Arginine Vasopressin Antagonist Research Articles

Arginine vasopressin effects on membrane potentials of preoptic area temperature-sensitive and -insensitive neurons in rat hypothalamic tissue slices

Arginine vasopressin (AVP) plays a hypothermic regulatory role in thermoregulation and is an important endogenous mediator in this mechanism. In the preoptic area (POA), AVP increases the spontaneous firing and thermosensitivity of warm-sensitive neurons and decreases those of cold-sensitive and temperature-insensitive neurons. Because POA neurons play a crucial role in precise thermoregulatory responses, these findings indicate that there is an association between the hypothermia and changes in the firing activity of AVP-induced POA neurons. However, the electrophysiological mechanisms by which AVP controls this firing activity remain unclear. Therefore, in the present study, using in vitro hypothalamic brain slices and whole-cell recordings, we elucidated the membrane potential responses of temperature-sensitive and –insensitive POA neurons to identify the applications of AVP or V1a vasopressin receptor antagonists. By monitoring changes in the resting potential and membrane potential thermosensitivity of the neurons before and during experimental perfusion, we observed that AVP increased the changes in the resting potential of 50% of temperature-insensitive neurons but reduced them in others. These changes are because AVP enhances the membrane potential thermosensitivity of nearly 50% of the temperature-insensitive neurons. On the other hand, AVP changes both the resting potential and membrane potential thermosensitivity of temperature-sensitive neurons, with no differences between the warm- and cold-sensitive neurons. Before and during AVP or V1a vasopressin receptor antagonist perfusion, no correlation was observed between changes in the thermosensitivity and membrane potential of all neurons. Furthermore, no correlation was observed between the thermosensitivity and membrane potential thermosensitivity of the neurons during experimental perfusion. In the present study, we found that AVP induction did not result in any changes in resting potential, which is unique to temperature-sensitive neurons. The study results suggest that AVP-induced changes in the firing activity and firing rate thermosensitivity of POA neurons are not controlled by resting potentials.

Betamethasone reverses AVP-induced dysfunction in trophoblast cells

Previously published data demonstrate that arginine vasopressin (AVP) secretion is elevated throughout gestation in pregnancies affected by preeclampsia. Additionally, chronic infusion of AVP in mice mimics human preeclampsia with pregnancy-specific hypertension, glomerular endotheliosis, proteinuria, and inflammation. In this AVP-infusion mouse model, betamethasone (BMTZ) has been shown to reverse the preeclampsia phenotype. Corticosteroids have previously been used to ameliorate human HELLP syndrome. Steroids have pleotropic therapeutic effects. The mechanism of BMTZ in reversing preeclampsia is unknown. The objective of this study is to determine if BMTZ improves AVP-induced placental dysfunction. Cell migration of HTR8/SVneo cells was analyzed via closure of a 500um gap over 48 hours (Ibidi). Cells were treated with saline, AVP + vasopressin receptor antagonists, and AVP + BMTZ. The area of migration was imaged and calculated (Olympus Cell Sens) and percent change from baseline area was calculated. MMP-9, a marker of inflammation, was measured in cultured media using a commercially available ELISA (Invitrogen). Statistical significance was determined by ANOVA (α=0.05). At 48 hours, AVP demonstrated lower cell migration in comparison to saline (23.8 vs. 32.3 percent change). This dysfunction was reversed with the addition BMTZ (53.8 vs. 32.3 percent change, p< 0.001). Administration of AVP + AVP antagonists (Conivaptan [29.4], Relcovaptan [32.5], Tolvaptan [35.4]) did not significantly affect migration (p >0.05). MMP-9 concentration was significantly lowered in the cell culture supernatant of cells treated with AVP+BMTZ vs. AVP alone (0.242 vs. 0.286 ng/mL, p=0.04). Treating HTR8/Svneo trophoblastic cells in vitro with AVP results in abnormal migration and cytokine expression. BMTZ reverses this AVP-induced dysfunction. In part, this effect may be due to a reversal of MMP-9 associated inflammation. Our results suggest that further investigation is warranted in the use of betamethasone as a novel therapeutic strategy for preeclampsia.

Hyponatremia in the frail.

