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Cardiovascular Diabetology Aug 2023Patients with heart failure have increased cardiac filling pressures, circulating natriuretic peptides, and physical signs of fluid retention, which are related to... (Review)
Review
Patients with heart failure have increased cardiac filling pressures, circulating natriuretic peptides, and physical signs of fluid retention, which are related to sodium retention by the kidneys and are alleviated by conventional diuretics. Sodium-glucose cotransporter 2 (SGLT2) inhibitors interfere with sodium and glucose reabsorption in the proximal renal tubule, but they evoke a marked counterregulatory activation of sodium and water reabsorption in distal nephron segments, which opposes and negates any diuretic effect. Nevertheless, it has been postulated that SGLT2 inhibitors modulate the volume set point, leading selectively to decongestion in patients with fluid overload. This hypothesis was tested in a review of 15 randomized controlled trials of SGLT2 inhibitors in patients with heart failure, with 7 trials focusing on urinary volume within the first week, and 8 trials focusing on objective decongestion at 12 weeks. In trials < 1 week, SGLT2 inhibition increased urine volume in the first 24 h, but typically without a change in urinary sodium excretion, and this diuresis was not sustained. In 8 trials of 12 weeks' duration, none reported alleviation of edema, ascites or pulmonary rales. The 2 trials that evaluated changes in left ventricular filling pressure noted no or small changes (1-2 mm Hg); the two trials that measured interstitial lung water or total blood volume found no effect; and 6 of the 7 trials found no decrease in circulating natriuretic peptides. Therefore, randomized controlled trials do not indicate that SGLT2 inhibitors produce a durable natriuresis or objective decongestion in patients with heart failure.
Topics: Humans; Diuretics; Heart Failure; Natriuresis; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 37533009
DOI: 10.1186/s12933-023-01946-w -
Frontiers in Endocrinology 2020The identification of structurally related hypothalamic hormones that regulate blood pressure and diuresis (vasopressin, VP; CYFQNCPRG-NH) or lactation and uterine... (Comparative Study)
Comparative Study Review
The identification of structurally related hypothalamic hormones that regulate blood pressure and diuresis (vasopressin, VP; CYFQNCPRG-NH) or lactation and uterine contraction (oxytocin, OT; CYIQNCPLG-NH) was a major advance in neuroendocrinology, recognized in the award of the Nobel Prize for Chemistry in 1955. Furthermore, the discovery of central actions of VP and OT as regulators of reproductive and social behavior in humans and other mammals has broadened interest in these neuropeptides beyond physiology into psychology. VP/OT-type neuropeptides and their G-protein coupled receptors originated in a common ancestor of the Bilateria (Urbilateria), with invertebrates typically having a single VP/OT-type neuropeptide and cognate receptor. Gene/genome duplications followed by gene loss gave rise to variety in the number of VP/OT-type neuropeptides and receptors in different vertebrate lineages. Recent advances in comparative transcriptomics/genomics have enabled discovery of VP/OT-type neuropeptides in an ever-growing diversity of invertebrate taxa, providing new opportunities to gain insights into the evolution of VP/OT-type neuropeptide function in the Bilateria. Here we review the comparative physiology of VP/OT-type neuropeptides in invertebrates, with roles in regulation of reproduction, feeding, and water/salt homeostasis emerging as common themes. For example, we highlight recent reports of roles in regulation of oocyte maturation in the sea-squirt , extraoral feeding behavior in the starfish and energy status and dessication resistance in ants. Thus, VP/OT-type neuropeptides are pleiotropic regulators of physiological processes, with evolutionarily conserved roles that can be traced back to Urbilateria. To gain a deeper understanding of the evolution of VP/OT-type neuropeptide function it may be necessary to not only determine the actions of the peptides but also to characterize the transcriptomic/proteomic/metabolomic profiles of cells expressing VP/OT-type precursors and/or VP/OT-type receptors within the framework of anatomically and functionally identified neuronal networks. Furthermore, investigation of VP/OT-type neuropeptide function in a wider range of invertebrate species is now needed if we are to determine how and when this ancient signaling system was recruited to regulate diverse physiological and behavioral processes in different branches of animal phylogeny and in contrasting environmental contexts.
