Evaluation of Diuretic and Antioxidant Properties in Aqueous Bark and Fruit Extracts of Pine.

OBJECTIVE: The present study has been carried out to evaluate the diuretic and antioxidant properties of pine herb in an animal model. MATERIALS AND METHODS: 45 adult male rats were randomly divided into nine groups including: groups I (the negative control), groups II (positive control, furosemide 10 mg/kg), groups III to VIII (treatment groups received 100, 200, 400 mg/kg of the aqueous extracts of bark and fruit) and group IX received the combination of aqueous extract of bark (100 mg/kg) and the fruit (100 mg/kg). The urine output, glomerular filtration rate (GFR), electrolytes, urea, and creatinine levels were evaluated. Furthermore, the phenolic content and antioxidant activity of both extracts were also assessed using 2, 2-diphenyl-1-picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP) and Folin-Ciocalteu methods. RESULTS: The aqueous extracts of the pine bark and fruit increased the urinary output in a dosedependent manner. The combination of the two extracts compared to the other extracts alone significantly increased the serum potassium level. This study also showed each extract increase creatinine clearance in a dose-dependent manner (p<0.01 and p<0.05). The increase of GFR in the combination group was not significant. The current data showed a significant increase in the total phenolic content in pine bark extract in compared with the fruit extract. CONCLUSION: The pine bark and fruit can be useful in the prevention and treatment of kidney stones due to the high diuretic properties and antioxidant activity.

Abatement of neurobehavioral and neurochemical dysfunctions in cerebral ischemia/reperfusion injury by Tetrapleura tetraptera fruit extract.

ETHNOPHARMACOLOGICAL RELEVANCE: Tetrapleura tetraptera Taub. (family Fabaceae), is generally found in the lowland forest of tropical Africa. Its leaves and fruits are traditionally used in West Africa for the management of brain disorders. AIM OF THE STUDY: This study evaluated the effect of Tetrapleura tetraptera methanol fruit extract (TT) on bilateral common carotid artery occlusion-induced cerebral ischemia/reperfusion (I/R) injury in male Wistar rats. MATERIALS AND METHODS: Rats pretreated with TT for 7 days before a 30 min bilateral common carotid artery occlusion and reperfusion for 24 h were assessed for neurobehavioural deficits. Cortical, striatal and hippocampal oxidative stress, pro-inflammatory events, electrolyte imbalance and neurochemical dysfunctions, as well as hippocampal histopathological alterations, were also evaluated. HPLC-DAD analysis was performed to identify likely compounds contributing to the bioactivity of the extract. RESULTS: TT reduced I/R-induced behavioral deficits and ameliorated I/R-induced oxidative stress by restoring reduced glutathione level, increasing catalase and superoxide dismutase activities, and also reducing both lipid peroxidation and xanthine oxidase activity in the brain. TT attenuated I/R-increased myeloperoxidase and lactate dehydrogenase activities as well as disturbances in Na+ and K+ levels. Alterations elicited by I/R in the activities of Na+/K+ ATPase, complex I, glutamine synthetase, acetylcholinesterase, and dopamine metabolism were abated by TT pretreatment. TT prevented I/R-induced histological changes in the hippocampus. HPLC-DAD analysis revealed the presence of aridanin, a marker compound for Tetrapleura tetraptera, and other phytochemicals. CONCLUSIONS: These findings indicate that Tetrapleura tetraptera fruit has a protective potential against stroke through modulation of redox and electrolyte imbalances, and attenuation of neurotransmitter dysregulation and other neurochemical dysfunctions. Tetrapleura tetraptera fruit could be a promising source for the discovery of bioactives for stroke therapy.

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

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

Glucocorticoids Reverse Diluted Hyponatremia Through Inhibiting Arginine Vasopressin Pathway in Heart Failure Rats.

