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Annual Review of Medicine 2015The synthesis of nonpeptide orally bioavailable vasopressin antagonists devoid of agonistic activity (vaptans) has made possible the selective blockade of vasopressin... (Review)
Review
The synthesis of nonpeptide orally bioavailable vasopressin antagonists devoid of agonistic activity (vaptans) has made possible the selective blockade of vasopressin receptor subtypes for therapeutic purposes. Vaptans acting on the vasopressin V2 receptors (aquaretics) have attracted attention as a possible therapy for heart failure and polycystic kidney disease. Despite a solid rationale and encouraging preclinical testing, aquaretics have not improved clinical outcomes in randomized clinical trials for heart failure. Additional clinical trials with select population targets, more flexible dosing schedules, and possibly a different drug type or combination (balanced V1a/V2 receptor antagonism) may be warranted. Aquaretics are promising for the treatment of autosomal dominant polycystic kidney disease and have been approved in Japan for this indication. More studies are needed to better define their long-term safety and efficacy and optimize their utilization.
Topics: Antidiuretic Hormone Receptor Antagonists; Heart Failure; Humans; Polycystic Kidney Diseases; Receptors, Vasopressin
PubMed: 25493947
DOI: 10.1146/annurev-med-050913-022838 -
Advances in Kidney Disease and Health May 2023Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of numerous kidney cysts which leads to kidney failure. ADPKD is responsible for... (Review)
Review
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of numerous kidney cysts which leads to kidney failure. ADPKD is responsible for approximately 10% of patients with kidney failure. Overwhelming evidence supports that vasopressin and its downstream cyclic adenosine monophosphate signaling promote cystogenesis, and targeting vasopressin 2 receptor with tolvaptan and other antagonists ameliorates cyst growth in preclinical studies. Tolvaptan is the only drug approved by Food and Drug Administration to treat ADPKD patients at the risk of rapid disease progression. A major limitation of the widespread use of tolvaptan is aquaretic events. This review discusses the potential strategies to improve the tolerability of tolvaptan, the progress on the use of an alternative vasopressin 2 receptor antagonist lixivaptan, and somatostatin analogs. Recent advances in understanding the pathophysiology of PKD have led to new approaches of treatment via targeting different signaling pathways. We review the new pharmacotherapies and dietary interventions of ADPKD that are promising in the preclinical studies and investigated in clinical trials.
Topics: United States; Humans; Polycystic Kidney, Autosomal Dominant; Tolvaptan; Antidiuretic Hormone Receptor Antagonists; Vasopressins; Receptors, Vasopressin; Renal Insufficiency
PubMed: 37088527
DOI: 10.1053/j.akdh.2023.01.003 -
American Journal of Physiology. Renal... Jan 2024Tolvaptan, a vasopressin antagonist selective for the V2-subtype vasopressin receptor (V2R), is widely used in the treatment of hyponatremia and autosomal-dominant...
Tolvaptan, a vasopressin antagonist selective for the V2-subtype vasopressin receptor (V2R), is widely used in the treatment of hyponatremia and autosomal-dominant polycystic kidney disease (ADPKD). Its effects on signaling in collecting duct cells have not been fully characterized. Here, we perform RNA-seq in a collecting duct cell line (mpkCCD). The data show that tolvaptan inhibits the expression of mRNAs that were previously shown to be increased in response to vasopressin including aquaporin-2, but also reveals mRNA changes that were not readily predictable and suggest off-target actions of tolvaptan. One such action is activation of the MAPK kinase (ERK1/ERK2) pathway. Prior studies have shown that ERK1/ERK2 activation is essential in the regulation of a variety of cellular and physiological processes and can be associated with cell proliferation. In immunoblotting experiments, we demonstrated that ERK1/ERK2 phosphorylation in mpkCCD cells was significantly reduced by vasopressin, in contrast to the increases seen in non-collecting-duct cells overexpressing V2R in prior studies. We also found that tolvaptan has a strong effect to increase ERK1/ERK2 phosphorylation in the presence of vasopressin and that tolvaptan's effect to increase ERK1/ERK2 phosphorylation is absent in mpkCCD cells in which both protein kinase A (PKA)-catalytic subunits have been deleted. Thus, it appears that the tolvaptan effect to increase ERK activation is PKA-dependent and is not due to an off-target effect of tolvaptan. We conclude that in cells expressing V2R at endogenous levels: ) vasopressin decreases ERK1/ERK2 activation; ) in the presence of vasopressin, tolvaptan increases ERK1/ERK2 activation; and ) these effects are PKA-dependent. Vasopressin is a key hormone that regulates the function of the collecting duct of the kidney. ERK1 and ERK2 are enzymes that play key roles in physiological regulation in all cells. The authors used collecting duct cell cultures to investigate the effects of vasopressin and the vasopressin receptor antagonist tolvaptan on ERK1 and ERK2 phosphorylation and activation.
