58%; P<0.001) exceeded the antidiuresis ( P<0.001). ΔRBF (−10%; P<0.001) was less pronounced ( P<0.001) during AII in sodium deplete dogs, GFR remained unchanged, but FF increased to the same extent (+16%; P<0.05); diuresis and urinary electrolyte excretion were however not affected. AIIA did not affect RBF, GFR, FF, nor diuresis in sodium replete dogs suggesting that endogenous AII has no tonic influence on renal function in these conditions. In sodium deplete animals AIIA produced an 11% ( P<0.001) increase of RBF, without changes of GFR; FF decreased by 12% ( P<0.01), but diuresis, natriuresis and kaliuresis were not affected. [ABSTRACT FROM AUTHOR]

Compares the natruretic, kaluretic and hypotensive action of chlorothiazide and hydrochlorothiazide. Results of oral administration of the two compounds on systolic and diastolic blood pressure, serum and urine electrolytes; Association between chlorothiazide and hyperuricemia.

Experiments on Wistar rats showed that exenatide (0.015-0.5 nmol per 100 g body weight) somewhat increased renal excretion of potassium from 7 ± 1 to 16 ± 1 μmol/h/100 g body weight ( p < 0.05) in animals with normal serum concentration of glucose (4.6 ± 0.4 mM) and potassium (4.3 ± 0.1 mM). Exenatide dramatically enhanced excretion of potassium under conditions of hyperkalemia (11.4 ± 0.4 mM) produced by intraperitoneal injection of 1.25% KCl solution (5 ml per 100 g body weight). During the fi rst postinjection hour, potassium excretion increased 2-fold and attained 97 ± 11 μmol/h/100 g body weight in comparison with potassium load alone (47 ± 9 μmol/h/100 g body weight, p < 0.05). The data attest to a possible role of peptide regulators in normalization of potassium balance via renal mechanisms. [ABSTRACT FROM AUTHOR]