Search Results (48)

Background: Even in current guideline-directed medical therapy, including recently introduced vasopressin type 2 receptor antagonist tolvaptan, congestion has not been resolved in patients with heart failure. Kampo medicine goreisan has been receiving considerable attention as an additional therapy for patients who are refractory to conventional diuretics therapy, including tolvaptan. However, the impact of goreisan on urine electrolytes remains uncertain. Methods: Patients with congestive heart failure who received goreisan as an add-on therapy to tolvaptan-incorporated medical therapy were prospectively included. The changes in urine parameters during the first 24 h were assessed as a primary concern. Baseline factors associated with an increase in urine sodium excretion were investigated. Results: A total of 21 patients were included. The median age was 81 (77, 86), and 13 (62%) were men. Twenty-four hours after the initiation of goreisan, urine osmolality decreased significantly, urine sodium level remained unchanged, urine potassium and glucose levels decreased significantly, urine urea nitrogen level tended to decrease, and urine volume tended to increase. The fractional excretion of sodium tended to increase. Baseline plasma B-type natriuretic peptide level had a positive correlation with a change in fractional excretion of sodium from baseline to day 1 (r = 0.52, p = 0.015). Conclusions: Goreisan may increase urine volume via aquaretic and natriuretic effects in patients with congestive heart failure receiving tolvaptan-incorporated medical therapy. Goreisan may have the ability to “modulate” fluid balance depending on congestion status. Full article

We have previously demonstrated that the vasopressin type 2 receptor (AVPR2) antagonist tolvaptan reduces cell proliferation and invasion and triggers apoptosis in different human cancer cell lines. To study this effect in vivo, a xenograft model of small cell lung cancer was developed in Fox1^nu/nu nude mice through the subcutaneous inoculation of H69 cells, which express AVPR2. One group of mice (n = 5) was treated with tolvaptan for 60 days, whereas one group (n = 5) served as the control. A reduced growth was observed in the tolvaptan group in which the mean tumor volume was significantly smaller on day 60 compared to the control group. In the latter group, a significantly lower survival was observed. The analysis of excised tumors revealed that tolvaptan effectively inhibited the cAMP/PKA and PI3K/AKT signaling pathways. The expression of the proliferative marker proliferating cell nuclear antigen (PCNA) was significantly lower in tumors excised from tolvaptan-treated mice, whereas the expression levels of the apoptotic marker caspase-3 were higher than those in control animals. Furthermore, tumor vascularization was significantly lower in the tolvaptan group. Overall, these findings suggest that tolvaptan counteracts tumor progression in vivo and, if confirmed, might indicate a possible role of this molecule as an adjuvant in anticancer strategies. Full article

The neuropeptide vasopressin is known for its regulation of osmotic balance in mammals. Arginine vasotocin (AVT) is a non-mammalian homolog of this neuropeptide that is present in fish. Limited information suggested that vasopressin and its homologs may also influence reproductive function. In the present study, we investigated the direct effect of AVT on spermatogenesis, using zebrafish as a model organism. Results demonstrate that AVT and its receptors (avpr1aa, avpr2aa, avpr1ab, avpr2ab, and avpr2l) are expressed in the zebrafish brain and testes. The direct action of AVT on spermatogenesis was investigated using an ex vivo culture of mature zebrafish testes for 7 days. Using histological, morphometric, and biochemical approaches, we observed direct actions of AVT on zebrafish testicular function. AVT treatment directly increased the number of spermatozoa in an androgen-dependent manner, while reducing mitotic cells and the proliferation activity of type B spermatogonia. The observed stimulatory action of AVT on spermiogenesis was blocked by flutamide, an androgen receptor antagonist. The present results support the novel hypothesis that AVT stimulates short-term androgen-dependent spermiogenesis. However, its prolonged presence may lead to diminished spermatogenesis by reducing the proliferation of spermatogonia B, resulting in a diminished turnover of spermatogonia, spermatids, and spermatozoa. The overall findings offer an insight into the physiological significance of vasopressin and its homologs in vertebrates as a contributing factor in the multifactorial regulation of male reproduction. Full article