Topics: Tolvaptan; Receptors, Vasopressin; Phosphorylation; MAP Kinase Signaling System; Kidney; Antidiuretic Hormone Receptor Antagonists; Vasopressins
PubMed: 37916285
DOI: 10.1152/ajprenal.00124.2023 -
Endocrine, Metabolic & Immune Disorders... 2018The nonapeptide hypothalamic hormone vasopressin (VP), exerts important effects on cardiovascular system via its receptors V1, V2 and V3. Patients with congestive heart... (Review)
Review
BACKGROUND AND OBJECTIVE
The nonapeptide hypothalamic hormone vasopressin (VP), exerts important effects on cardiovascular system via its receptors V1, V2 and V3. Patients with congestive heart failure (CHF) present elevated plasma VP levels. Aim of this paper is to review the role of vasopressin in CHF.
METHODS
We analyzed the best of published literature dealing with the role of VP in patients affected by CHF, identifying keywords and MeSH terms in Pubmed and then searching them. The last search was performed on August 2017.
RESULTS
Scientific articles dealing with the relationship between VP and CHF show that circulating high VP levels found in CHF despite an exaggerated increase in circulatory blood volume can contribute to CHF exacerbation. In particular, the stimulation of V1R induces vascular constriction responsible for increased systemic vascular resistance and afterload, and, in addition, coronary vasoconstriction with consequent reduced coronary circulation and cardiac contractility, whereas the stimulation of V2R induces free water reabsorption and this is responsible of preload increase and congestion of pulmonary vascular bed with edema and hyponatremia, markers of advanced CHF.
CONCLUSION
VP can play an important role among the derangements of the endocrine system in CHF even being a possible target in the treatment of this condition. Vaptans, antagonists of VP receptors, in fact, are able to increase urine output and plasma sodium levels without the increased risk of arrhythmic death induced by diuretics, even though, further studies are needed to establish a possible role of these drugs in the treatment of CHF.
Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Cardiovascular Agents; Cardiovascular System; Heart Failure; Hemodynamics; Humans; Hypothalamus; Receptors, Vasopressin; Signal Transduction; Up-Regulation; Vasopressins
PubMed: 29437026
DOI: 10.2174/1871530318666180212095235 -
The Pan African Medical Journal 2019Disorders of water balance are a disease commonly encountered in our clinical practice. Analysis of vasopressin receptor type II (V2R) is essential to understand the... (Review)
Review
Disorders of water balance are a disease commonly encountered in our clinical practice. Analysis of vasopressin receptor type II (V2R) is essential to understand the physiology of water balance and it is used as a biological prototype of G protein-coupled receptors (GPCRs). Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a syndrome of inappropriate antidiuretic hormone secretion (SIADH) with low plasmatic vasopressin. The evidence on the role of V2 receptor and of aquaporin (AQP) in the mechanism of action for antidiuretic hormone (ADH) was based on the identification of protein gene mutations in patients with nephrogenic diabetes insipidus and NSIAD syndrome. V2R activating mutations were found in patients with NSIAD, contrasting with the numerous V2R inactivating mutations related to X-linked mutations described in patients with nephrogenic diabetes insipidus.
