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Expert Opinion on Pharmacotherapy 2023Terlipressin is a synthetic vasopressin analog which has been recently approved in the United States by the Food and Drug Administration for the treatment of hepatorenal... (Review)
Review
INTRODUCTION
Terlipressin is a synthetic vasopressin analog which has been recently approved in the United States by the Food and Drug Administration for the treatment of hepatorenal syndrome. Terlipressin stimulates vasopressin receptors located on the smooth muscle vasculature of the splanchnic circulation and renal tubules which results in splanchnic vasoconstriction with improved renal perfusion and antidiuretic activity, respectively.
AREAS COVERED
In this review, we discuss available data regarding the FDA approved use of terlipressin, safety, and tolerability, as well as highlight alternative uses in chronic liver disease currently still under investigation.
EXPERT OPINION
Terlipressin is more efficacious compared to other vasoactive agents including midodrine octreotide and norepinephrine in reversal of hepatorenal syndrome and improves short-term survival. Other potential applications of terlipressin's vasoconstrictor actions reported in the literature include management of variceal hemorrhage and other complications of portal hypertension.
Topics: Humans; Terlipressin; Lypressin; Hepatorenal Syndrome; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Vasoconstrictor Agents; Liver Cirrhosis
PubMed: 37535437
DOI: 10.1080/14656566.2023.2244427 -
Cardiovascular Research Dec 2023Cardiovascular disease is the leading cause of death worldwide. Its prevalence is rising due to ageing populations and the increasing incidence of diseases such as... (Review)
Review
Cardiovascular disease is the leading cause of death worldwide. Its prevalence is rising due to ageing populations and the increasing incidence of diseases such as chronic kidney disease, obesity, and diabetes that are associated with elevated cardiovascular risk. Despite currently available treatments, there remains a huge burden of cardiovascular disease-associated morbidity for patients and healthcare systems, and newer treatments are needed. The apelin system, comprising the apelin receptor and its two endogenous ligands apelin and elabela, is a broad regulator of physiology that opposes the actions of the renin-angiotensin and vasopressin systems. Activation of the apelin receptor promotes endothelium-dependent vasodilatation and inotropy, lowers blood pressure, and promotes angiogenesis. The apelin system appears to protect against arrhythmias, inhibits thrombosis, and has broad anti-inflammatory and anti-fibrotic actions. It also promotes aqueous diuresis through direct and indirect (central) effects in the kidney. Thus, the apelin system offers therapeutic promise for a range of cardiovascular, kidney, and metabolic diseases. This review will discuss current cardiovascular disease targets of the apelin system and future clinical utility of apelin receptor agonism.
Topics: Humans; Apelin; Apelin Receptors; Cardiovascular Diseases; Cardiovascular System; Heart
PubMed: 37956047
DOI: 10.1093/cvr/cvad171 -
Frontiers in Endocrinology 2023The diabetic kidney disease (DKD) is the major cause of the chronic kidney disease (CKD). Enhanced plasma vasopressin (VP) levels have been associated with the... (Review)
Review
The diabetic kidney disease (DKD) is the major cause of the chronic kidney disease (CKD). Enhanced plasma vasopressin (VP) levels have been associated with the pathophysiology of DKD and CKD. Stimulation of VP release in DKD is caused by glucose-dependent reset of the osmostat leading to secondary pathophysiologic effects mediated by distinct VP receptor types. VP is a stress hormone exhibiting the antidiuretic action in the kidney along with broad adaptive effects in other organs. Excessive activation of the vasopressin type 2 (V2) receptor in the kidney leads to glomerular hyperfiltration and nephron loss, whereas stimulation of vasopressin V1a or V1b receptors in the liver, pancreas, and adrenal glands promotes catabolic metabolism for energy mobilization, enhancing glucose production and aggravating DKD. Increasing availability of selective VP receptor antagonists opens new therapeutic windows separating the renal and extra-renal VP effects for the concrete applications. Improved understanding of these paradigms is mandatory for further drug design and translational implementation. The present concise review focuses on metabolic effects of VP affecting DKD pathophysiology.