Background Arginine vasopressin dependent antidiuresis plays a key role in water-sodium retention in heart failure. In recent years, the role of glucocorticoids in the control of body fluid homeostasis has been extensively investigated. Glucocorticoid deficiency can activate V2R (vasopressin receptor 2), increase aquaporins expression, and result in hyponatremia, all of which can be reversed by glucocorticoid supplement. Methods and Results Heart failure was induced by coronary artery ligation for 8 weeks. A total of 32 rats were randomly assigned to 4 groups (n=8/group): sham surgery group, congestive heart failure group, dexamethasone group, and dexamethasone in combination with glucocorticoid receptor antagonist RU486 group. An acute water loading test was administered 6 hours after drug administration. Left ventricular function was measured by a pressure-volume catheter. Protein expressions were determined by immunohistochemistry and immunoblotting. The pressure-volume loop analysis showed that dexamethasone improves cardiac function in rats with heart failure. Western blotting confirmed that dexamethasone remarkably reduces the expressions of V2R, aquaporin 2, and aquaporin 3 in the renal-collecting ducts. As a result of V2R downregulation, the expressions of glucocorticoid regulated kinase 1, apical epithelial sodium channels, and the furosemide-sensitive Na-K-2Cl cotransporter were also downregulated. These favorable effects induced by dexamethasone were mostly abolished by the glucocorticoid receptor inhibitor RU486, indicating that the aforementioned effects are glucocorticoid receptor mediated. Conclusions Glucocorticoids can reverse diluted hyponatremia via inhibiting the vasopressin receptor pathway in rats with heart failure.

Effects of diluted bitumen exposure and recovery on the seawater acclimation response of Atlantic salmon smolts.

Petrogenic chemicals are common and widespread contaminants in the aquatic environment. In Canada, increased extraction of bitumen from the oil sands and transport of the major crude oil export product, diluted bitumen (dilbit), amplifies the risk of a spill and contamination of Canadian waterways. Fish exposed to sublethal concentrations of crude oil can experience a variety of adverse physiological effects including osmoregulatory dysfunction. As regulation of water and ion balance is crucial during the seawater transition of anadromous fish, the hypothesis that dilbit impairs seawater acclimation in Atlantic salmon smolts (a fish at risk of exposure in Canada) was tested. Smolts were exposed for 24 d to the water-soluble fraction of dilbit in freshwater, and then transferred directly to seawater or allowed a 1 wk depuration period in uncontaminated freshwater prior to seawater transfer. The seawater acclimation response was quantified at 1 and 7 d post-transfer using established hematological, tissue, and molecular endpoints including gill Na+/K+-ATPase gene expression (nka). All smolts, irrespective of dilbit exposure, increased serum Na+ concentrations and osmolality within 1 d of seawater transfer. The recovery of these parameters to freshwater values by 7 d post-transfer was likely driven by the increased expression and activity of Na+/K+-ATPase in the gill. Histopathological changes in the gill were not observed; however, CYP1A-like immunoreactivity was detected in the pillar cells of gill lamellae of fish exposed to 67.9 µg/L PAC. Concentration-specific changes in kidney expression of a transmembrane water channel, aquaporin 3, occurred during seawater acclimation, but were resolved with 1 wk of depuration and were not associated with histopathological changes. In conclusion, apart from a robust CYP response in the gill, dilbit exposure did not greatly impact common measures of seawater acclimation, suggesting that significant osmoregulatory dysfunction is unlikely to occur if Atlantic salmon smolts are exposed sub-chronically to dilbit.

Bromelain reversed electrolyte imbalance in the chronically constricted sciatic nerve of Wistar rats.