Topics: Aquaporins; Diabetes Insipidus, Nephrogenic; Genetic Diseases, X-Linked; Humans; Inappropriate ADH Syndrome; Mutation; Neurophysins; Protein Precursors; Receptors, Vasopressin; Vasopressins
PubMed: 31312322
DOI: 10.11604/pamj.2019.32.210.6006 -
Journal of Neuroendocrinology Apr 2016In the last several decades, sophisticated experimental techniques have been used to determine the neurobiology of the oxytocin and vasopressin systems in rodents. Using... (Review)
Review
In the last several decades, sophisticated experimental techniques have been used to determine the neurobiology of the oxytocin and vasopressin systems in rodents. Using a suite of methodologies, including electrophysiology, site-specific selective pharmacology, receptor autoradiography, in vivo microdialysis, and genetic and optogenetic manipulations, we have gained unprecedented knowledge about how these neuropeptides engage neural circuits to regulate behaviour, particularly social behaviour. Based on this foundation of information from rodent studies, we have started generating new hypotheses and frameworks about how the oxytocin and vasopressin systems could be acting in humans to influence social cognition. However, despite the recent inundation of publications using intranasal oxytocin in humans, we still know very little about the neurophysiology of the oxytocin system in primates more broadly. Furthermore, the design and analysis of these human studies have remained largely uninformed of the potential neurobiological mechanisms underlying their findings. Although the methods available for studying the oxytocin and vasopressin systems in humans are incredibly limited as a result of practical and ethical considerations, there is great potential to fill the gaps in our knowledge by developing better nonhuman primate models of social functioning. Behavioural pharmacology and receptor autoradiography have been used to study the oxytocin and vasopressin systems in nonhuman primates, and there is now great potential to broaden our understanding of the neurobiology of these systems. In this review, we discuss comparative findings in receptor distributions in rodents and primates, with perspectives on the functionality of conserved regions of expression in these distinct mammalian clades. We also identify specific ways that established technologies can be used to answer basic research questions in primates. Finally, we highlight areas of future research in nonhuman primates that are experimentally poised to yield critical insights into the anatomy, physiology and behavioural effects of the oxytocin system, given its remarkable translational potential.
Topics: Animals; Receptors, Oxytocin; Receptors, Vasopressin; Species Specificity; Translational Research, Biomedical
PubMed: 26940141
DOI: 10.1111/jne.12382 -
Life Science Alliance Apr 2023Specific receptors for the neurohypophyseal hormones, arginine vasopressin (AVP) and oxytocin, are present in the male reproductive organs. However, their exact roles...
Specific receptors for the neurohypophyseal hormones, arginine vasopressin (AVP) and oxytocin, are present in the male reproductive organs. However, their exact roles remain unknown. To elucidate the physiological functions of pituitary hormones in male reproduction, this study first focused on the distribution and function of one of the AVP receptors, V1a. In situ hybridization analysis revealed high expression of the in Leydig cells of the testes and narrow/clear cells in the epididymis, with the expression pattern differing from that of the oxytocin receptor (OTR). Notably, persistent motility and highly proportional hyperactivation were observed in spermatozoa from V1a receptor-deficient mice. In contrast, OTR blocking by antagonist atosiban decreased hyperactivation rate. Furthermore, AVP stimulation could alter the extracellular pH mediated by the V1a receptor. The results highlight the crucial role of neurohypophyseal hormones in male reproductive physiology, with potential contradicting roles of V1a and OTR in sperm maturation. Our findings suggest that V1a receptor antagonists are potential therapeutic drugs for male infertility.
Topics: Male; Mice; Animals; Receptors, Oxytocin; Receptors, Vasopressin; Sperm Motility; Semen; Oxytocin; Arginine Vasopressin
PubMed: 36650057
DOI: 10.26508/lsa.202201488 -
Journal of Critical Care Aug 2017Septic shock remains one of the major causes of morbidity and mortality in the critically ill. Despite early goal therapy and administration of cathecholaminergic... (Review)
Review
Septic shock remains one of the major causes of morbidity and mortality in the critically ill. Despite early goal therapy and administration of cathecholaminergic agents, up to 30% of patients succumb to the disease. In this manuscript, we first summarize the standard of care of patients with septic shock and current guidelines. We review the physiologic role of vasopressin and its role in septic shock management. We then review the most up-to-date evidence on the potential role of V1a receptor agonists such as Selepressin, in septic shock. Exciting new trials are being completed in order to elucidate the role of V1a receptor agonists as potential first-line vasopressor alternatives in the therapy of circulatory shock in septic patients.