As the lifespan increases, special attention has been given to the supportive care needs of the elderly. Frailty is an important issue in third age, since it is related to poor quality of life and mortality. The prevalence of pathological conditions related to sodium levels, specifically hyponatremia, is also present in the elderly. Yet, it is unclear, if hyponatremia and frailty are related to each other. This review summarizes the current state of knowledge regarding hyponatremia and frailty and analyzes five independent studies which searched for an association between those two parameters. As indicated by this study results, hyponatremia consists a risk factor for frailty. This could be explained by an effect of hyponatremia on sarcopenia and on cognitive function, which consist components of frailty. Thus, it is essential to monitor sodium levels in the elderly and to develop related interventions (e.g. using arginine vasopressin antagonists) in order to prevent frailty.

Structure-based drug repurposing for targeting Nsp9 replicase and spike proteins of severe acute respiratory syndrome coronavirus 2

Drug re-purposing might be a fast and efficient way of drug development against the novel coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We applied a bioinformatics approach using molecular dynamics and docking to identify FDA-approved drugs that can be re-purposed to potentially inhibit the non-structural protein 9 (Nsp9) replicase and spike proteins in SARS-CoV-2. We performed virtual screening of FDA-approved compounds, including antiviral, anti-malarial, anti-parasitic, anti-fungal, anti-tuberculosis, and active phytochemicals against the Nsp9 replicase and spike proteins. Selected hit compounds were identified based on their highest binding energy and favorable absorption, distribution, metabolism and excretion (ADME) profile. Conivaptan, an arginine vasopressin antagonist drug exhibited the highest binding energy (-8.4 Kcal/mol) and maximum stability with the amino acid residues present at the active site of the Nsp9 replicase. Tegobuvir, a non-nucleoside inhibitor of the hepatitis C virus, also exhibited maximum stability along with the highest binding energy (-8.1 Kcal/mol) at the active site of the spike proteins. Molecular docking scores were further validated by molecular dynamics using Schrodinger, which supported the strong stability of ligands with the proteins at their active sites through water bridges, hydrophobic interactions, and H-bonding. Our findings suggest Conivaptan and Tegobuvir as potential therapeutic agents against SARS-CoV-2. Further in vitro and in vivo validation and evaluation are warranted to establish how these drug compounds target the Nsp9 replicase and spike proteins.

Arginine Vasopressin Modulates Ion and Acid/Base Balance by Regulating Cell Numbers of Sodium Chloride Cotransporter and H+-ATPase Rich Ionocytes

Arginine vasopressin (Avp) is a conserved pleiotropic hormone that is known to regulate both water reabsorption and ion balance; however, many of the mechanisms underlying its effects remain unclear. Here, we used zebrafish embryos to investigate how Avp modulates ion and acid–base homeostasis. After incubating embryos in double-deionized water for 24 h, avp mRNA expression levels were significantly upregulated. Knockdown of Avp protein expression by an antisense morpholino oligonucleotide (MO) reduced the expression of ionocyte-related genes and downregulated whole-body Cl− content and H+ secretion, while Na+ and Ca2+ levels were not affected. Incubation of Avp antagonist SR49059 also downregulated the mRNA expression of sodium chloride cotransporter 2b (ncc2b), which is a transporter responsible for Cl− uptake. Correspondingly, avp morphants showed lower NCC and H+-ATPase rich (HR) cell numbers, but Na+/K+-ATPase rich (NaR) cell numbers remained unchanged. avp MO also downregulated the numbers of foxi3a- and p63-expressing cells. Finally, the mRNA expression levels of calcitonin gene-related peptide (cgrp) and its receptor, calcitonin receptor-like 1 (crlr1), were downregulated in avp morphants, suggesting that Avp might affect Cgrp and Crlr1 for modulating Cl− balance. Together, our results reveal a molecular/cellular pathway through which Avp regulates ion and acid–base balance, providing new insights into its function.

The protective effect of vasopressin deficiency in liver fibrosis in rats with chronic portocaval anastomosis