Tolvaptan, an oral vasopressin V2 receptor antagonist, reduces renal volume expansion and loss of renal function in patients with autosomal dominant polycystic kidney disease (ADPKD). Data for predictive factors indicating patients more likely to benefit from long-term tolvaptan are lacking. Data were retrospectively collected from 55 patients on tolvaptan for 6 years. Changes in renal function, progression of renal dysfunction (estimated glomerular filtration rate [eGFR], 1-year change in eGFR [ΔeGFR/year]), and renal volume (total kidney volume [TKV], percentage 1-year change in TKV [ΔTKV%/year]) were evaluated at 3-years pre-tolvaptan, at baseline, and at 6 years. In 76.4% of patients, ΔeGFR/year improved at 6 years. The average 6-year ΔeGFR/year (range) minus baseline ΔeGFR/year: 3.024 (−8.77–20.58 mL/min/1.73 m²). The increase in TKV was reduced for the first 3 years. A higher BMI was associated with less of an improvement in ΔeGFR (p = 0.027), and family history was associated with more of an improvement in ΔeGFR (p = 0.044). Hypernatremia was generally mild; 3 patients had moderate-to-severe hyponatremia due to prolonged, excessive water intake in response to water diuresis—a side effect of tolvaptan. Family history of ADPKD and baseline BMI were contributing factors for ΔeGFR/year improvement on tolvaptan. Hyponatremia should be monitored with long-term tolvaptan administration. Full article

In patients with heart failure (HF), the neuroendocrine systems of the sympathetic nervous system (SNS), the renin–angiotensin–aldosterone system (RAAS) and the arginine vasopressin (AVP) system, are activated to various degrees producing often-observed tachycardia and concomitant increased systemic vascular resistance. Furthermore, sustained neurohormonal activation plays a key role in the progression of HF and may be responsible for the pathogenetic mechanisms leading to the perpetuation of the pathophysiology and worsening of the HF signs and symptoms. There are biomarkers of activation of these neurohormonal pathways, such as the natriuretic peptides, catecholamine levels and neprilysin and various newer ones, which may be employed to better understand the mechanisms of HF drugs and also aid in defining the subgroups of patients who might benefit from specific therapies, irrespective of the degree of left ventricular dysfunction. These therapies are directed against these neurohumoral systems (neurohumoral antagonists) and classically comprise beta blockers, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers and vaptans. Recently, the RAAS blockade has been refined by the introduction of the angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan, which combines the RAAS inhibition and neprilysin blocking, enhancing the actions of natriuretic peptides. All these issues relating to the neurohumoral activation in HF are herein reviewed, and the underlying mechanisms are pictorially illustrated. Full article

Autosomal-Dominant Polycystic Kidney Disease (ADPKD) is a monogenic disorder initiated by mutations in either PKD1 or PKD2 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. Full article

Autism spectrum disorder (ASD) is rather common, presenting with prevalent early problems in social communication and accompanied by repetitive behavior. As vasopressin was implicated not only in salt-water homeostasis and stress-axis regulation, but also in social behavior, its role in the development of ASD might be suggested. In this review, we summarized a wide range of problems associated with ASD to which vasopressin might contribute, from social skills to communication, motor function problems, autonomous nervous system alterations as well as sleep disturbances, and altered sensory information processing. Beside functional connections between vasopressin and ASD, we draw attention to the anatomical background, highlighting several brain areas, including the paraventricular nucleus of the hypothalamus, medial preoptic area, lateral septum, bed nucleus of stria terminalis, amygdala, hippocampus, olfactory bulb and even the cerebellum, either producing vasopressin or containing vasopressinergic receptors (presumably V_1a). Sex differences in the vasopressinergic system might underline the male prevalence of ASD. Moreover, vasopressin might contribute to the effectiveness of available off-label therapies as well as serve as a possible target for intervention. In this sense, vasopressin, but paradoxically also V_1a receptor antagonist, were found to be effective in some clinical trials. We concluded that although vasopressin might be an effective candidate for ASD treatment, we might assume that only a subgroup (e.g., with stress-axis disturbances), a certain sex (most probably males) and a certain brain area (targeting by means of virus vectors) would benefit from this therapy. Full article

