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Peptides Jun 2024Glucagon is best known for its contribution to glucose regulation through activation of the glucagon receptor (GCGR), primarily located in the liver. However, glucagon's...
Glucagon is best known for its contribution to glucose regulation through activation of the glucagon receptor (GCGR), primarily located in the liver. However, glucagon's impact on other organs may also contribute to its potent effects in health and disease. Given that glucagon-based medicine is entering the arena of anti-obesity drugs, elucidating extrahepatic actions of glucagon are of increased importance. It has been reported that glucagon may stimulate secretion of arginine-vasopressin (AVP)/copeptin, growth hormone (GH) and adrenocorticotrophic hormone (ACTH) from the pituitary gland. Nevertheless, the mechanisms and whether GCGR is present in human pituitary are unknown. In this study we found that intravenous administration of 0.2 mg glucagon to 14 healthy subjects was not associated with increases in plasma concentrations of copeptin, GH, ACTH or cortisol over a 120-min period. GCGR immunoreactivity was present in the anterior pituitary but not in cells containing GH or ACTH. Collectively, glucagon may not directly stimulate secretion of GH, ACTH or AVP/copeptin in humans but may instead be involved in yet unidentified pituitary functions.
Topics: Humans; Glycopeptides; Glucagon; Adrenocorticotropic Hormone; Male; Adult; Female; Pituitary Gland; Hydrocortisone; Receptors, Glucagon; Human Growth Hormone; Growth Hormone; Middle Aged
PubMed: 38604379
DOI: 10.1016/j.peptides.2024.171213 -
Planta Medica May 2024The medicinal plant was previously shown to block oxytocin (OT)-induced signals in myometrial cells, consistent with its tocolytic effect observed in patients. OT...
The medicinal plant was previously shown to block oxytocin (OT)-induced signals in myometrial cells, consistent with its tocolytic effect observed in patients. OT activates not only OT receptors but also V receptors, two receptors with high receptor homology that are both expressed in the myometrium and play a crucial role in myometrial contraction signaling. We aimed to study the molecular pharmacology of herbal preparations using specific receptor ligands, the human myometrial cell line hTERT-C3, and cell lines expressing recombinant human OT and V receptors.We found that press juice from (BPJ) inhibits both OT- and vasopressin (AVP)-induced intracellular calcium increases in hTERT-C3 myometrial cells. In additional assays performed with cells expressing recombinant receptors, BPJ also inhibited OT and V receptor-mediated signals with a similar potency (IC about 0.5 mg/mL). We further studied endogenous OT- and AVP-sensitive receptors in hTERT-C3 cells and found that OT and AVP stimulated those receptors with similar potency (EC of ~ 1 nM), suggesting expression of both receptor subtypes. This interpretation was corroborated by the antagonist potencies of atosiban and relcovaptan that we found. However, using qPCR, we almost exclusively found expression of OT receptors suggesting a pharmacological difference between recombinant OT receptors and native receptors expressed in hTERT-C3 cells.In conclusion, we show that inhibits both OT and AVP signaling, which may point beyond its tocolytic effects to other indications involving a disbalance in the vasopressinergic system.
PubMed: 38599625
DOI: 10.1055/a-2303-9608 -
Cell Communication and Signaling : CCS Apr 2024VEGFR2 (Vascular endothelial growth factor receptor 2) is a central regulator of placental angiogenesis. The study of the VEGFR2 proteome of chorionic villi at term...