Derangement of electrolyte in the sensory nervous system has been attributed to the development and maintenance of hyperalgesic and allodynic symptoms in painful neuropathy. This study investigated the effect of bromelain on electrolyte imbalance in chronically constricted sciatic nerve of rats (a model of neuropathic pain). Forty Wistar rats, divided into five groups of eight animals each were used for this study. von Frey filaments, tail immersion and acetone spray tests were used to assessed allodynic and thermal hyperalgesic symptoms in the Wistar rats. Sodium ion (Na+), potassium ion (K+), calcium ion (Ca2+) and chloride ion (Cl-) concentrations as well as sodium-potassium and calcium electrogenic pump (Na-K ATPase and Ca ATPase, respectively) activities were estimated using spectrophotometry techniques. Bromelain significantly (p < 0.05) reversed elevation of Na+ and Ca2+ concentration compared with sciatic nerve chronic constriction injury (snCCI) group (35.68 ± 1.71 vs 44.46 ± 1.24 mg/ml/mg protein and 1.06 ± 0.19 vs 6.66 ± 0.03 mg/ml/mg protein, respectively). There were also significant (p < 0.05) increases in the level of K+ (0.84 ± 0.02 vs 0.36 ± 0.05 mg/ml/mg protein) and Cl- (18.51 ± 0.29 vs 15.82 ± 0.21 mg/ml/mg protein). Bromelain reduced the activities of Ca2+ electrogenic pumps significantly compared with snCCI. This study therefore suggests that bromelain mitigated electrolyte imbalance in chronic constricted injury of the sciatic nerve implying that this may be an important mechanism for the anti-nociceptive effect of bromelain.

Aquaporins in cancer development: opportunities for bioinorganic chemistry to contribute novel chemical probes and therapeutic agents.

Aquaporins (AQPs) are membrane proteins allowing permeation of water, glycerol & hydrogen peroxide across biomembranes, and playing an important role in water homeostasis in different organs, exocrine gland secretion, urine concentration, skin moisturization, fat metabolism and neural signal transduction. Notably, a large number of studies showed that AQPs are closely associated with cancer biological functions and expressed in more than 20 human cancer cell types. Furthermore, AQP expression is positively correlated with tumour types, grades, proliferation, migration, angiogenesis, as well as tumour-associated oedema, rendering these membrane channels attractive as both diagnostic and therapeutic targets in cancer. Recent developments in the field of AQPs modulation have identified coordination metal-based complexes as potent and selective inhibitors of aquaglyceroporins, opening new avenues in the application of inorganic compounds in medicine and chemical biology. The present review is aimed at providing an overview on AQP structure and function, mainly in relation to cancer. In this context, the exploration of coordination metal compounds as possible inhibitors of aquaporins may open the way to novel chemical approaches to study AQP roles in tumour growth and potentially to new drug families. Thus, we describe recent results in the field and reflect upon the potential of inorganic chemistry in providing compounds to modulate the activity of "elusive" membrane targets as the aquaporins.

Efficacy of Glucose or Amino Acid-Based Commercial Beverages in Meeting Oral Rehydration Therapy Goals After Acute Hypertonic and Isotonic Dehydration.

BACKGROUND: The efficacy of different commercial beverage compositions for meeting oral rehydration therapy (ORT) goals in the treatment of acute dehydration in healthy humans has not been systematically tested. The objective of the study was to compare fluid retention, plasma volume (PV), and interstitial fluid (ISF) volume restoration when using 1 popular glucose-based and 1 novel amino acid-based (AA) commercial ORT beverage following experimental hypertonic or isotonic dehydration. METHODS: Twenty-six healthy adults (21 males, 5 females) underwent either a controlled bout of hypertonic (n = 13) or isotonic (n = 13) dehydration (3%-4% body mass) via eccrine or renal body water and electrolyte losses induced using exercise-heat stress (EHS) or Lasix administration (LAS), respectively. Rehydration was achieved over 90 minutes by matching fluid intake to water losses (1:1) using a sports drink (SP) or AA commercial ORT beverage. Fluid retention (water and electrolytes), PV, and ISF volume changes were tracked for 180 minutes. RESULTS: AA produced significantly (P <0.05) greater fluid retention (75% vs 57%), ISF volume restoration, and tended (P = 0.06) to produce greater PV restoration in trial EHS. In trial LAS, neither beverage exceeded 65% retention, but AA replaced electrolytes and preserved ISF volume better than SP (P <0.05). CONCLUSION: The results of this study demonstrate superior rehydration when using AA compared with SP for both hypertonic and isotonic dehydration.

