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Clinical Kidney Journal Aug 2023Despite its discovery more than 150 years ago, the cause of primary hypertension remains unknown. Most studies suggest that hypertension involves genetic, congenital or... (Review)
Review
Despite its discovery more than 150 years ago, the cause of primary hypertension remains unknown. Most studies suggest that hypertension involves genetic, congenital or acquired risk factors that result in a relative inability of the kidney to excrete salt (sodium chloride) in the kidneys. Here we review recent studies that suggest there may be two phases, with an initial phase driven by renal vasoconstriction that causes low-grade ischemia to the kidney, followed by the infiltration of immune cells that leads to a local autoimmune reaction that maintains the renal vasoconstriction. Evidence suggests that multiple mechanisms could trigger the initial renal vasoconstriction, but one way may involve fructose that is provided in the diet (such as from table sugar or high fructose corn syrup) or produced endogenously. The fructose metabolism increases intracellular uric acid, which recruits NADPH oxidase to the mitochondria while inhibiting AMP-activated protein kinase. A drop in intracellular ATP level occurs, triggering a survival response. Leptin levels rise, triggering activation of the sympathetic central nervous system, while vasopressin levels rise, causing vasoconstriction in its own right and stimulating aldosterone production via the vasopressin 1b receptor. Low-grade renal injury and autoimmune-mediated inflammation occur. High-salt diets can amplify this process by raising osmolality and triggering more fructose production. Thus, primary hypertension may result from the overactivation of a survival response triggered by fructose metabolism. Restricting salt and sugar and hydrating with ample water may be helpful in the prevention of primary hypertension.
PubMed: 37529651
DOI: 10.1093/ckj/sfad058 -
Endocrine Nov 2023Tolvaptan, a selective vasopressin V2-receptor antagonist, is approved for the treatment of SIADH-related hyponatremia, but its use is limited. The starting dose is...
PURPOSE
Tolvaptan, a selective vasopressin V2-receptor antagonist, is approved for the treatment of SIADH-related hyponatremia, but its use is limited. The starting dose is usually 15 mg/day, but recent clinical experience suggests a lower starting dose (<15 mg/day) to reduce the risk of sodium overcorrection. However, long-term low-dose efficacy and safety has not been explored, so far. Aim of our study is to characterize safety and efficacy of long-term SIADH treatment with low-dose Tolvaptan.
METHODS
We retrospectively evaluated 11 patients receiving low-dose Tolvaptan (<15 mg/day) for chronic SIADH due to neurological, idiopathic and neoplastic causes. Plasma sodium levels were measured before and 1, 3, 5, 15 and 30 days after starting Tolvaptan and then at 3-month intervals. Anamnestic and clinical data were collected.
RESULTS
Mean time spanned 27.3 ± 29.8 months (range 6 months-7 years). Mean plasma sodium levels were within normal range 1, 3 and 6 months after starting Tolvaptan as well as after 1, 2, 3, 5 and 7 years of therapy. Neither osmotic demyelination syndrome nor overcorrection were observed. Plasma sodium levels normalization was associated with beneficial clinical effects. Neurological patients obtained seizures disappearance, improvement in neurological picture and good recovery from rehabilitation. Neoplastic patients were able to start chemotherapy and improved their general condition. Patients did not show hypernatremia during long-term follow-up and reported mild thirst and pollakiuria.
CONCLUSIONS
The present study shows that long-term low-dose Tolvaptan is safe and effective in SIADH treatment. No cases of overcorrection were documented and mild side effects were reported.
Topics: Humans; Tolvaptan; Inappropriate ADH Syndrome; Antidiuretic Hormone Receptor Antagonists; Retrospective Studies; Benzazepines; Hyponatremia; Sodium
PubMed: 37507553
DOI: 10.1007/s12020-023-03457-w -
International Journal of Molecular... Sep 2023Autosomal-Dominant Polycystic Kidney Disease (ADPKD) is a monogenic disorder initiated by mutations in either or genes, responsible for encoding polycystin 1 and... (Review)
Review
Autosomal-Dominant Polycystic Kidney Disease (ADPKD) is a monogenic disorder initiated by mutations in either or genes, responsible for encoding polycystin 1 and polycystin 2, respectively. These proteins are primarily located within the primary cilia. The disease follows an inexorable progression, leading most patients to severe renal failure around the age of 50, and extra-renal complications are frequent. A cure for ADPKD remains elusive, but some measures can be employed to manage symptoms and slow cyst growth. Tolvaptan, a vasopressin V2 receptor antagonist, is the only drug that has been proven to attenuate ADPKD progression. Recently, autophagy, a cellular recycling system that facilitates the breakdown and reuse of aged or damaged cellular components, has emerged as a potential contributor to the pathogenesis of ADPKD. However, the precise role of autophagy in ADPKD remains a subject of investigation, displaying a potentially twofold impact. On the one hand, impaired autophagy may promote cyst formation by inducing apoptosis, while on the other hand, excessive autophagy may lead to fibrosis through epithelial to mesenchymal transition. Promising results of autophagy inducers have been observed in preclinical studies. Clinical trials are warranted to thoroughly assess the long-term safety and efficacy of a combination of autophagy inducers with metabolic and/or aquaferetic drugs. This research aims to shed light on the complex involvement of autophagy in ADPKD, explore the regulation of autophagy in disease progression, and highlight the potential of combination therapies as a promising avenue for future investigations.