Liver fibrosis occur in liver diseases and its complications is cause of the increased rate of human mortality. The disease is characterized by the gradual accumulation of scar tissue in the liver parenchyma with decrease in metabolic capacity and liver failure. It is known that arginine vasopressin (AVP) participate in the regulation of the immune responses, including the scarring. However, the effect of how AVP regulates this process is not clear. Here we study the role of the AVP deficiency induced by the neurointermediate pituitary lobectomy (NIL) in rats with chronic anastomosis portocaval (APC) model (sixteen weeks). Groups of young male Wistar rats of 8–10 each were prepared: Sham operated (SHAM), APC, LNI and APC+NIL. Blood, plasma and serum biochemical variables were assessed: prothrombin time (TP), blood NH3, transaminases (TGO and TGP), bilirubins and γ‐Glutamyl Transpeptidase (GGT). Liver histological slides were stained with H‐E, Masson, Sirius Red and PAS. Results showed that in the APC group: the TP, NH3, TGO and TGP, bilirubins and GGT were significantly increased, whereas serum glucose levels, cholesterol, triglycerides, albumin, total proteins and the liver glycogen content where significantly augmented. Comparisons between SHAM and NIL groups did not shown significant differences in all these variables. As compared with the APC, the APC+NIL group developed a significant improvement in all these variables. The liver histopathology showed that the APC group developed a significant increase in fibrosis septa, inflammatory infiltrates and diminution of the glycogen content. The NIL group we do not have available data yet. In the NIL+APC group histology data showed a significant liver regeneration; less fibrosis, disappearance of inflammatory infiltrates and liver glycogen restoration.ConclusionsResults indicate the AVP play a role in liver fibrosis (demonstrated by the AVP deficiency). Results also suggest that AVP antagonists may be used for liver fibrosis treatment.Support or Funding InformationUniversidad Autónoma de Aguascalientes PIFF14‐1 andCONACYT 221262. México

Hyponatremia in Heart Failure: Pathogenesis and Management.

Hyponatremia is a very common electrolyte abnormality, associated with poor short- and long-term outcomes in patients with heart failure (HF). Two opposite processes can result in hyponatremia in this setting: Volume overload with dilutional hypervolemic hyponatremia from congestion, and hypovolemic hyponatremia from excessive use of natriuretics. These two conditions require different therapeutic approaches. While sodium in the form of normal saline can be lifesaving in the second case, the same treatment would exacerbate hyponatremia in the first case. Hypervolemic hyponatremia in HF patients is multifactorial and occurs mainly due to the persistent release of arginine vasopressin (AVP) in the setting of ineffective renal perfusion secondary to low cardiac output. Fluid restriction and loop diuretics remain mainstay treatments for hypervolemic/dilutional hyponatremia in patients with HF. In recent years, a few strategies, such as AVP antagonists (Tolvaptan, Conivaptan, and Lixivaptan), and hypertonic saline in addition to loop diuretics, have been proposed as potentially promising treatment options for this condition. This review aimed to summarize the current literature on pathogenesis and management of hyponatremia in patients with HF.

Effects of Conivaptan versus Mannitol on Post-Ischemic Brain Injury and Edema.

The aim of this study was to compare the effects of conivaptan, an arginine vasopressin antagonist, and mannitol, a sugar alcohol, on cerebral ischemia-induced brain injury and edema in rats. Fifty-eight 8-week-old male Sprague Dawley rats were randomly divided into five groups: control, ischemia-reperfusion (I/R)+saline, I/R+mannitol, I/R+10 mg/ml conivaptan, and I/R+20 mg/ml conivaptan. Cerebral ischemia was induced by common carotid artery occlusion for 30 minutes. Saline, mannitol, or conivaptan were administered intravenously at the onset of reperfusion. Blood and brain tissue samples were taken at the 6th hour of reperfusion. The electrolytes (Na+-K+-Cl-), osmolality, arginine vasopressin, albumin, progranulin (PGRN), neuron-specific enolase (NSE), and myeloperoxidase activity were measured in rat serum samples. Brain frontal/hippocampal sections were stained with hematoxylin-eosin and TUNEL techniques to evaluate histopathological changes. Statistical analyses revealed that conivaptan caused significant changes in the electrolyte, NSE, and PGRN levels and osmolality when compared with mannitol. Conivaptan treatment showed positive effects on serum biochemistry and tissue histology. Our findings revealed that conivaptan shows more diuretic activity than mannitol and triggers neither any damages nor edema in the brain tissue. This study may provide beneficial information for the development of treatment strategies for ischemia-related cerebrovascular diseases.

Hypervolemic Hyponatremia in Heart Failure.

Heart failure (HF) represents the most common cause of hypervolemic hyponatremia in current clinical practice. The presence of hyponatremia has been independently associated with worse outcomes in this patient population. The pathogenesis of hyponatremia in HF involves complex neurohormonal and cardio-renal interactions, including an increase in non osmotic secretion of arginine vasopressin (AVP) and insufficient tubular flow in the diluting segments of the nephron. The treatment of hyponatremia in HF involves decongestant therapy with diuretics, neurohormonal blockade and in certain occasions the use of AVP antagonists. The aim of this chapter is to summarize the pathophysiology, current evidence, and management recommendations for hyponatremia in patients with HF, with a specific focus on AVP homeostasis.

