Electrolyte Homoeostasis Research Articles

Effects of Ethanolic Extracts of Fruits of Dennettia tripetala on Kidney Function of Male Albino Rats

This study examined the effects of ethanolic extracts of fruits of Dennettia tripetala on kidney function of healthy male albino rats. Dennettia tripetala is commonly also referred to as pepper fruit. Antioxidant, anti-inflammatory, and antidiarrheal characteristics are only a few of the fruit's many known therapeutic benefits. Fifty healthy adult male albino rats were utilized in this study and were randomly distributed into 5 groups of 10 animals each. The test animals were orally administered ethanolic extracts of fruits of D. tripetala (200 mg/kg and 400 mg/kg) for twenty-one days and were sacrificed at the end of the 21 days. The result of kidney function biochemical parameters revealed that sodium increased significantly (p<0.05) in all the test groups, potassium increased significantly in all the test groups except in group 4 which showed no significant alteration, chloride was lowered in all the groups except in group 2 which increased significantly. Urea was lowered significantly in all the test groups; creatinine was significantly elevated in groups 4 and 5, while groups 2 and 3 showed no significant alteration. Photomicrograph of kidney section of normal control rat (group 1) showed normal glomerulus (G), Bowman’s capsule (Bc), Bowman’s space (Bs) and tubules (T) as well as group 2 and 3, while group 4 and 5 showed slightly shrunken glomerulus (SG) with increased Bowman’s capsular space (IBs) and dilated tubules (DT) within the tissue stroma. This study suggests that both the extracts may possess active ingredients that may aid in electrolyte homoeostasis while the unriped fruit extract contains some chemicals that may cause mild kidney toxicity when consumed for a long duration.

Regulation of the human placental (pro)renin receptor-prorenin-angiotensin system by microRNAs.

Are any microRNAs (miRNAs) that target the placental renin-angiotensin system (RAS) in the human placenta suppressed in early gestation? Overall, 21 miRNAs with predicted RAS mRNA targets were less abundant in early versus term placentae and nine were more highly expressed. Regulation of human placental RAS expression could alter placental development and therefore normal pregnancy outcome. The expression of genes encoding prorenin (REN), angiotensinogen, (pro)renin receptor, angiotensin converting enzyme 2, and the angiotensin II type 1 receptor are highest in early gestation, at a time when oxygen tension is at its lowest. Studies have shown that the human placental RAS is sensitive to oxygen, as are some miRNAs that regulate RAS mRNAs. We propose that in early pregnancy, the prevailing low O2 tension, by suppression of levels of miRNAs that target RAS mRNAs, results in increased expression of RAS mRNAs and encoded proteins. As gestation proceeds and the prevailing oxygen tension rises, abundance of these miRNAs increases, and placental RAS mRNA expression is suppressed. The expression of miRNAs was compared in human placentae collected in early (10-11 weeks; n = 7) and mid-gestation (14-18 weeks; n = 8) with placenta collected at term (38-40 weeks; n = 8). Expression of placental miRNAs in women with early (29-35.1 weeks; n = 8) or late-onset pre-eclampsia (PE) (>34-weeks gestation; n = 8) and gestational age matched preterm (31.6-35.1 weeks; n = 8) and term normotensive controls were also compared. Agilent Human miRNA microarray v19 was used to detect up to 2006 miRNAs in four placentae from each group. Statistically different levels of expression were determined and refined using predictive modelling. Placental miRNAs predicted to target RAS mRNAs were identified in three databases. Differences detected on the array were confirmed for some miRNAs by semi-quantitative RT-PCR (qPCR, n = 7-8 for all groups). Two differentially expressed miRNAs that were known to target human renal REN mRNA (miR-181a-5p and miR-663) were transfected into human HTR-8/SVneo trophoblast cells to examine their effect on placental REN expression and prorenin levels. In early gestation placentae, 186 miRNAs were differentially expressed compared with term placentae (109 increased, 77 decreased). Thirty of the differentially expressed miRNAs were predicted to target RAS components. In mid-gestation placentae, 117 miRNAs were differentially expressed compared with term placentae (69 increased, 48 decreased). Of these, 19 had RAS mRNAs as predicted targets. Eight miRNAs that were lower in early gestation and predicted to target RAS mRNAs were confirmed by qPCR. All showed an increase during gestation and could influence the transgestational profile of the human placental RAS. Additionally, on the array, three miRNAs predicted to target RAS mRNAs (miR-892c-3p, miR-378c and miR-514b-3p) were overexpressed in placentae from women with late-onset PE (P = 3.6E-10, P = 1.8E-05, P = 5.3E-06; respectively). miR-663, which suppresses renal REN mRNA expression, was overexpressed in early-onset PE placentae as determined by qRT-PCR analysis (P = 0.014). Transfection of miR-181a-5p and miR-663 into HTR-8/SVneo trophoblast cells suppressed REN mRNA expression (P = 0.05) and prorenin protein production (P = 0.001). Data can be found via GEO accession number GSE109832. Further validation that the differentially expressed miRNAs do indeed directly target RAS mRNAs and affect placental development and function is required. This study is limited by the small sample size. Therefore independent validation in a larger cohort is required. We propose that suppression of miRNAs that target the placental RAS in early gestation is partly responsible for the increase in RAS expression at this time, in order to promote placental development. Later in pregnancy, we have detected overexpression of several miRNAs in placentae from women with PE. These may prove to be biomarkers for early detection of women at risk of developing PE. Since the placenta produces at least two miRNAs that were found in the kidney to target REN mRNA, and that also target placental REN mRNA, the escape of these miRNAs into the maternal circulation in excess amounts could affect maternal renal REN mRNA production and thereby disturb maternal fluid and electrolyte homoeostasis. This work was supported by the National Health and Medical Research Council, Australia (APP1043537). K.G.P. is supported by an Australian Research Council Future Fellowship (FT150100179). C.T.R. is supported by a Lloyd Cox Professorial Research Fellowship from the University of Adelaide. F.Z.M. is supported by a National Heart Foundation Future Leader Fellowship and Baker Heart and Diabetes Institute Fellowship. The authors declare that they have no competing interests.