Topics: Humans; Aged; Polycystic Kidney, Autosomal Dominant; Epithelial-Mesenchymal Transition; Kidney; Autophagy; Cysts
PubMed: 37834113
DOI: 10.3390/ijms241914666 -
International Journal of Molecular... Jan 2024The present review draws attention to the specific role of angiotensin peptides [angiotensin II (Ang II), angiotensin-(1-7) (Ang-(1-7)], vasopressin (AVP), and insulin... (Review)
Review
The present review draws attention to the specific role of angiotensin peptides [angiotensin II (Ang II), angiotensin-(1-7) (Ang-(1-7)], vasopressin (AVP), and insulin in the regulation of the coronary blood flow and cardiac contractions. The interactions of angiotensin peptides, AVP, and insulin in the heart and in the brain are also discussed. The intracardiac production and the supply of angiotensin peptides and AVP from the systemic circulation enable their easy access to the coronary vessels and the cardiomyocytes. Coronary vessels and cardiomyocytes are furnished with AT1 receptors, AT2 receptors, Ang (1-7) receptors, vasopressin V1 receptors, and insulin receptor substrates. The presence of some of these molecules in the same cells creates good conditions for their interaction at the signaling level. The broad spectrum of actions allows for the engagement of angiotensin peptides, AVP, and insulin in the regulation of the most vital cardiac processes, including (1) cardiac tissue oxygenation, energy production, and metabolism; (2) the generation of the other cardiovascular compounds, such as nitric oxide, bradykinin (Bk), and endothelin; and (3) the regulation of cardiac work by the autonomic nervous system and the cardiovascular neurons of the brain. Multiple experimental studies and clinical observations show that the interactions of Ang II, Ang(1-7), AVP, and insulin in the heart and in the brain are markedly altered during heart failure, hypertension, obesity, and diabetes mellitus, especially when these diseases coexist. A survey of the literature presented in the review provides evidence for the belief that very individualized treatment, including interactions of angiotensins and vasopressin with insulin, should be applied in patients suffering from both the cardiovascular and metabolic diseases.
Topics: Humans; Angiotensin II; Arginine Vasopressin; Diabetes Mellitus; Insulin; Obesity; Receptors, Angiotensin; Receptors, Vasopressin; Vasopressins
PubMed: 38279313
DOI: 10.3390/ijms25021310 -
Frontiers in Neuroscience 2024
PubMed: 38352043
DOI: 10.3389/fnins.2024.1372140 -
Journal of Personalized Medicine Feb 2024Sex hormones and migraine are closely interlinked. Women report higher levels of migraine symptoms during periods of sex hormone fluctuation, particularly during... (Review)
Review
Sex hormones and migraine are closely interlinked. Women report higher levels of migraine symptoms during periods of sex hormone fluctuation, particularly during puberty, pregnancy, and perimenopause. Ovarian steroids, such as estrogen and progesterone, exert complex effects on the peripheral and central nervous systems, including pain, a variety of special sensory and autonomic functions, and affective processing. A panel of basic scientists, when challenged to explain what was known about how sex hormones affect the nervous system, focused on two hormones: estrogen and oxytocin. Notably, other hormones, such as progesterone, testosterone, and vasopressin, are less well studied but are also highlighted in this review. When discussing what new therapeutic agent might be an alternative to hormone therapy and menopause replacement therapy for migraine treatment, the panel pointed to oxytocin delivered as a nasal spray. Overall, the conclusion was that progress in the preclinical study of hormones on the nervous system has been challenging and slow, that there remain substantial gaps in our understanding of the complex roles sex hormones play in migraine, and that opportunities remain for improved or novel therapeutic agents. Manipulation of sex hormones, perhaps through biochemical modifications where its positive effects are selected for and side effects are minimized, remains a theoretical goal, one that might have an impact on migraine disease and other symptoms of menopause. This review is a call to action for increased interest and funding for preclinical research on sex hormones, their metabolites, and their receptors. Interdisciplinary research, perhaps facilitated by a collaborative communication network or panel, is a possible strategy to achieve this goal.