Topics: Critical Illness; Humans; Receptors, Vasopressin; Shock, Septic; Vasoconstrictor Agents; Vasopressins
PubMed: 28319910
DOI: 10.1016/j.jcrc.2017.03.008 -
Cellular Signalling Mar 2016Heart failure (HF) continues to be a highly prevalent syndrome, affecting millions of patients and costing billions of dollars in treatment per year in the United States... (Review)
Review
Heart failure (HF) continues to be a highly prevalent syndrome, affecting millions of patients and costing billions of dollars in treatment per year in the United States alone. Studies in failing human heart and in transgenic HF models led to the recognition that enhanced neurohormonal signaling plays a causative role in HF progression, and the use of neurohormone receptor antagonists have proven to decrease hospitalization rates. It has also been long recognized that patients with HF have abnormal water retention, hypo-osmolality, and hyponatremia secondary to elevations in the levels of the neurohormone arginine vasopressin (AVP). AVP is released from the hypothalamus in response to changes in plasma osmolality and pressure, acting at three distinct G protein-coupled receptors: V1AR, V1BR and V2R. Persistent AVP release causes hyponatremia via renal V2R activation, a risk factor for death and hospitalization, and there is a correlation between plasma AVP levels and HF severity/survival of chronic HF patients. Because of the adverse clinical consequences associated with the development of hyponatremia, V2R antagonists were developed for the treatment of HF patients with hyponatremia, however in contrast to other neurohormone blockers they do not relay a survival benefit and may exacerbate decompensated HF requiring inotropic support. Renewed interest in the cardiac V1AR system during HF has arisen due to several recent findings: 1) mice with myocyte-selective transgenic overexpression of cardiac V1AR developed cardiomyopathy in the absence of any pathological insult, 2) cardiac V1AR expression was shown to be increased late-stage human HF, and 3) V1AR antagonism prevented cardiomyopathy development in a mouse model of HF. While cardiac V1AR expression is increased in HF, the role of V1AR signaling in various forms of cardiac injury and in distinct cardiac cell types has been controversial. Therefore this review will primarily focus on V1AR signaling as a potential therapeutic target for HF treatment.
Topics: Animals; Fibroblasts; Heart Failure; Humans; Kidney; Muscle, Smooth, Vascular; Myocytes, Cardiac; Receptors, Vasopressin; Signal Transduction
PubMed: 26232615
DOI: 10.1016/j.cellsig.2015.07.021 -
Current Drug Metabolism 2017Vasopressin (AVP) and its receptors play a pivotal role in maintaining body homeostasis under physiological and pathophysiological conditions. As a consequence, the... (Review)
Review
Vasopressin (AVP) and its receptors play a pivotal role in maintaining body homeostasis under physiological and pathophysiological conditions. As a consequence, the vasopressin system has emerged as an important target for both diagnostic and therapeutic applications in a number of medical conditions. Stoichiometric generation of AVP with copeptin, which is relatively accessible in the blood for measurements, makes copeptin a valuable surrogate of AVP. In this review, we present the regulation of release of AVP and activation of V1a, V1b, and V2 vasopressin receptors under physiological and pathological conditions. We make a survey of the role of AVP in: the regulation of the cardiovascular system; body fluid osmolality; natraemia; endocrine regulation; food intake; metabolism; circadian rhythmicity, immunological processes; and in the formation of learning, memory, cognition, and emotional and social behaviours. We also discuss the significance of the inappropriate functioning of the vasopressin system for: the development of cardiovascular diseases; disturbances of the water-electrolyte balance; energy metabolism; inflammatory processes; pain; neurogenic stress; memory disorders; depression; anxiety; autism; and schizophrenia. The structure and biological properties of peptide and non-peptide agonists and antagonists of V1a, V1b and V2 vasopressin receptors are presented and the potential use of copeptin and the current and likely indications for AVP agonists and antagonists in the diagnosis and therapeutics of multiple pathological conditions is discussed.
Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Diagnosis; Drug Therapy; Humans; Prognosis; Receptors, Vasopressin; Vasopressins
PubMed: 28117000
DOI: 10.2174/1389200218666170119145900