Effect of isotonic versus hypotonic maintenance fluid therapy on urine output, fluid balance, and electrolyte homeostasis: a crossover study in fasting adult volunteers.

BACKGROUND.: Daily and globally, millions of adult hospitalized patients are exposed to maintenance i.v. fluid solutions supported by limited scientific evidence. In particular, it remains unclear whether fluid tonicity contributes to the recently established detrimental effects of fluid, sodium, and chloride overload. METHODS.: This crossover study consisted of two 48 h study periods, during which 12 fasting healthy adults were treated with a frequently prescribed solution (NaCl 0.9% in glucose 5% supplemented by 40 mmol litre -1 of potassium chloride) and a premixed hypotonic fluid (NaCl 0.32% in glucose 5% containing 26 mmol litre -1 of potassium) at a daily rate of 25 ml kg -1 of body weight. The primary end point was cumulative urine volume; fluid balance was thus calculated. We also explored the physiological mechanisms behind our findings and assessed electrolyte concentrations. RESULTS.: After 48 h, 595 ml (95% CI: 454-735) less urine was voided with isotonic fluids than hypotonic fluids ( P <0.001), or 803 ml (95% CI: 692-915) after excluding an outlier with 'exaggerated natriuresis of hypertension'. The isotonic treatment was characterized by a significant decrease in aldosterone ( P <0.001). Sodium concentrations were higher in the isotonic arm ( P <0.001), but all measurements remained within the normal range. Potassium concentrations did not differ between the two solutions ( P =0.45). Chloride concentrations were higher with the isotonic treatment ( P <0.001), even causing hyperchloraemia. CONCLUSIONS.: Even at maintenance rate, isotonic solutions caused lower urine output, characterized by decreased aldosterone concentrations indicating (unintentional) volume expansion, than hypotonic solutions and were associated with hyperchloraemia. Despite their lower sodium and potassium content, hypotonic fluids were not associated with hyponatraemia or hypokalaemia. CLINICAL TRIAL REGISTRATION.: ClinicalTrials.gov (NCT02822898) and EudraCT (2016-001846-24).

Furosemide Prescription During the Dry State Is a Predictor of Long-Term Survival of Stable, Optimally Medicated Patients With Systolic Heart Failure.

BACKGROUND: Furosemide is associated with poor prognosis in patients with heart failure and reduced ejection fraction (HFrEF). AIM: To evaluate the association between daily furosemide dose prescribed during the dry state and long-term survival in stable, optimally medicated outpatients with HFrEF. POPULATION AND METHODS: Two hundred sixty-six consecutive outpatients with left ventricular ejection fraction <40%, clinically stable in the dry state and on optimal heart failure therapy, were followed up for 3 years in a heart failure unit. The end point was all-cause death. There were no changes in New York Heart Association class and therapeutics, including diuretics, and no decompensation or hospitalization during 6 months. Furosemide doses were categorized as low or none (0-40 mg/d), intermediate (41-80 mg/d), and high (>80 mg). Cox regression was adjusted for significant confounders. RESULTS: The 3-year mortality rate was 33.8%. Mean dose of furosemide was 57.3 ± 21.4 mg/d. A total of 47.6% of patients received the low dose, 42.1% the intermediate dose, and 2.3% the high dose. Receiver operating characteristics for death associated with furosemide dose showed an area under the curve of 0.74 (95% confidence interval [CI]: 0.68-0.79; P < .001), and the best cutoff was >40 mg/d. An increasing daily dose of furosemide was associated with worse prognosis. Those receiving the intermediate dose (hazard ratio [HR] = 4.1; 95% CI: 2.57-6.64; P < .001) or high dose (HR = 19.8; 95% CI: 7.9-49.6; P < .001) had a higher risk of mortality compared to those receiving a low dose. Patients receiving >40 mg/d, in a propensity score-matched cohort, had a greater risk of mortality than those receiving a low dose (HR = 4.02; 95% CI: 1.8-8.8; P = .001) and those not receiving furosemide (HR = 3.9; 95% CI: 0.07-14.2; P = .039). CONCLUSION: Furosemide administration during the dry state in stable, optimally medicated outpatients with HFrEF is unfavorably associated with long-term survival. The threshold dose was 40 mg/d.