PubMed: 38392617
DOI: 10.3390/jpm14020184 -
Biomedicine & Pharmacotherapy =... Sep 2023The vasopressin system has emerged as a therapeutic focus for lowering portal hypertension and reducing splanchnic vasodilation in patients with refractory ascites....
Partial vasopressin 1a receptor agonism reduces portal hypertension and hyperaldosteronism and induces a powerful diuretic and natriuretic effect in rats with cirrhosis and ascites.
The vasopressin system has emerged as a therapeutic focus for lowering portal hypertension and reducing splanchnic vasodilation in patients with refractory ascites. Clinically available vasopressin agonists are limited by preferential selectivity for V1 receptors that also have steep concentration-response curves with potential risks of excess vasoconstriction and/or complete antidiuretic effects. OCE-205 is a novel, selective, partial V1a receptor agonist with mixed agonist/antagonist activity and no V2 receptor activation at therapeutic doses. We carried out two studies assessing the in vivo effects of OCE-205 in different rat models of cirrhosis and ascites. In a carbon tetrachloride rat cirrhosis model, OCE-205 administration produced a marked reduction in portal hypertension and hyperaldosteronism, along with robust diuretic and natriuretic effects. These effects were accompanied by marked decreases in ascites volume, with three of five animals experiencing total mobilization of ascites. There was no evidence of fluid overload or sodium or water retention, confirming OCE-205's lack of V2 receptor activity. In a second, corroborative study using a bile duct ligation rat model of ascites, OCE-205 produced significant decreases in ascites volume and body weight and a significant increase in urine volume versus vehicle. Urine sodium excretion increased significantly after the first administration of OCE-205 relative to vehicle; however, repeat administration over 5 days did not lead to hyponatremia. Thus, in separate in vivo models, the mixed agonist/antagonist OCE-205 demonstrated relevant and expected endpoint findings consistent with its known mechanism of action and in vitro pharmacology without apparent unwanted effects or nonspecific toxicities.
Topics: Rats; Animals; Diuretics; Natriuretic Agents; Ascites; Vasopressins; Liver Cirrhosis; Sodium; Receptors, Vasopressin; Hypertension, Portal; Hyperaldosteronism
PubMed: 37418980
DOI: 10.1016/j.biopha.2023.115116 -
Kidney360 Dec 2023In a analysis, short-term reduction in spot urine osmolality (Uosm) was associated with decreased kidney volume growth in autosomal dominant polycystic kidney disease...
KEY POINTS
In a analysis, short-term reduction in spot urine osmolality (Uosm) was associated with decreased kidney volume growth in autosomal dominant polycystic kidney disease for both tolvaptan and instruction to increase hydration alone. For the same spot Uosm reduction, however, the kidney volume benefit was greater with tolvaptan, possibly because of greater cumulative 24-hour Uosm suppression by tolvaptan.
BACKGROUND
In addition to decreasing water excretion and increasing urinary concentration, the antidiuretic hormone vasopressin plays a role in the pathophysiology of autosomal dominant polycystic kidney disease. It has been hypothesized that by suppressing vasopressin release, drinking large amounts of water might exert therapeutic effects in autosomal dominant polycystic kidney disease similar to those of tolvaptan, an antagonist of the vasopressin type 2 receptor, but evidence is lacking. We analyzed data from tolvaptan clinical trials to evaluate relationships among water intake, urine osmolality (Uosm), and change in total kidney volume (TKV).
METHODS
Analysis of the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes 3:4 clinical trial in which participants were randomized to tolvaptan or placebo and instructed to drink large amounts of water. The relationship between change in spot Uosm from baseline to week 3 and change in TKV to month 12 was assessed using linear regression modeling. Two short-term tolvaptan trials were analyzed to explore relationships between intermittent Uosm sampling and 24-hour Uosm suppression.
RESULTS
With both tolvaptan and placebo (, mandated high water intake alone), Uosm reduction at week 3 was associated with reduction in TKV growth at month 12. However, for the same decrease in spot Uosm, the corresponding reduction in TKV growth was greater for tolvaptan (, a −250 mOsm/kg reduction in Uosm at week 3 was associated with a −1% change in TKV at month 12 for tolvaptan versus +4.5% for placebo). In short-term trials, similar reductions in spot or trough Uosm values were achievable with tolvaptan and high water intake, but cumulative 24-hour suppression was greater with tolvaptan.
CONCLUSIONS
This analysis supports a relationship between effects on Uosm and inhibition of disease progression by tolvaptan and high water intake alone. The findings further suggest that 24-hour Uosm measurement is superior to spot Uosm for assessing suppression of vasopressin activity by tolvaptan.