The renin–angiotensin–aldosterone system (RAAS) plays a crucial role in maintaining various physiological processes in the body, including blood pressure regulation, electrolyte balance, and overall cardiovascular health. However, any compounds or drugs known to perturb the RAAS might have an additional impact on transmembrane ionic currents. In this retrospective review article, we aimed to present a selection of chemical compounds or medications that have long been recognized as interfering with the RAAS. It is noteworthy that these substances may also exhibit regulatory effects in different types of ionic currents. Apocynin, known to attenuate the angiotensin II-induced activation of epithelial Na⁺ channels, was shown to stimulate peak and late components of voltage-gated Na⁺ current (I_Na). Esaxerenone, an antagonist of the mineralocorticoid receptor, can exert an inhibitory effect on peak and late I_Na directly. Dexamethasone, a synthetic glucocorticoid, can directly enhance the open probability of large-conductance Ca²⁺-activated K⁺ channels. Sparsentan, a dual-acting antagonist of the angiotensin II receptor and endothelin type A receptors, was found to suppress the amplitude of peak and late I_Na effectively. However, telmisartan, a blocker of the angiotensin II receptor, was effective in stimulating the peak and late I_Na along with a slowing of the inactivation time course of the current. However, telmisartan’s presence can also suppress the erg-mediated K⁺ current. Moreover, tolvaptan, recognized as an aquaretic agent that can block the vasopressin receptor, was noted to suppress the amplitude of the delayed-rectifier K⁺ current and the M-type K⁺ current directly. The above results indicate that these substances not only have an interference effect on the RAAS but also exert regulatory effects on different types of ionic currents. Therefore, to determine their mechanisms of action, it is necessary to gain a deeper understanding. Full article

Previously, we reported that intracerebroventricularly administered kisspeptin-13 (KP-13) induces anxiety-like behavior and activates the hypothalamic-pituitary-adrenal (HPA) axis in rats. In the present study, we aimed to shed light on the mediation of KP-13′s stress-evoking actions. The relative gene expressions of the corticotropin-releasing factor (Crf, Crfr1, and Crfr2) and arginine vasopressin (Avp, Avpr1a, and Avpr1b) systems were measured in the amygdala and hippocampus of male Wistar rats after icv KP-13 treatment. CRF and AVP protein content were also determined. A different set of animals received CRF or V1 receptor antagonist pretreatment before the KP-13 challenge, after which either an open-field test or plasma corticosterone levels measurement was performed. In the amygdala, KP-13 induced an upregulation of Avp and Avpr1b expression, and a downregulation of Crf. In the hippocampus, the mRNA level of Crf increased and the level of Avpr1a decreased. A significant rise in AVP protein content was also detected in the amygdala. KP-13 also evoked anxiety-like behavior in the open field test, which the V1 receptor blocker antagonized. Both CRF and V1 receptor blockers reduced the KP-13-evoked rise in the plasma corticosterone level. This suggests that KP-13 alters the AVP and CRF signaling and that might be responsible for its effect on the HPA axis and anxiety-like behavior. Full article

Tolvaptan, a selective vasopressin V2 receptor antagonist, is the first and only approved specific treatment for Autosomal-Dominant Polycystic Kidney Disease (ADPKD), and is used in current clinical practice. Real clinical data are missing. In this retrospective study, 41 ADPKD patients received tolvaptan for 3 years, from 2018 to 2021. Total kidney volume (TKV) was measured using Magnetic Resonance Imaging, at initiation and at the end of the treatment period. A complete biochemistry/hematology profile and a 24 h urine volume collection were performed monthly for the first 18 months and every 3 months thereafter. At the end of the treatment period, the median (IQR) estimated Glomerular Filtration Rate (e-GFR) was 5.3 (−1.3, 8.7) mL/min higher than the expected e-GFR decline without treatment, while the prediction for End Stage Chronic Kidney Disease (ESKD) had been prolonged by 1 (0, 2) year. Total Kidney Volume did not change significantly (2250 (1357) mL at 3 years of treatment vs. 2180 (1091) mL expected without treatment, p = 0.48). Younger patients with a relatively preserved e-GFR, lower hypertension burden, better familiar renal prognosis and more severe imaging data showed better outcomes. The aquaretic adverse effects of tolvaptan did not affect renal function and electrolyte balance in 51 patients, in a follow-up period of 18 months. Consequently, tolvaptan seems to be effective in preventing progression of ADPKD when administered in a timely manner in patients with better familiar renal history, shorter hypertension duration and worse imaging profile. Increased diuresis does not affect treatment efficacy. Full article