VEGFR2 (Vascular endothelial growth factor receptor 2) is a central regulator of placental angiogenesis. The study of the VEGFR2 proteome of chorionic villi at term revealed its partners MDMX (Double minute 4 protein) and PICALM (Phosphatidylinositol-binding clathrin assembly protein). Subsequently, the oxytocin receptor (OT-R) and vasopressin V1aR receptor were detected in MDMX and PICALM immunoprecipitations. Immunogold electron microscopy showed VEGFR2 on endothelial cell (EC) nuclei, mitochondria, and Hofbauer cells (HC), tissue-resident macrophages of the placenta. MDMX, PICALM, and V1aR were located on EC plasma membranes, nuclei, and HC nuclei. Unexpectedly, PICALM and OT-R were detected on EC projections into the fetal lumen and OT-R on 20-150 nm clusters therein, prompting the hypothesis that placental exosomes transport OT-R to the fetus and across the blood-brain barrier. Insights on gestational complications were gained by univariable and multivariable regression analyses associating preeclampsia with lower MDMX protein levels in membrane extracts of chorionic villi, and lower MDMX, PICALM, OT-R, and V1aR with spontaneous vaginal deliveries compared to cesarean deliveries before the onset of labor. We found select associations between higher MDMX, PICALM, OT-R protein levels and either gravidity, diabetes, BMI, maternal age, or neonatal weight, and correlations only between PICALM-OT-R (p < 2.7 × 10), PICALM-V1aR (p < 0.006), and OT-R-V1aR (p < 0.001). These results offer for exploration new partnerships in metabolic networks, tissue-resident immunity, and labor, notably for HC that predominantly express MDMX.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Diabetes Mellitus; Gravidity; Oxytocin; Placenta; Pre-Eclampsia; Proteomics; Receptors, Oxytocin; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2
PubMed: 38594674
DOI: 10.1186/s12964-024-01567-0 -
Journal of Cardiothoracic and Vascular... Jul 2024Consensus statements recommend the use of norepinephrine and/or vasopressin for hypotension in cardiac surgery. However, there is a paucity of data among other surgical... (Comparative Study)
Comparative Study Review
Consensus statements recommend the use of norepinephrine and/or vasopressin for hypotension in cardiac surgery. However, there is a paucity of data among other surgical subgroups and vasopressin analogs. Therefore, the authors conducted a systematic review of randomized controlled trials (RCTs) to compare vasopressin-receptor agonists with norepinephrine for hypotension among those undergoing surgery with general anesthesia. This review was registered prospectively (CRD42022316328). Literature searches were conducted by a medical librarian to November 28, 2023, across MEDLINE, EMBASE, CENTRAL, and Web of Science. The authors included RCTs enrolling adults (≥18 years of age) undergoing any surgery under general anesthesia who developed perioperative hypotension and comparing vasopressin receptor agonists with norepinephrine. The risk of bias was assessed by the Cochrane risk of bias tool for randomized trials (RoB-2). Thirteen (N = 719) RCTs were included, of which 8 (n = 585) enrolled patients undergoing cardiac surgery. Five trials compared norepinephrine with vasopressin, 4 trials with terlipressin, 1 trial with ornipressin, and the other 3 trials used vasopressin as adjuvant therapy. There was no significant difference in all-cause mortality. Among patients with vasoplegic shock after cardiac surgery, vasopressin was associated with significantly lower intensive care unit (N = 385; 2 trials; mean 100.8 v 175.2 hours, p < 0.005; median 120 [IQR 96-168] v 144 [96-216] hours, p = 0.007) and hospital lengths of stay, as well as fewer cases of acute kidney injury and atrial fibrillation compared with norepinephrine. One trial also found that terlipressin was associated with a significantly lower incidence of acute kidney injury versus norepinephrine overall. Vasopressin and norepinephrine restored mean arterial blood pressure with no significant differences; however, the use of vasopressin with norepinephrine was associated with significantly higher mean arterial blood pressure versus norepinephrine alone. Further high-quality trials are needed to determine pooled treatment effects, especially among noncardiac surgical patients and those treated with vasopressin analogs.
Topics: Humans; Norepinephrine; Hypotension; Vasoconstrictor Agents; Vasopressins; Receptors, Vasopressin; Adult; Randomized Controlled Trials as Topic; Cardiac Surgical Procedures; Treatment Outcome
PubMed: 38580478
DOI: 10.1053/j.jvca.2024.03.014 -
Clinical Nephrology Jun 2024Tolvaptan is a vasopressin V2 receptor antagonist that is commonly prescribed to alleviate edema associated with renal diseases. However, the clinical benefits of...