Topics: Humans; Tolvaptan; Polycystic Kidney, Autosomal Dominant; Drinking; Antidiuretic Hormone Receptor Antagonists; Benzazepines
PubMed: 37986188
DOI: 10.34067/KID.0000000000000302 -
Journal of Neuroendocrinology Jul 2023Parenting induces many neurological and behavioral changes that enable parents to rear offspring. Vasopressin plays an important role in this process via its effects on...
Parenting induces many neurological and behavioral changes that enable parents to rear offspring. Vasopressin plays an important role in this process via its effects on cognition, affect, and neuroplasticity, and in some cases, via interactions with decreased parental androgens. Thus far, the role of these hormones has been primarily studied in rodents. To address this gap, we explored vasopressin receptors and androgens in titi monkeys, a pair-bonding and biparental primate species. In Studies 1 and 2, we used receptor autoradiography to correlate arginine vasopressin receptor 1a (AVPR1a) binding in the hippocampus (Study 1, n = 10) and the rest of the forebrain (Study 2, n = 23) with parental status, parental experience, parity, infant carrying, and pair affiliation. We found that parents exhibited lower AVPR1a binding than non-parents throughout most brain regions assessed, with especially strong effects in the hippocampus (β = -.61), superior colliculus (β = -.88), lateral septum (β = -.35), and medial preoptic area (β = -.29). The other measures of parental experience also tended to be negatively associated with AVPR1a binding across different brain regions. In Study 3 (n = 44), we compared pre- and postpartum urinary androgen levels in parents and non-parents and found that mothers exhibited a sustained androgen decrease across 3-4 months postpartum (relative to 3 months prepartum; β ranged from -.72 to -.62 for different comparisons). For males, we found that multiparous fathers exhibited decreased androgen levels at 1-2 weeks postpartum (β = -.25) and at 3-4 months postpartum (β = -.40) compared to the prepartum, indicating both immediate and long-term reductions with subsequent paternal experience. Together, the results of this study suggest that decreases in AVPR1a binding and circulating androgens are associated with parental behavior and physiology in titi monkeys.
Topics: Male; Humans; Animals; Pregnancy; Female; Receptors, Vasopressin; Androgens; Callicebus; Brain; Postpartum Period
PubMed: 37267441
DOI: 10.1111/jne.13304 -
Biochemical and Biophysical Research... Nov 2023Many insects produce the cyclic neuropeptide inotocin (CLITNCPRGamide), which is the insect orthologue of the mammalian neuropeptides oxytocin and vasopressin. These...
Many insects produce the cyclic neuropeptide inotocin (CLITNCPRGamide), which is the insect orthologue of the mammalian neuropeptides oxytocin and vasopressin. These insects also have one inotocin G protein-coupled receptor (GPCR), which is the orthologue of the mammalian oxytocin and vasopressin receptors. The tick Ixodes scapularis belongs to the subphylum Chelicerata, an arthropod taxon different from insects, to which also spiders, scorpions, and mites belong. I. scapularis is an ectoparasite and a health risk for humans, because it transfers pathogenic microorganisms to its human host during a blood meal, thereby causing serious neurological diseases, among them Lyme disease and tick-borne encephalitis (TBE). By annotating the genomic sequence of I. scapularis, we previously found one presumed tick inotocin preprohormone gene and, in contrast to insects, three genes coding for presumed inotocin GPCRs. We now find that these GPCR genes cluster on one genomic contig, suggesting that they originated by recent gene duplications. Closely located on the same contig are also four adipokinetic hormone/corazonin-related peptide (ACP) GPCR genes, and one crustacean cardioactive peptide (CCAP) GPCR gene, suggesting evolutionary relationships. These evolutionary relationships are confirmed by phylogenetic tree analyses of their gene products. We also cloned the tick inotocin preprohormone, which has a structural organization closely resembling mammalian oxytocin and vasopressin preprohormones, including the presence of a conserved neurophysin sequence, having seven cystine bridges. This neurophysin sequence has two cystine-knot domains, but in contrast to mammalian neurophysins, the tick neurophysin contains a canonical prohormone convertase cleavage signal and a peptide C-terminal amidation sequence (GKR), suggesting cleavage into two biologically active cystine-knot peptides. This cleavage/amidation sequence occurs in neurophysins from most hard tick species, but not in other chelicerates. Mature tick inotocin is different from insect inotocin and has the sequence CFITNCPPGamide. Finally, we cloned and stably expressed the three tick inotocin receptors in Chinese Hamster Ovary cells and found that each of them was activated by nanomolar concentrations of tick inotocin (EC for ITR1 = 1.6 × 10 M; EC for ITR2 = 5.8 × 10 M; EC for ITR3 = 9.3 × 10 M), thereby establishing that they are genuine tick inotocin receptors.
PubMed: 37716155
DOI: 10.1016/j.bbrc.2023.09.009