Carbohydrate supplementation stabilises plasma sodium during training with high intensity.

BACKGROUND: Investigations of the effect of beverages containing carbohydrates, only, on the sodium and fluid balance during intermittent exercise of high intensity are rare. Therefore, we compared the effects of water and carbohydrate supplementation on plasma, blood volume, and electrolyte shifts during intermittent exercise. METHODS: Ten male subjects performed an intermittent exercise test twice. In one trial, tap water (4 ml/kg/15 min) was consumed (Plac trial). In the other trial, the same amount of water supplemented with maltodextrin to achieve a 9.1 % carbohydrate solution (CHO trial) was ingested. Training schedule: warm-up at 50 % for 15 min. Afterwards, power changed between 100 % of the maximum power from a previous incremental test minus 10 and 10 W for each 30 s. Venous blood was sampled to measure electrolytes, osmolality, [protein], hct, [Lactate], [glucose], [Hb] and catecholamines. Hydration status was evaluated by BIA before and after exercise. RESULTS: After beverage ingestion [glucose] was significantly higher in CHO until the end of the trial. Starting with similar resting values, osmolality increased significantly more during CHO (p = 0.002). PV decreased by 5 % under both conditions, but recovered partly during exercise under Plac (p = 0.002). [Na+] and [Cl(-)] decreased with Plac during exercise (both p < 0.001) but remained constant during exercise with CHO. CONCLUSIONS: Sole carbohydrate supplementation seems to stabilise plasma [Na+]. This cannot be explained simply by a cotransport of glucose and [Na+], because that should lead to a recovery of the blood and plasma volume under CHO. In contrast, this was found during exercise with Plac.

Diuretic and serum electrolyte regulation potential of aqueous methanolic extract of Solanum surattense fruit validates its folkloric use in dysuria.

BACKGROUND: Solanum surattense Burm. (Solanaceae) is traditionally used for management of various ailments. The study was conducted for provision of pharmacological justification for folkloric uses of Solanum surattense in the treatment of dysuria. METHODS: Rats were randomly divided into 5 groups, each of (n = 6). Aqueous methanolic fruit extract of S. surattense were also administered intraperitoneally to the rats at doses of 50, 70 and 100 mg/kg. Furosemide (10 mg/kg i.p) was used as standard drug whereas controls were given saline solution (40 mL/kg i.p). The electrolytes in urine were measured using a flame photometer whereas serum sodium, potassium, calcium, bicarbonate and blood urea nitrogen (BUN) were determined by using an automatic analyzer. Urine osmolality was assayed by the micro-osmometer. RESULTS: The extract S. surattense induced diuretic effects in a dose-dependent manner as compared with control. Upon administration of extract (70 and 100 mg/kg), we observed the prominent (p < 0.01) increase in the urine volume and osmolality in comparison to control group. However, plant extract (100 mg/kg) significantly increase the urinary electrolyte excretion especially calcium (p < 0.05) to that of the furosemide whereas level of magnesium remains constant. Moreover, our results showed a decrease in serum levels of sodium, potassium, calcium and blood urea nitrogen (BUN), but concentration dependent increase in bicarbonate was found in the test groups. There was no substantial change in the pH of urine samples of the extract-treated groups. CONCLUSION: These results indicate that S. surattense investigated exert its action by causing diuresis in the treatment of dysuria.

The liquorice root derivative glycyrrhetinic acid can ameliorate ionoregulatory disturbance in rainbow trout (Oncorhynchus mykiss) abruptly exposed to ion-poor water.