Topics: Animals; Evolution, Molecular; Humans; Invertebrates; Neuropeptides; Oxytocin; Vasopressins
PubMed: 32362874
DOI: 10.3389/fendo.2020.00225 -
Journal of the American Society of... Nov 2021Over the last decade, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless,...
BACKGROUND
Over the last decade, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, approximately 20% of all patients with tubulopathy lack a genetic diagnosis.
METHODS
We performed whole-exome and -genome sequencing of a patient cohort with a novel, inherited, salt-losing tubulopathy; hypomagnesemia; and dilated cardiomyopathy. We also conducted subsequent functional analyses of identified variants of , a gene that encodes a small Rag guanosine triphosphatase (GTPase).
RESULTS
In eight children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt wasting, and nephrocalcinosis, we identified heterozygous missense variants in that mostly occurred . Six of these patients also had dilated cardiomyopathy and three underwent heart transplantation. We identified a heterozygous variant in that segregated with the phenotype in eight members of a large family with similar kidney manifestations. The GTPase RagD, encoded by , plays a role in mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron included the thick ascending limb and the distal convoluted tubule. The identified variants were shown to induce a constitutive activation of mTOR signaling .
CONCLUSIONS
Our findings establish a novel disease, which we call autosomal dominant kidney hypomagnesemia (ADKH-RRAGD), that combines an electrolyte-losing tubulopathy and dilated cardiomyopathy. The condition is caused by variants in the gene, which encodes Rag GTPase D; these variants lead to an activation of mTOR signaling, suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function.
Topics: Cardiomyopathy, Dilated; Female; HEK293 Cells; Humans; Hypercalciuria; Kidney Diseases; Kidney Tubules, Distal; Male; Models, Molecular; Monomeric GTP-Binding Proteins; Mutation, Missense; Natriuresis; Nephrocalcinosis; Pedigree; Protein Conformation; Renal Tubular Transport, Inborn Errors; Seizures; Signal Transduction; TOR Serine-Threonine Kinases; Exome Sequencing; Whole Genome Sequencing
PubMed: 34607910
DOI: 10.1681/ASN.2021030333 -
Frontiers in Endocrinology 2021Apelin, a (neuro)vasoactive peptide, plays a prominent role in controlling body fluid homeostasis and cardiovascular functions. Experimental data performed in rodents... (Review)
Review
Apelin, a (neuro)vasoactive peptide, plays a prominent role in controlling body fluid homeostasis and cardiovascular functions. Experimental data performed in rodents have shown that apelin has an aquaretic effect its central and renal actions. In the brain, apelin inhibits the phasic electrical activity of vasopressinergic neurons and the release of vasopressin from the posterior pituitary into the bloodstream and in the kidney, apelin regulates renal microcirculation and counteracts in the collecting duct, the antidiuretic effect of vasopressin occurring the vasopressin receptor type 2. In humans and rodents, if plasma osmolality is increased by hypertonic saline infusion/water deprivation or decreased by water loading, plasma vasopressin and apelin are conversely regulated to maintain body fluid homeostasis. In patients with the syndrome of inappropriate antidiuresis, in which vasopressin hypersecretion leads to hyponatremia, the balance between apelin and vasopressin is significantly altered. In order to re-establish the correct balance, a metabolically stable apelin-17 analog, LIT01-196, was developed, to overcome the problem of the very short half-life (in the minute range) of apelin In a rat experimental model of vasopressin-induced hyponatremia, subcutaneously (.) administered LIT01-196 blocks the antidiuretic effect of vasopressin and the vasopressin-induced increase in urinary osmolality, and induces a progressive improvement in hyponatremia, suggesting that apelin receptor activation constitutes an original approach for hyponatremia treatment.
Topics: Apelin; Apelin Receptors; Brain; Humans; Neurons; Vasopressins; Water-Electrolyte Balance
PubMed: 34880830
DOI: 10.3389/fendo.2021.735515 -
Journal of Clinical Medicine Aug 2023(1) Background: This study aimed to determine the relationship between metabolic urine conditions and the formation, severity, and composition of encrustations in...