Pathophysiology, diagnosis and management of nephrogenic diabetes insipidus.

Healthy kidneys maintain fluid and electrolyte homoeostasis by adjusting urine volume and composition according to physiological needs. The final urine composition is determined in the last tubular segment: the collecting duct. Water permeability in the collecting duct is regulated by arginine vasopressin (AVP). Secretion of AVP from the neurohypophysis is regulated by a complex signalling network that involves osmosensors, barosensors and volume sensors. AVP facilitates aquaporin (AQP)-mediated water reabsorption via activation of the vasopressin V2 receptor (AVPR2) in the collecting duct, thus enabling concentration of urine. In nephrogenic diabetes insipidus (NDI), inability of the kidneys to respond to AVP results in functional AQP deficiency. Consequently, affected patients have constant diuresis, resulting in large volumes of dilute urine. Primary forms of NDI result from mutations in the genes that encode the key proteins AVPR2 and AQP2, whereas secondary forms are associated with biochemical abnormalities, obstructive uropathy or the use of certain medications, particularly lithium. Treatment of the disease is informed by identification of the underlying cause. Here we review the clinical aspects and diagnosis of NDI, the various aetiologies, current treatment options and potential future developments.

Epoxyeicosatrienoic acid analogue lowers blood pressure through vasodilation and sodium channel inhibition.

Epoxyeicosatrienoic acids (EETs) contribute to haemodynamics, electrolyte homoeostasis and blood pressure regulation, leading to the concept that EETs can be therapeutically targeted for hypertension. In the present study, multiple structural EET analogues were synthesized based on the EET pharmacophore and vasodilator structure-activity studies. Four EET analogues with 91-119% vasodilatory activity in the isolated bovine coronary artery (EC50: 0.18-1.6 μM) were identified and studied for blood-pressure-lowering in hypertension. Two EET analogues in which the COOH group at carbon 1 of the EET pharmacophore was replaced with either an aspartic acid (EET-A) or a heterocyclic surrogate (EET-X) were administered for 14 days [10 mg/kg per day intraperitoneally (i.p.)]. Both EET-A and EET-X lowered blood pressure in spontaneously hypertensive rats (SHRs) and in angiotensin II (AngII) hypertension. On day 14, the mean arterial pressures in EET analogue-treated AngII-hypertensive and SHRs were 30-50 mmHg (EET-A) and 15-20 mmHg (EET-X) lower than those in vehicle-treated controls. These EET analogues (10 mg/kg per day) were further tested in AngII hypertension by administering orally in drinking water for 14 days and EET-A lowered blood pressure. Additional experiments demonstrated that EET-A inhibits epithelial sodium channel (ENaC) activity in cultured cortical collecting duct cells and reduced renal expression of ENaC subunits in AngII hypertension. In conclusion, we have characterized EET-A as an orally active antihypertensive EET analogue that protects vascular endothelial function and has ENaC inhibitory activity in AngII hypertension.