To consider the idea that a dietary botanical supplement could act as an adaptogen in a teleost fish, the effect of a liquorice root derivative (18ß-glycyrrhetinic acid, 18ßGA) on rainbow trout following an acute ionoregulatory stressor was examined. Freshwater (FW) trout were fed a control or 18ßGA supplemented diet (0, 5, or 50µg 18ßGA/g diet) for 2weeks, then abruptly exposed to ion-poor water (IPW) for 24h. Following IPW exposure, muscle moisture content and serum cortisol levels elevated and serum [Na(+)] and/or [Cl(-)] reduced in control and 50µg/g 18ßGA-fed fish. However, these endpoints were unaltered in 5µg/g 18ßGA-fed fish. Gill tissue was investigated for potential mechanisms of 18ßGA action by examining mRNA abundance of genes encoding corticosteroid receptors (CRs), 11ß-hydroxysteroid dehydrogenase 2 (11ß-hsd2), and tight junction (TJ) proteins, as well as Na(+)-K(+)-ATPase and H(+)-ATPase activity, and mitochondrion-rich cell (MRC) morphometrics. Following IPW exposure, CR and 11ß-hsd2 mRNA, MRC fractional surface, Na(+)-K(+)-ATPase and H(+)-ATPase activity were unaltered or decreased in 50µg 18ßGA fish, as was mRNA encoding select TJ proteins. In contrast, 5µg 18ßGA-fed fish exhibited elevated 11ß-hsd2 and CR mRNA abundance versus 50µg 18ßGA-fed, and reduced MRC apical area as well as some differences in TJ protein mRNA abundance versus control fish. Data suggest that 18ßGA, at low levels, may be adaptogenic in trout and might help to ameliorate ionoregulatory perturbation following IPW exposure. This seems to occur, in part, through 18ßGA-induced alterations in the biochemistry and physiology of the gill.

Corticosteroids in the Management of Hyponatremia, Hypovolemia, and Vasospasm in Subarachnoid Hemorrhage: A Meta-Analysis.

BACKGROUND: Cerebral vasospasm and sodium and fluid imbalances are common sequelae of aneurysmal subarachnoid hemorrhage (SAH) and cause of significant morbidity and mortality. Studies have shown the benefit of corticosteroids in the management of these sequelae. We have reviewed the literature and analyzed the available data for corticosteroid use after SAH. METHODS: PubMed, EMBASE, and Cochrane electronic databases were searched without language restrictions, and 7 observational, controlled clinical studies of the effect of corticosteroids in the management of SAH patients were identified. Data on sodium and fluid balances, symptomatic vasospasm (SVS), and outcomes were pooled for meta-analyses using the Mantel-Haenszel random effects model. RESULTS: Corticosteroids, specifically hydrocortisone and fludrocortisone, decreased natriuretic diuresis and incidence of hypovolemia. Corticosteroid administration is associated with lower incidence of SVS in the absence of nimodipine, but does not alter the neurological outcome. CONCLUSIONS: Supplementation of corticosteroids with mineralocorticoid activity, such as hydrocortisone or fludrocortisone, helps in maintaining sodium and volume homeostasis in SAH patients. Larger trials are warranted to confirm the effects of corticosteroids on SVS and patient outcomes.

Creatine for women: a review of the relationship between creatine and the reproductive cycle and female-specific benefits of creatine therapy.

The creatine/phosphocreatine/creatine kinase circuit is instrumental in regulating high-energy phosphate metabolism, and the maintenance of cellular energy turnover. The mechanisms by which creatine is able to buffer and regulate cellular energy balance, maintain acid-base balance, and reduce the effects of oxidative stress have led to a large number of studies into the use of creatine supplementation in exercise performance and to treat diseases associated with cellular energy depletion. Some of these studies have identified sex-specific responses to creatine supplementation, as such; there is the perception, that females might be less receptive to the benefits of creatine supplementation and therapy, compared to males. This review will describe the differences in male and female physique and physiology that may account for such differences, and discuss the apparent endocrine modulation of creatine metabolism in females. Hormone-driven changes to endogenous creatine synthesis, creatine transport and creatine kinase expression suggest that significant changes in this cellular energy circuit occur during specific stages of a female's reproductive life, including pregnancy and menopause. Recent studies suggest that creatine supplementation may be highly beneficial for women under certain conditions, such as depression. A greater understanding of these pathways, and the consequences of alterations to creatine bioavailability in females are needed to ensure that creatine is used to full advantage as a dietary supplement to optimize and enhance health outcomes for women.