(1) Background: This study aimed to determine the relationship between metabolic urine conditions and the formation, severity, and composition of encrustations in ureteral stents. (2) Methods: Ninety stone-former patients requiring a double-J stent were prospectively enrolled. We collected 24 h metabolic urine samples and demographic data, including indwelling time and previous stone composition. The total deposit weight was obtained, and a macroscopic classification according to the degree of encrustation (null, low, moderate, and high) was created, allowing for intergroup comparisons. Stereoscopic and scanning electron microscopy were performed to identify the type of embedded deposits (calcium oxalate, uric acid, and infectious and non-infectious phosphates). (3) Results: In total, 70% of stents were encrusted; thereof, 42% had a moderate degree of encrustation. The most common encrustation type was calcium oxalate, but infectious phosphates were predominant in the high-encrustation group ( < 0.05). A direct correlation was observed between the purpose-built macroscopic classification and the encrustation weights ( < 0.001). Greater calciuria, uricosuria, indwelling time, and decreased diuresis were observed in stents with a higher degree of encrustation ( < 0.05). The urinary pH values were lower in patients with uric acid encrustations and higher in those with infectious phosphate encrustations ( < 0.05). When compared to non-encrusted stents, patients with calcium-oxalate-encrusted stent showed greater calciuria, phosphaturia, indwelling time, and reduced diuresis; patients with uric-acid-encrusted stent showed greater uricosuria; and patients with infectious and non-infectious phosphate encrustation showed greater urinary pH ( < 0.05). (4) Conclusions: Metabolic urine conditions play a critical role in the formation, composition, and severity of double-J stent encrustation.
PubMed: 37568551
DOI: 10.3390/jcm12155149 -
Journal of the American College of... Apr 2024Sodium-glucose cotransporter 2 inhibitors are believed to improve cardiac outcomes due to their osmotic diuretic potential. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Sodium-glucose cotransporter 2 inhibitors are believed to improve cardiac outcomes due to their osmotic diuretic potential.
OBJECTIVES
The goal of this study was to test the hypothesis that vasopressin-driven urine concentration overrides the osmotic diuretic effect of glucosuria induced by dapagliflozin treatment.
METHODS
DAPA-Shuttle1 (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment) was a single-center, double-blind, randomized, placebo-controlled trial, in which patients with chronic heart failure NYHA functional classes I/II and reduced ejection fraction were randomly assigned to receive dapagliflozin 10 mg daily or placebo (1:1) for 4 weeks. The primary endpoint was change from baseline in urine osmolyte concentration. Secondary endpoints included changes in copeptin levels and solute free water clearance.
RESULTS
Thirty-three randomized, sodium-glucose cotransporter 2 inhibitor-naïve participants completed the study, 29 of whom (placebo: n = 14; dapagliflozin: n = 15) provided accurate 24-hour urine collections (mean age 59 ± 14 years; left ventricular ejection fraction 31% ± 9%). Dapagliflozin treatment led to an isolated increase in urine glucose excretion by 3.3 mmol/kg/d (95% CI: 2.51-4.04; P < 0.0001) within 48 hours (early) which persisted after 4 weeks (late; 2.7 mmol/kg/d [95% CI: 1.98-3.51]; P < 0.0001). Dapagliflozin treatment increased serum copeptin early (5.5 pmol/L [95% CI: 0.45-10.5]; P < 0.05) and late (7.8 pmol/L [95% CI: 2.77-12.81]; P < 0.01), leading to proportional reductions in free water clearance (early: -9.1 mL/kg/d [95% CI: -14 to -4.12; P < 0.001]; late: -11.0 mL/kg/d [95% CI: -15.94 to -6.07; P < 0.0001]) and elevated urine concentrations (late: 134 mmol/L [95% CI: 39.28-229.12]; P < 0.01). Therefore, urine volume did not significantly increase with dapagliflozin (mean difference early: 2.8 mL/kg/d [95% CI: -1.97 to 7.48; P = 0.25]; mean difference late: 0.9 mL/kg/d [95% CI: -3.83 to 5.62]; P = 0.70).
CONCLUSIONS
Physiological-adaptive water conservation eliminated the expected osmotic diuretic potential of dapagliflozin and thereby prevented a glucose-driven increase in urine volume of approximately 10 mL/kg/d · 75 kg = 750 mL/kg/d. (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment [DAPA-Shuttle1]; NCT04080518).