The utilization of vasopressin receptor antagonists, known as vaptans, in the management of hyponatremia among patients afflicted with the syndrome of inappropriate antidiuretic hormone (SIADH) remains a contentious subject. This meta-analysis aimed to evaluate the safety and efficacy of vaptans for treating chronic hyponatremia in adult SIADH patients. Clinical trials and observational studies were identified by a systematic search using MEDLINE, EMBASE, and Cochrane Database from inception through September 2022. The inclusion criteria were the studies that reported vaptans’ safety or efficacy outcomes compared to placebo or standard therapies. The study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD 42022357307). Five studies were identified, comprising three RCTs and two cohort studies, enrolling a total of 1840 participants. Regarding short-term efficacy on days 4–5, vaptans exhibited a significant increase in serum sodium concentration from the baseline in comparison to the control group, with a weighted mean difference of 4.77 mmol/L (95% CI, 3.57, 5.96; I² = 34%). In terms of safety outcomes, the pooled incidence rates of overcorrection were 13.1% (95% CI 4.3, 33.6; I² = 92%) in the vaptans group and 3.3% (95% CI 1.6, 6.6; I² = 27%) in the control group. Despite the higher correction rate linked to vaptans, with an OR of 5.72 (95% CI 3.38, 9.70; I² = 0%), no cases of osmotic demyelination syndrome were observed. Our meta-analysis comprehensively summarizes the efficacy and effect size of vaptans in managing SIADH. While vaptans effectively raise the serum sodium concentration compared to placebo/fluid restriction, clinicians should exercise caution regarding the potential for overcorrection. Full article

The aim of the present study was to determine the effects of alcohol intoxication and withdrawal on hypothalamic neurohormones such as corticotropin-releasing factor (CRF) and arginine vasopressin (AVP), and extrahypothalamic neurotransmitters such as striatal dopamine (DA), amygdalar gamma aminobutyric acid (GABA), and hippocampal glutamate (GLU). In addition, the participation of the two CRF receptors, CRF1 and CRF2, was investigated. For this purpose, male Wistar rats were exposed to repeated intraperitoneal (ip) administration of alcohol every 12 h, for 4 days and then for 1 day of alcohol abstinence. On the fifth or sixth day, intracerebroventricular (icv) administration of selective CRF1 antagonist antalarmin or selective CRF2 antagonist astressin₂B was performed. After 30 min, the expression and concentration of hypothalamic CRF and AVP, the concentration of plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT), and the release of striatal DA, amygdalar GABA, and hippocampal GLU were measured. Our results indicate that the neuroendocrine changes induced by alcohol intoxication and withdrawal are mediated by CRF1, not CRF2, except for the changes in hypothalamic AVP, which are not mediated by CRF receptors. Full article

The type 2 vasopressin receptor (V2R) is expressed in the kidneys, and it is the keystone of water homeostasis. Under the control of the antidiuretic hormone vasopressin, the V2R ensures vital functions, and any disturbance has dramatic consequences. Despite decades of research to develop drugs capable of activating or blocking V2R function to meet real medical needs, only one agonist and one antagonist are virtually used today. These two drugs cover only a small portion of patients’ needs, leaving millions of patients without treatment. Natural peptide toxins known to act selectively and at low doses on their receptor target could offer new therapeutic options. Full article

Decompensated liver cirrhosis is often complicated by refractory ascites, and intractable ascites are a predictor of poor prognosis in patients with liver cirrhosis. The treatment of ascites in patients with cirrhosis is based on the use of aldosterone blockers and loop diuretics, and occasionally vasopressin receptor antagonists are also used. Recent reports suggest that sodium–glucose cotransporter 2 (SGLT2) inhibitors may be a new treatment for refractory ascites with a different mechanism with respect to conventional agents. The main mechanisms of ascites reduction with SGLT2 inhibitors appear to be natriuresis and osmotic diuresis. However, other mechanisms, including improvements in glucose metabolism and nutritional status, hepatoprotection by ketone bodies and adiponectin, amelioration of the sympathetic nervous system, and inhibition of the renin–angiotensin–aldosterone system, may also contribute to the reduction of ascites. This literature review describes previously reported cases in which SGLT2 inhibitors were used to effectively treat ascites caused by liver cirrhosis. The discussion of the mechanisms involved is expected to contribute to establishing SGLT2 therapy for ascites in the future. Full article