Effect of Vasopressin V1b Receptor Blockade on Activity of the Hypothalamic-Pituitary-Adrenal Axis in Old Monkeys with Depression-Like and Anxious Behavior Subjected to Stress or Injected with Vasopressin.

The effect of selective antagonist of the arginine vasopressin (AVP) V1b receptors on the secretion of ACTH and corticosteroids in response to insulin-induced hypoglycemia and injection of AVP is studied in old Macaca mulatta females with depression-like and anxious behavior. Intravenous antagonist in a dose of 1.1-1.7 μg/kg inhibits the increase of ACTH concentration, induced by hypoglycemia or injection of AVP. The degree of increase in the concentrations of hydrocortisone and dehydroepiandrosterone sulfate has not changed or increased. The effects of AVP antagonist prove that previously detected disorders in the reaction of the hypothalamic-pituitary-adrenal system in old Macaca mulatta with depression-like and anxious behavior could be caused by excessive activation of vasopressin V1b receptors on the pituitary corticotrophs, while the use of V1b receptor antagonists seems to be a promising method for prevention of these disorders.

Hyponatremia in Cirrhosis: Implications for Liver Transplantation.

Hyponatremia in cirrhosis is defined as a serum sodium level ≤130 mEq/L and occurs in approximately 22% of patients with cirrhosis. The appearance of hyponatremia in patients with cirrhosis portends a poor prognosis before liver transplantation (LT), independent of the Model for End-Stage Liver Disease (MELD) score. With the development of the MELD-sodium score, the management of hyponatremia has become more relevant than ever before. Overcorrection of hyponatremia before LT or perioperatively can lead to the devastating neurologic condition known as osmotic demyelination syndrome, which is often irreversible and fatal. Therefore, the most important tenet of hyponatremia is to avoid correcting the serum sodium by ≥8 mEq/L in a 24-hour period. Treatment of hyponatremia is highly challenging. The vast majority of patients with cirrhosis have chronic hypervolemic hyponatremia. Fluid restriction increases serum sodium levels, but tolerance and compliance are significant barriers. Diuretic withdrawal is helpful but contributes to worsening fluid overload. There are limited data to support use of intravenous concentrated albumin solutions. The use of the arginine vasopressin antagonists ("vaptans") is contentious; however, they may have a limited role. Risk factors for intraoperative overcorrection of serum sodium include increased utilization of packed red blood cell and fresh frozen plasma transfusions, which are often unavoidable. Intraoperative management is evolving, and more data are needed in regard to the use of sodium-reduced continuous venovenous hemofiltration and the use of trishydroxymethylaminomethane (Tris) to avoid excess sodium rebound. A thorough discussion of the current treatment options before and during LT is given in this review.

Vasopressin and oxytocin in sensory neurones: expression, exocytotic release and regulation by lactation

The neurohormones arginine-vasopressin (AVP) and oxytocin (OT) synthesised in supraoptic and paraventricular nuclei of neurohypophysis regulate lactation, systemic water homeostasis and nociception. Using transgenic rats expressing AVP and OT tagged with fluorescent proteins we demonstrate that both neurohormones are expressed in sensory neurones both in vitro, in primary cultures, and in situ, in the intact ganglia; this expression was further confirmed with immunocytochemistry. Both neurohormones were expressed in nociceptive neurones immunopositive to transient receptor potential vannilloid 1 (TRPV1) channel antibodies. The AVP and OT-expressing DRG neurones responded to AVP, OT, 50 mM K+ and capsaicin with [Ca2+]i transients; responses to AVP and OT were specifically blocked by the antagonists of V1 AVP and OT receptors. Probing the extracellular incubation saline with ELISA revealed AVP and OT secretion from isolated DRGs; this secretion was inhibited by tetanus toxin (TeNT) indicating the role for vesicular release. Expression of OT, but not AVP in DRG neurones significantly increased during lactation. Together, the results indicate novel physiological roles (possibly related to nociception and mood regulation) of AVP and OT in the sensory neurones.

Association of copeptin, a surrogate marker of arginine vasopressin, with cerebral vasospasm and delayed ischemic neurologic deficit after aneurysmal subarachnoid hemorrhage.