Non-steroidal mineralocorticoid receptor antagonism for the treatment of cardiovascular and renal disease.

Pharmaceutical antagonism of the mineralocorticoid receptor (MR) can protect against organ damage caused by elevated aldosterone levels in patients experiencing heart failure (HF), chronic kidney disease (CKD), primary aldosteronism, and hypertension. While traditional steroid-based MR antagonists effectively reduce mortality rates and extend patient survival, their broad application has been limited by significant side effects, most notably hyperkalaemia. Recently, finerenone (BAY 94-8862) has emerged as a next-generation non-steroidal dihydropyridine-based MR antagonist designed to minimize off-target effects while maintaining potent efficacy. In this review, the outcomes of finerenone therapy in several diseases associated with MR activity are explored. The (pre-) clinical efficacy of finerenone is compared with that of traditional steroid-based MR antagonists. Finally, recent and ongoing clinical trials using finerenone to treat chronic HF, CKD, and diabetic nephropathy are discussed. Taken together, pre-clinical and clinical evidence suggests that finerenone may achieve equivalent organ-protective effects with reduced levels of electrolyte disturbance compared with traditional steroid-based MR antagonists. This supports further clinical development of finerenone for the treatment of cardiovascular and renal disease.

Pathophysiology and clinical presentations of salt-losing tubulopathies.

At least three renal tubular segments are involved in the pathophysiology of salt-losing tubulopathies (SLTs). Whether the pathogenesis starts either in the thick ascending limb of the loop of Henle (TAL) or in the distal convoluted tubule (DCT), it is the function of the downstream-localized aldosterone sensitive distal tubule (ASDT) to contribute to the adaptation process. In isolated TAL defects (loop disorders) ASDT adaptation is supported by upregulation of DCT, whereas in DCT disorders the ASDT is complemented by upregulation of TAL function. This upregulation has a major impact on the clinical presentation of SLT patients. Taking into account both the symptoms and signs of primary tubular defect and of the secondary reactions of adaptation, a clinical diagnosis can be made that eventually leads to an appropriate therapy. In addition to salt wasting, as occurs in all SLTs, characteristic features of loop disorders are hypo- or isosthenuric polyuria and hypercalciuria, whereas characteristics of DCT disorders are hypokalemia and (symptomatic) hypomagnesemia. In both SLT categories, replacement of urinary losses is the primary goal of treatment. In loop disorders COX inhibitors are also recommended to mitigate polyuria, and in DCT disorders magnesium supplementation is essential for effective treatment. Of note, the combination of a salt- and potassium-rich diet together with an adequate fluid intake is always the basis of long-term treatment in all SLTs.

The type-1 cannabinoid receptor modulates the hydroelectrolytic balance independently of the energy homeostasis during salt load.

Hydroelectrolytic imbalances, such as saline load (SL), trigger behavioral and neuroendocrine responses, such as thirst, hypophagia, vasopressin (AVP) and oxytocin (OT) release and hypothalamus­pituitary­adrenal (HPA) axis activation. To investigate the participation of the type-1 cannabinoid receptor (CB1R) in these homeostatic mechanisms,male adult Wistar rats were subjected to SL (0.3MNaCl) for four days. SL induced not only increases in the water intake and plasma levels of AVP, OT and corticosterone, as previously described, but also increases in CB1R expression in the lamina terminalis, which integrates sensory afferents, aswell as in the hypothalamus, the main integrative and effector area controlling hydroelectrolytic homeostasis. A more detailed analysis revealed that CB1R-positive terminals are in close apposition with not only axons but also dendrites and secretory granules of magnocellular neurons, particularly vasopressinergic cells. In satiated and euhydrated animals, the intracerebroventricular administration of the CB1R selective agonist ACEA (0.1 µg/5 µL) promoted hyperphagia, but this treatment did not reverse the hyperosmolality-induced hypophagia in the SL group. Furthermore, ACEA pretreatment potentiated water intake in the SL animals during rehydration as well as enhanced the corticosterone release and prevented the increase in AVP and OT secretion induced by SL. The same parameters were not changed by ACEA in the animals whose daily food intake was matched to that of the SL group (Pair-Fed). These data indicate that CB1Rs modulate the hydroelectrolytic balance independently of the food intake during sustained hyperosmolality and hypovolemia.