Topics: Aged; Humans; Middle Aged; Benzhydryl Compounds; Conservation of Water Resources; Diuresis; Diuretics, Osmotic; Glucosides; Heart Failure; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume; Ventricular Function, Left; Water
PubMed: 38599715
DOI: 10.1016/j.jacc.2024.02.020 -
Endocrinology and Metabolism (Seoul,... Aug 2023When sodium-glucose cotransporter-2 (SGLT2) inhibitors were first introduced a decade ago, no one expected them to have substantial effects beyond their known... (Review)
Review
When sodium-glucose cotransporter-2 (SGLT2) inhibitors were first introduced a decade ago, no one expected them to have substantial effects beyond their known glucose-lowering effects, until the emergence of evidence of their robust renal and cardiovascular benefits showing that they could attenuate progression of kidney disease, irrespective of diabetes, as well as prevent the development of acute kidney injury. Still, the precise and elaborate mechanisms underlying the major organ protection of SGLT2 inhibitors remain unclear. SGLT2 inhibitors inhibit the reabsorption of sodium and glucose in the proximal tubule of the kidney and then recovers tubuloglomerular feedback, whereby SGLT2 inhibitors reduce glomerular hyperfiltration. This simple demonstration of their beneficial effects has perplexed experts in seeking more plausible and as yet undisclosed explanations for the whole effects of SGLT2 inhibitors, including metabolism reprogramming and the modulation of hypoxia, inflammation, and oxidative stress. Given that the renal benefits of SGLT2 inhibitors in patients with kidney disease but without diabetes were comparable to those seen in patients with diabetes, it may be reasonable to keep the emphasis on their hemodynamic actions. In this context, the aim of the present review is to provide a comprehensive overview of renal hemodynamics in individuals with diabetes who are treated with SGLT2 inhibitors, with a focus on natriuresis associated with the regulation of tubuloglomerular feedback and potential aquaresis. Throughout the discussion of alterations in renal sodium and water transports, particular attention will be given to the potential enhancement of adenosine and its receptors following SGLT2 inhibition.
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Sodium-Glucose Transporter 2; Natriuresis; Feedback; Glucose; Sodium
PubMed: 37482684
DOI: 10.3803/EnM.2023.1764 -
Frontiers in Cardiovascular Medicine 2023To evaluate the safety, efficacy, and outcomes of outpatient intravenous diuresis in a rural setting and compare it to urban outcomes.
PURPOSE
To evaluate the safety, efficacy, and outcomes of outpatient intravenous diuresis in a rural setting and compare it to urban outcomes.
METHODS
A single-center study was conducted on 60 patients (131 visits) at the Dartmouth-Hitchcock Medical Center (DHMC) from 1/2021-12/2022. Demographics, visit data, and outcomes were collected and compared to urban outpatient IV centers, and inpatient HF hospitalizations from DHMC FY21 and national means. Descriptive statistics, T-tests and chi-squares were used.
RESULTS
The mean age was 70 ± 13 years, 58% were male, and 83% were NYHA III-IV. Post-diuresis, 5% had mild-moderate hypokalemia, 16% had mild worsening of renal function, and 3% had severe worsening of renal function. No hospitalizations occurred due to adverse events. The mean infusion-visit urine output was 761 ± 521 ml, and post-visit weight loss was -3.9 ± 5.0 kg. No significant differences were observed between HFpEF and HFrEF groups. 30-day readmissions were similar to urban outpatient IV centers, DHMC FY21, and the national mean (23.3% vs. 23.5% vs. 22.2% vs. 22.6%, respectively; = 0.949). 30-day mortality was similar to urban outpatient IV centers but lower than DHMC FY21 and the national means (1.7% vs. 2.5% vs. 12.3% vs. 10.7%, respectively; < 0.001). At 60 days, 42% of patients had ≥1 clinic revisit, 41% had ≥1 infusion revisit, 33% were readmitted to the hospital, and two deaths occurred. The clinic avoided 21 hospitalizations, resulting in estimated cost savings of $426,111.