Elderly men with renal dysfunction are most at risk for poor outcome after neck of femur fractures

both acute and chronic renal dysfunction (ARD and CRD) have been reported to influence outcomes after neck of femur fractures. We have examined the relationship between the length of stay, mortality and renal dysfunction using biomarkers. These included pre-operative (admission) serum concentrations of urea, creatinine and albumin, and estimated glomerular filtration rates (eGFR) derived from four- and six-variable Modification of Diet in Renal Disease (MDRD) study equations. complete outcomes data for 566 patients and the patterns of variations in the biomarkers were analysed using generalised linear models. Cox-proportional hazard analyses investigated the association between kidney function (as assessed by the above-mentioned biochemical data) and post-operative length of stay and mortality. All patients were stratified for CRD according to their eGFR. serum urea and creatinine were significantly, positively correlated with age. After adjusting for age and sex, risk of mortality was positively related to six-variable eGFR and creatinine, and marginally so for urea. One-year mortality risk thus worsened with stages of CRD (1-4), increasing age and male gender. Risk of discharge from trauma ward, the length of stay in trauma ward and the overall length of stay were not related to urea and creatinine, but were negatively related to both four- and six-variable eGFR. the study has identified elderly renal-impaired males as the subgroup of patients most at risk for poor survival. This subgroup may require a more targeted approach to the management of their fluid and electrolyte homoeostasis to help improve their outcomes.

Carbamazepine affects water and electrolyte homoeostasis in rat--similarities and differences to vasopressin antagonism

Carbamazepine (CBZ) is a drug widely used in the therapy of epilepsy and mood disorders. One frequently observed side effect is hyponatraemia. The role of vasopressin in hyponatraemic action of CBZ is discussed controversially. In this study, we tested the influence of CBZ on water and salt homoeostasis in rat under different hydration states and under vasopressin 2 receptor (V2R) antagonism by satavaptan to elucidate the renal and vasopressin independent action of CBZ. CBZ-treated rats were investigated on metabolic cages after (i) 6 day with ad libitum fluid intake, (ii) moderate water load and (iii) water restriction. The effect of satavaptan was tested in clearance experiments under continuous saline infusion in anaesthetized rats after CBZ pretreatment. Compared to controls, CBZ induced a higher urinary flow rate which was most pronounced (20-fold) after water load and significantly elevated (2-fold) after 10-h water restriction. In addition, CBZ consistently increased renal sodium loss but failed to decrease plasma sodium concentration. In the presence of satavaptan, urinary flow and natriuresis were further increased by CBZ, while there was no differential effect on urea excretion and anion gap. At the investigated dose (50 mg/kg body weight), CBZ did not induce hyponatraemia or antidiuresis in the rat. However, depending on the hydration state, it induced an increased water and electrolyte loss. Its enhanced influence on urinary flow and natriuresis in the presence of satavaptan suggests additional renal targets for CBZ, independent of vasopressin signalling.

Significance of Molecular Testing for Congenital Chloride Diarrhea

Autosomal recessive, congenital chloride diarrhea (CLD) is a form of persistent secretory diarrhea, presenting with polyhydramnios and intractable diarrhea from birth. CLD is caused by mutations in the SLC26A3 gene, encoding a Na+-independent Cl/HCO3- exchanger. The diagnosis is generally made on the basis of high fecal chloride concentration in patients with serum electrolyte homoeostasis corrected by salt substitution. We aimed to evaluate the role of diagnostic genetic testing in CLD. Clinical and laboratory data were collected from 8 unrelated children diagnosed as having or suspected to have CLD. The evaluation included physical examination, routine clinical chemistry, and SLC26A3 mutation analysis by direct sequencing of DNA extracted from buccal swabs or peripheral leukocytes. CLD was initially diagnosed on high fecal chloride concentrations in 7 patients, and by mutation analysis in 1 patient. In 3 of these patients the correct diagnosis was made more than 6 months after birth. We identified SLC26A3 mutations on both alleles in all 8 patients with CLD, including 3 novel missense and 4 novel truncating mutations. We present a compilation of reported SLC26A3 mutations and polymorphisms. The diagnosis and therapy of CLD were considerably delayed in 3 of 8 patients from this series, highlighting the potential of misdiagnosing CLD. We add 7 novel mutations, including 3 missense changes of highly conserved residues to a total of 41 mutations in this gene. Molecular analysis is efficient and should be considered as a means of early diagnosis of CLD, especially if the clinical diagnosis remains uncertain.