Topics: Humans; Diabetic Nephropathies; Vasopressins; Receptors, Vasopressin; Renal Insufficiency, Chronic; Glucose; Diabetes Mellitus
PubMed: 37790608
DOI: 10.3389/fendo.2023.1176199 -
Nature Reviews. Endocrinology Dec 2023Traditional textbook physiology has ascribed unitary functions to hormones from the anterior and posterior pituitary gland, mainly in the regulation of effector hormone... (Review)
Review
Traditional textbook physiology has ascribed unitary functions to hormones from the anterior and posterior pituitary gland, mainly in the regulation of effector hormone secretion from endocrine organs. However, the evolutionary biology of pituitary hormones and their receptors provides evidence for a broad range of functions in vertebrate physiology. Over the past decade, we and others have discovered that thyroid-stimulating hormone, follicle-stimulating hormone, adrenocorticotropic hormone, prolactin, oxytocin and arginine vasopressin act directly on somatic organs, including bone, adipose tissue and liver. New evidence also indicates that pituitary hormone receptors are expressed in brain regions, nuclei and subnuclei. These studies have prompted us to attribute the pathophysiology of certain human diseases, including osteoporosis, obesity and neurodegeneration, at least in part, to changes in pituitary hormone levels. This new information has identified actionable therapeutic targets for drug discovery.
Topics: Humans; Pituitary Hormones; Pituitary Gland; Prolactin; Adipose Tissue; Brain
PubMed: 37715028
DOI: 10.1038/s41574-023-00894-5 -
Trends in Biochemical Sciences Apr 2024Neurohypophysial peptides are ancient and evolutionarily highly conserved neuropeptides that regulate many crucial physiological functions in vertebrates and... (Review)
Review
Neurohypophysial peptides are ancient and evolutionarily highly conserved neuropeptides that regulate many crucial physiological functions in vertebrates and invertebrates. The human neurohypophysial oxytocin/vasopressin (OT/VP) signaling system with its four receptors has become an attractive drug target for a variety of diseases, including cancer, pain, cardiovascular indications, and neurological disorders. Despite its promise, drug development faces hurdles, including signaling complexity, selectivity and off-target concerns, translational interspecies differences, and inefficient drug delivery. In this review we dive into the complexity of the OT/VP signaling system in health and disease, provide an overview of relevant pharmacological probes, and discuss the latest trends in therapeutic lead discovery and drug development.
Topics: Animals; Humans; Oxytocin; Vasopressins; Receptors, Vasopressin
PubMed: 38418338
DOI: 10.1016/j.tibs.2024.01.010 -
Comprehensive Psychoneuroendocrinology Nov 2023The neuropeptide hormone oxytocin is involved in many processes in our bodies, linking our social lives to our internal states. I started out my career studying primate... (Review)
Review
The neuropeptide hormone oxytocin is involved in many processes in our bodies, linking our social lives to our internal states. I started out my career studying primate families, an interest that expanded into the role of oxytocin in family-oriented behaviors such as pair bonding and parenting in prairie voles, humans, and other primates. Starting as a post-doc with Dr. C. Sue Carter, I also became interested in the role of oxytocin during development and the way that we manipulate oxytocin clinically. During that post-doc and then as a faculty member at the University of California, Davis, I have worked on a number of these questions.
PubMed: 38108037
DOI: 10.1016/j.cpnec.2023.100203 -
Journal of Medicinal Chemistry Nov 2023Oxytocin (OT) and vasopressin (VP) are related neuropeptides that regulate many biological processes. In humans, OT and VP act via four G protein-coupled receptors, OTR,...
Oxytocin (OT) and vasopressin (VP) are related neuropeptides that regulate many biological processes. In humans, OT and VP act via four G protein-coupled receptors, OTR, VR, VR, and VR (VPRs), which are associated with several disorders. To investigate the therapeutic potential of these receptors, particularly in the receptor-dense areas of the brain, molecular probes with a high temporal and spatial resolution are required. Such a spatiotemporal resolution can be achieved by incorporating photochromic moieties into OT and VP. Here, we report the design, synthesis, and (photo)pharmacological characterization of 12 OT- and VP-derived photoprobes using different modification strategies. Despite OT's and VP's sensitivity toward structural changes, we identified two photoprobes with good potency and photoswitch window for investigating the OTR and VR. These photoprobes should be of high value for producing cutting-edge photocontrollable peptide probes for the study of dynamic and kinetic receptor activation processes in specific regions of the brain.
Topics: Humans; Oxytocin; Receptors, Oxytocin; Vasopressins; Receptors, G-Protein-Coupled; Neuropeptides
PubMed: 37857356
DOI: 10.1021/acs.jmedchem.3c01415 -
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 -
Biomedicines Sep 2023Autism spectrum disorder (ASD) is rather common, presenting with prevalent early problems in social communication and accompanied by repetitive behavior. As vasopressin... (Review)
Review
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). 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 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.
PubMed: 37892977
DOI: 10.3390/biomedicines11102603