CONCLUSION
OP IV diuresis appears safe and effective for rural HF patients, potentially decreasing mortality rates and healthcare expenses while mitigating rural-urban disparities.
PubMed: 37304943
DOI: 10.3389/fcvm.2023.1155957 -
Hypertension (Dallas, Tex. : 1979) May 2023The endogenous purine 8-aminoguanine induces diuresis/natriuresis/glucosuria by inhibiting PNPase (purine nucleoside phosphorylase); however, mechanistic details are...
BACKGROUND
The endogenous purine 8-aminoguanine induces diuresis/natriuresis/glucosuria by inhibiting PNPase (purine nucleoside phosphorylase); however, mechanistic details are unknown.
METHODS
Here, we further explored in rats 8-aminoguanine's effects on renal excretory function by combining studies using intravenous 8-aminoguanine, intrarenal artery infusions of PNPase substrates (inosine and guanosine), renal microdialysis, mass spectrometry, selective adenosine receptor ligands, adenosine receptor knockout rats, laser doppler blood flow analysis, cultured renal microvascular smooth muscle cells, HEK293 cells expressing A receptors and homogeneous time resolved fluorescence assay for adenylyl cyclase activity.
RESULTS
Intravenous 8-aminoguanine caused diuresis/natriuresis/glucosuria and increased renal microdialysate levels of inosine and guanosine. Intrarenal inosine, but not guanosine, exerted diuretic/natriuretic/glucosuric effects. In 8-aminoguanine-pretreated rats, intrarenal inosine did not induce additional diuresis/natriuresis/glucosuria. 8-Aminoguanine did not induce diuresis/natriuresis/glucosuria in A-receptor knockout rats, yet did so in A- and A-receptor knockout rats. Inosine's effects on renal excretory function were abolished in A knockout rats. Intrarenal BAY 60-6583 (A agonist) induced diuresis/natriuresis/glucosuria and increased medullary blood flow. 8-Aminoguanine increased medullary blood flow, a response blocked by pharmacological inhibition of A, but not A, receptors. In HEK293 cells expressing A receptors, inosine activated adenylyl cyclase, and this was abolished by MRS 1754 (A antagonist). In renal microvascular smooth muscle cells, 8-aminoguanine and forodesine (PNPase inhibitor) increased inosine and 3',5'-cAMP; however, in cells from A knockout rats, 8-aminoguanine and forodesine did not augment 3',5'-cAMP yet increased inosine.
CONCLUSIONS
8-Aminoguanine induces diuresis/natriuresis/glucosuria by increasing renal interstitial levels of inosine which, via A receptor activation, increases renal excretory function, perhaps in part by increasing medullary blood flow.
Topics: Rats; Humans; Animals; Adenylyl Cyclases; HEK293 Cells; Diuresis; Diuretics; Natriuresis; Receptors, Purinergic P1; Inosine
PubMed: 36802842
DOI: 10.1161/HYPERTENSIONAHA.122.20760 -
Biophysical Reviews Apr 2021Sulfonamide (or sulphonamide) functional group chemistry (SN) forms the basis of several groups of drug. In vivo sulfonamides exhibit a range of pharmacological... (Review)
Review
Sulfonamide (or sulphonamide) functional group chemistry (SN) forms the basis of several groups of drug. In vivo sulfonamides exhibit a range of pharmacological activities, such as anti-carbonic anhydrase and anti-t dihydropteroate synthetase allowing them to play a role in treating a diverse range of disease states such as diuresis, hypoglycemia, thyroiditis, inflammation, and glaucoma. Sulfamethazine (SMZ) is a commonly used sulphonamide drug in veterinary medicine that acts as an antibacterial compound to treat livestock diseases such as gastrointestinal and respiratory tract infections. Sulfadiazine (SDZ) is another frequently employed sulphonamide drug that is used in combination with the anti-malarial drug pyrimethamine to treat toxoplasmosis in warm-blooded animals. This study explores the research findings and the work behaviours of SN (SMZ and SDZ) drugs. The areas covered include SN drug structure, SN drug antibacterial activity, SN drug toxicity, and SN environmental toxicity.
PubMed: 33936318
DOI: 10.1007/s12551-021-00795-9