Type 1 cannabinoid receptor modulates water deprivation-induced homeostatic responses.

The present study investigated the type 1 cannabinoid receptor (CB1R) as a potential candidate to mediate the homeostatic responses triggered by 24 h of water deprivation, which constitutes primarily a hydroelectrolytic challenge and also significantly impacts energy homeostasis. The present results demonstrated for the first time that CB1R mRNA expression is increased in the hypothalamus of water-deprived (WD) rats. Furthermore, the administration of ACEA, a CB1R selective agonist, potentiated WD-induced dipsogenic effect, whereas AM251, a CB1R antagonist, attenuated not only water but also salt intake in response to WD. In parallel with the modulation of thirst and salt appetite, we confirmed that CB1Rs are essential for the development of appropriated neuroendocrine responses. Although the administration of ACEA or AM251 did not produce any effects on WD-induced arginine vasopressin (AVP) secretion, oxytocin (OXT) plasma concentrations were significantly decreased in WD rats treated with ACEA. At the genomic level, ACEA significantly decreased AVP and OXT mRNA expression in the hypothalamus of WD rats, whereas AM251 potentiated both basal and WD-induced stimulatory effects on the transcription of AVP and OXT genes. In addition, we showed that water deprivation alone upregulated proopiomelanocortin, Agouti-related peptide, melanin-concentrating hormone, and orexin A mRNA levels in the hypothalamus, and that CB1Rs regulate main central peptidergic pathways controlling food intake, being that most of these effects were also significantly influenced by the hydration status. In conclusion, the present study demonstrated that CB1Rs participate in the homeostatic responses regulating fluid balance and energy homeostasis during water deprivation.

Urinary parameters predictive and electrolyte disturbances of cisplatin-induced acute renal associated with cancer as a critical target of the chemotherapeutic agent in patients with solid tumors.

Cisplatin (CP) is a remarkably effective Pt-based anticancer drug, but it also exhibits severe toxic side effects, including nephrotoxicity and ototoxicity, and CP nephrotoxicity is a major constraint for the treatment of solid tumors. This study was designed to evaluate the electrolyte and biochemical changes in dogs with acute kidney injury (acute renal failure) following administration of CP as a chemotherapeutic agent to exhibit broad efficacy in solid tumors. A total of 10 adult male dogs were selected (treated dogs = 7 and control dogs = 3). Cisplatin-treated animals were received 0.75 mg/kg via intravenous for 5 consecutive days. Urine and blood samples on days 0 (pre-dosing), 1, 2, 3, 4, 7, 10, 14, and 28 (post-dosing) were collected. For tracking the signs of toxicity with cisplatin, clinical examination was performed for 2 times a day. Serum samples were assayed urea, creatinine, sodium, chloride, potassium, calcium, phosphorus, and urine samples were used to measure creatinine. Serum creatinine levels indicating renal function (glomerular filtration rate) was 0.66 and 0.94 mg/dL in day 0, respectively, in treatment and control animals. After day 2, a significant change in creatinine was observed in treatment animals. On the end day of the study control and treatments, creatinine was measured with mean of 1.35 and 1.00 mg/dL, respectively. Electrolyte disturbances were observed after several days of cisplatin administration including changes in levels of sodium, potassium, phosphorus, calcium, and chloride. Clinical observations also identified CP toxicity. This study for the first time showed that compensation electrolyte abnormalities in dogs following administration of cisplatin is essential to prevent deaths by daily monitoring and measurement of electrolytes in patients. This may be advantageous if repetitive cycles of chemotherapy or subsequent administration of high dose chemotherapy were planned.