Hypotonic versus isotonic saline in hospitalised children: a systematic review

Background: The traditional recommendations which suggest that hypotonic intravenous (IV) maintenance fluids are the solutions of choice in paediatric patients have not been rigorously tested in clinical trials, and may...

Prognosis in heart failure with preserved left ventricular systolic function: prospective cohort study

Chronic heart failure due to left ventricular systolic impairment is characterised by a poor prognosis and abnormalities of cardiac structure, autonomic and neurohumoral function, and fluid and electrolyte homoeostasis, all...

ANGIOTENSIN II TYPE 1 RECEPTOR BLOCKADE: A NEW DEVELOPMENT IN CARDIOVASCULAR PHARMACOLOGY

SUMMARY The renin‐angiotensin‐aldosterone system (RAS) plays a central role in blood pressure regulation and fluid and electrolyte homoeostasis. Blockade of this system with inhibitors of angiotensin‐converting enzyme (ACE) has been shown to benefit several groups of patients, including those with essential hypertension, congestive heart failure, and post myocardial infarction. Inhibition of ACE also slows the progression of diabetic renal disease and diabetic retinopathy. The recent development of agents that are specific antagonists of angiotensin II (All) has allowed us to block the RAS at receptor level. Inhibition of angiotensin II receptors has been shown to reduce blood pressure in hypertensive patients, without the side‐effect profile of ACE inhibitors. It has yet to be shown whether manipulating the RAS in this way will confer the same morbidity and mortality benefits as those seen with ACE inhibition. Ongoing research will reveal whether All antagonists are beneficial in congestive heart failure, ischaemic heart disease and diabetes mellitus. The development of this new class of agent provides an exciting opportunity for clinicians to increase their understanding of the role of the RAS in health and disease.

Surgery in patients with renal failure in emergency and elective interventions

The classification of renal insufficiency into stages of full compensation, compensated and decompensated retention and terminal renal failure is of importance if patients with impaired renal function are to undergo elective and emergency surgery. Furthermore, it should be established whether the renal disease is stable or progressive. Preoperatively, particular attention should be paid to problems of fluid and electrolyte homoeostasis as well as to acid-base balance. Many drugs should be avoided altogether in patients with kidney disease.

Non-steroidal anti-inflammatory drugs and renal function.

The use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a range of renal effects, including interference with fluid and electrolyte homoeostasis. Common adverse effects are generally mild and transient; less common but more severe effects include reversible renal insufficiency, interstitial nephritis and papillary necrosis. Any of these effects can influence the clinical course of patients at risk because of illness, debility or age. Acute renal failure associated with NSAID use has been reported to account for up to 15.6% of cases of drug-induced renal failure. NSAID-induced haemodynamic renal failure is virtually always reversible with appropriate management; the relatively rare complications of interstitial nephritis and papillary necrosis are more often irreversible. NSAID-related impairment of kidney function is probably due in large part to inhibition of prostaglandin synthesis. Use of a prostaglandin E1 (PGE1) analogue has been suggested to prevent some of the adverse renal effects of NSAIDs in patients at high risk, an interesting possibility that deserves further evaluation.