OBJECTIVE
Tolvaptan is a vasopressin V2 receptor antagonist that is commonly prescribed to alleviate edema associated with renal diseases. However, the clinical benefits of tolvaptan in chronic kidney disease (CKD) remain unclear. This study aimed to evaluate the effectiveness of tolvaptan in managing edema caused by CKD.
MATERIALS AND METHODS
The efficacy and treatment regimen of tolvaptan were assessed in a cohort of 96 patients with renal edema and CKD. During the treatment, the patients' creatinine (CR), uric acid (UA), and estimated glomerular filtration rate (eGFR) were monitored as important indicators of kidney function. Coagulation-associated molecules including fibrinogen, D-dimer, and fibrin degradation products (FDPs) were measured. Electrolyte disorders and acute kidney injury were closely monitored. Tolvaptan was administered at a daily dose of 7.5 mg, and 30 mg of edoxaban was administered to manage deep vein thrombosis.
RESULTS
During the course of tolvaptan therapy, the eGFR of the patients was not declined. Edema was eliminated in 82.18% of patients. Proteinuria was reduced in the patients (p < 0.05). There were no significant changes in serum sodium levels throughout treatment, and no significant difference was observed in blood volume between the end of treatment and baseline levels. Importantly, acute kidney injury did not occur, and renal edema and deep vein thrombosis were successfully treated.
CONCLUSION
As long as a rational treatment regimen is followed, tolvaptan is a safe and effective diuretic for treating edema in CKD, even in the late stages of CKD without reducing residual renal function in the patients.
Topics: Humans; Tolvaptan; Male; Female; Antidiuretic Hormone Receptor Antagonists; Middle Aged; Renal Insufficiency, Chronic; Aged; Glomerular Filtration Rate; Edema; Treatment Outcome; Adult; Creatinine; Benzazepines
PubMed: 38577748
DOI: 10.5414/CN111365 -
BioMed Research International 2024[This retracts the article DOI: 10.1155/2022/7073158.].
Retracted: A Novel Missense Mutation of Arginine Vasopressin Receptor 2 in a Chinese Family with Congenital Nephrogenic Diabetes Insipidus: X-Chromosome Inactivation in Female CNDI Patients with Heterozygote 814A>G Mutation.
[This retracts the article DOI: 10.1155/2022/7073158.].
PubMed: 38550046
DOI: 10.1155/2024/9753837 -
Journal of Clinical Medicine Mar 2024The retracts the article "Vasopressin Receptor Antagonists for the Correction of Hyponatremia in Chronic Heart Failure: An Underutilized Therapeutic Option in Current...
RETRACTED: De Vecchis et al. Vasopressin Receptor Antagonists for the Correction of Hyponatremia in Chronic Heart Failure: An Underutilized Therapeutic Option in Current Clinical Practice? 2016, , 86.
The retracts the article "Vasopressin Receptor Antagonists for the Correction of Hyponatremia in Chronic Heart Failure: An Underutilized Therapeutic Option in Current Clinical Practice [...].
PubMed: 38542053
DOI: 10.3390/jcm13061743 -
Journal of Integrative Neuroscience Mar 2024Cardiac pain is an index of cardiac ischemia that helps the detection of cardiac hypoxia and adjustment of activity in the sufferer. Drivers and thresholds of cardiac... (Review)
Review
Cardiac pain is an index of cardiac ischemia that helps the detection of cardiac hypoxia and adjustment of activity in the sufferer. Drivers and thresholds of cardiac pain markedly differ in different subjects and can oscillate in the same individual, showing a distinct circadian rhythmicity and clinical picture. In patients with syndrome X or silent ischemia, cardiac pain intensity may cause neurogenic stress that potentiates the cardiac work and intensifies the cardiac hypoxia and discomfort of the patient. The reasons for individual differences in cardiac pain sensation are not fully understood. Thus far, most attention has been focused on inappropriate regulation of the heart by the autonomic nervous system, autacoids, and cardiovascular hormones. Herein, we summarize evidence showing that the autonomic nervous system regulates cardiac pain sensation in cooperation with vasopressin (AVP). AVP is an essential analgesic compound and it exerts its antinociceptive function through actions in the brain (the periaqueductal gray, caudate nucleus, nucleus raphe magnus), spinal cord, and heart and coronary vessels. Vasopressin acts directly by means of V1 and V2 receptors as well as through multiple interactions with the autonomic nervous system and cardiovascular hormones, in particular, angiotensin II and endothelin. The pain regulatory effects of the autonomic nervous system and vasopressin are significantly impaired in cardiovascular diseases.