Disturbed Fluid and Electrolyte Homoeostasis Following Dehydration in Elderly People

Disturbances in homoeostatic capacity are typical of the ageing process. Changes in the neuroendocrine controls of salt and water homoeostasis with age make elderly people more susceptible to fluid and electrolyte disturbances such as dehydration and overhydration. Not only do elderly subjects show reduced thirst and water intake following dehydration, but their kidneys are less able to retain water. This reduced thirst and water intake is not dependent on palatability of the liquids offered as the amounts drunk are no different if water alone or a variety of beverages are offered to healthy elderly dehydrated men. It is of interest that the arginine vasopressin (AVP) response to dehydration is maintained in elderly subjects, indicating that their reduced renal water retentive capacity is due to relative renal resistance to vasopressin. The mechanism underlying the reduced thirst is unclear. Dehydration causes plasma hypertonicity and reduced extracellular fluid (ECF) volume, both of which stimulate thirst and AVP secretion. Elderly subjects show deficits in sensing the reduced ECF volume through reduced low and high pressure baroreceptor sensitivity. In contrast, while the AVP responses to hypertonicity are maintained, the thirst responses seem to be reduced. It seems unlikely that the primary sensing 'osmoreceptor' neurons in the hypothalamus leading to AVP secretion or thirst would be differentially affected by age. Therefore the thirst deficit may result from changes with age in the more poorly defined pathways that bring thirst to consciousness. Following rehydration, thirst and AVP secretion are inhibited in young individuals thus avoiding overhydration.(ABSTRACT TRUNCATED AT 250 WORDS)

A comprehensive review of the salt and blood pressure relationship.

Salt has played an important role in the human diet since earliest times. However, increases in the availability and consumption of dietary salt have raised concerns that excessive intakes may cause hypertension. Although recent research has linked salt intake to variations in blood pressure, definitive conclusions have been lacking. Uncertainties in this area are due to the complex effects of salt on the cardiovascular system and on blood pressure regulation. Nevertheless, many of these complexities are now well understood and have been summarized in this review. Among the topics we examine are the effects of salt on fluid and electrolyte homoeostasis; potential mechanisms of salt-induced hypertension; the epidemiology of salt intake and blood pressure; the effects of salt restriction and supplementation on blood pressure regulation; the potential roles of sodium and chloride ions, as well as interactions with dietary potassium, calcium, and magnesium; current theories of salt sensitivity; the clinical risks of dietary salt depletion; and the dietary sources of salt.

The effect of aldosterone and the renin-angiotensin system on sodium, potassium and chloride transport by proximal and distal rat colon in vivo.

1. The roles of aldosterone and angiotensin in the direct control of epithelial sodium transport in vivo have been investigated by measurement of electrical p.d. changes and of the fluxes of sodium, potassium and chloride in rat colon, an organ actively involved in electrolyte homoeostasis. Exogenous angiotensin and aldosterone were given by both short- and long-term infusions and endogenous secretion of the hormones was varied by dietary sodium variation and by nephrectomy and/or adrenalectomy. 2. In vitro angiotensin has been shown to influence colonic salt and water absorption but in the present in vivo experiments administered angiotensin had no significant action on p.d. or on the ionic fluxes of the proximal or distal colon. The increase in p.d. produced by infusing aldosterone was unaffected by giving angiotensin concurrently. The effect of sodium depletion in stimulating sodium absorption and potassium secretion was completely abolished by adrenalectomy but was unaffected by nephrectomy. 3. During prolonged infusion of angiotensin into adrenalectomized rats, a small fall in faecal fluid and sodium content was observed, but this change would have little significance in sodium homoeostasis. 4. Aldosterone and sodium depletion stimulated sodium absorption in both proximal and distal colon but significant increase in potassium secretion was demonstrable only in the distal colon. Bicarbonate secretion (by calculation) was unaffected. In the proximal colon, the increased sodium absorption appeared to be accompanied by increased chloride absorption while in the distal colon it was principally the sodium-potassium exchange that was increased. 5. Adrenalectomy reduced potassium secretion in both proximal and distal colon but sodium absorption was only significantly reduced in the proximal colon. 6. It was concluded that there is no evidence that angiotensin in the living animal has a role as an important salt retaining hormone by direct epithelial action. Aldosterone has a considerable effect which is independent of the presence of angiotensin, and which differs in proximal and distal colon in regard to the relative effects on chloride absorption and potassium secretion.

Prolonged starvation--a dangerous procedure?

Experience with 18 obese patients who have undergone prolonged (60 days) therapeutic starvation shows that in general this is a safe procedure, but there are significant associated hazards, particularly a breakdown in electrolyte homoeostasis. The need for close biochemical control of such patients is stressed.