Topics: Humans; Autonomic Nervous System; Vasopressins; Angina Pectoris; Myocardial Ischemia
PubMed: 38538221
DOI: 10.31083/j.jin2303049 -
Comparative Medicine Feb 2024L-368,899 is a selective small-molecule oxytocin receptor (OXTR) antagonist originally developed in the 1990s to prevent preterm labor. Although its utility for that...
L-368,899 is a selective small-molecule oxytocin receptor (OXTR) antagonist originally developed in the 1990s to prevent preterm labor. Although its utility for that purpose was limited, L-368,899 is now one of the most commonly used drugs in animal research for the selective blockade of neural OXTR after peripheral delivery. A growing number of rodent and primate studies have used L-368,899 to evaluate whether certain behaviors are oxytocin dependent. These studies have improved our understanding of oxytocin's function in the brains of rodents and monkeys, but very little work has been done in other mammals, and only a single paper in macaques has provided any evidence that L-368,899 can be detected in the CNS after peripheral delivery. The current study sought to extend those findings in a novel species: coyotes ( ). Coyotes are ubiquitous North American canids that form long-term monogamous pair-bonds. Although monogamy is rare in rodents and primates, all wild canid species studied to date exhibit social monogamy. Coyotes are therefore an excellent model organism for the study of oxytocin and social bonds. Our goal was to determine whether L-368,899 is a viable candidate for future use in behavioral studies in coyotes. We used captive coyotes at the USDA National Wildlife Research Center's Predator Research Facility to evaluate the pharmacokinetics of L-368,899 in blood and CSF during a 90-min time course after intramuscular injection. We then characterized the binding affinity and selectivity of L-368,899 to coyote OXTR and the structurally similar vasopressin 1a receptor. We found that L-368,899 peaked in CSF at 15 to 30 min after intramuscular injection and slowly accumulated in blood. L-368,899 was 40 times more selective for OXTR than vasopressin 1a receptors and bound to the coyote OXTR with an affinity of 12 nM. These features of L-368,899 support its utility in future studies to probe the oxytocin system of coyotes.
Topics: Animals; Receptors, Oxytocin; Coyotes; Oxytocin; Primates; Vasopressins; Camphanes; Piperazines
PubMed: 38532262
DOI: 10.30802/AALAS-CM-23-000044 -
Journal of Medicinal Chemistry Apr 2024The dysregulated intracellular cAMP in the kidneys drives cystogenesis and progression in autosomal dominant polycystic kidney disease (ADPKD). Mounting evidence...
The dysregulated intracellular cAMP in the kidneys drives cystogenesis and progression in autosomal dominant polycystic kidney disease (ADPKD). Mounting evidence supports that vasopressin V receptor (VR) antagonism effectively reduces cAMP levels, validating this receptor as a therapeutic target. Tolvaptan, an FDA-approved VR antagonist, shows limitations in its clinical efficacy for ADPKD treatment. Therefore, the pursuit of better-in-class VR antagonists with an improved efficacy remains pressing. Herein, we synthesized a set of peptide VR antagonists. Peptide exhibited a high binding affinity for the VR ( = 6.1 ± 1.5 nM) and an extended residence time of 20 ± 1 min, 2-fold that of tolvaptan. This prolonged interaction translated into sustained suppression of cAMP production in washout experiments. Furthermore, peptide exhibited improved efficacies over tolvaptan in both ex vivo and in vivo models of ADPKD, underscoring its potential as a promising lead compound for the treatment of ADPKD.
Topics: Humans; Tolvaptan; Polycystic Kidney, Autosomal Dominant; Antidiuretic Hormone Receptor Antagonists; Kidney; Vasopressins; Receptors, Vasopressin
PubMed: 38509003
DOI: 10.1021/acs.jmedchem.4c00217