Delayed ischemic neurological deficit (DIND) is a leading cause of mortality and morbidity after aneurysmal subarachnoid hemorrhage (aSAH). Arginine vasopressin (AVP) is a hormone released by the posterior pituitary. It is known to cause cerebral vasoconstriction and has been implicated in hyponatremia secondary to the syndrome of inappropriate antidiuretic hormone secretion. Direct measurement of AVP is limited by its short half-life. Copeptin, a cleavage product of the AVP precursor protein, was therefore used as a surrogate marker for AVP. This study aimed to investigate the temporal relationship between changes in copeptin concentrations and episodes of DIND and hyponatremia. Copeptin concentrations in cerebrospinal fluid were quantified using enzyme-linked immunosorbent assay in 19 patients: 10 patients with DIND, 6 patients without DIND (no-DIND), and 3 controls. Copeptin concentrations were higher in DIND and no-DIND patients than in controls. In hyponatremic DIND patients, copeptin concentrations were higher compared with hyponatremic no-DIND patients. DIND was associated with a combination of decreasing sodium levels and increasing copeptin concentrations. Increased AVP may be the unifying factor explaining the co-occurrence of hyponatremia and DIND. Future studies are indicated to investigate this relationship and the therapeutic utility of AVP antagonists in the clinical setting.

Impact of vasopressin receptors on regulation of immune response in preeclampsia

Preeclampsia is a common disorder of pregnancy resulting in increased blood pressure and end organ effects. The pathogenesis of preeclampsia is multi-factorial. Arginine vasopressin (AVP) is increased in preeclampsia, and the chronic infusion of AVP throughout gestation has previously been shown to be sufficient to produce a phenotype of preeclampsia in C57BL/6J mice representative of some of the cardiovascular and renal events seen in humans. Alterations in T-helper cell populations and their effector cytokines are also known to occur in preeclampsia. Therefore, we proposed that the increased secretion of AVP may be responsible for the immune changes that occur in preeclampsia. We also hypothesized that known pharmacological AVP antagonist, vaptans, may be able to reverse the effects of AVP infusion.

Differential activation of arginine-vasopressin receptor subtypes in the amygdaloid modulation of anxiety in the rat by arginine-vasopressin.

The amygdala plays a paramount role in the modulation of anxiety and numerous studies have shown that arginine vasopressin (AVP) elicits anxiogenic effects following either its systemic or septal administration. The aim of this paper was to study the involvement of vasopressinergic neurotransmission in the amygdaloid modulation of unconditioned anxiety and to ascertain whether or not AVP receptor subtypes may have a differential role in this modulation. Anxiety behavior was evaluated both in Shock-Probe Burying Test and Light-Dark Box following the bilateral microinfusion of AVP alone or AVP together with either AVP 1a or AVP 1b receptor antagonists into the central amygdala (CeA). AVP microinfusion elicited at low (1ng/side) but not at high doses (10ng/side) anxiogenic-like responses in the Shock-Probe Burying Test but not in the Light-Dark Box. SSR149415, an AVP 1b antagonist unlike Manning compound, an AVP 1a antagonist, fully prevented AVP effects in the Shock-Probe Burying Test when it was administered simultaneously with AVP. In addition, oxytocin receptor blockade also failed to affect AVP effects. No effects of any AVP antagonist by itself were observed in both anxiety paradigms. Our results indicate that AVP 1b receptor contribute to the amygdaloid modulation of anxiety at least in the context of the Shock-Probe Burying Test since no effects were noticed in the Light-Dark Box. It remains to the future to ascertain whether AVP receptor subtypes have indeed differential actions either in the modulation of global or specific features of unconditioned anxiety.

Unduly Enhanced Response to Tolvaptan in a Woman Showing Syndrome of Inappropriate Antidiuretic Hormone Secretion: An Investigation of Possible Causes

ABSTRACT Objective: To investigate possible causes of an excessive response to tolvaptan in a woman with syndrome of inappropriate antidiuretic hormone secretion (SIADH). Methods: A 32-year-old woman was admitted to our cardiologic unit 3 months after delivery for hypertension and severe hyponatremia (120 mEq/L). Two hyponatremic episodes had already been documented in her medical history. SIADH was diagnosed and treatment with tolvaptan, an arginine vasopressin (AVP) antagonist, was instituted. After the first 15-mg dose, excessive polyuria (1 L/hour) and a rapid increase in serum sodium (13 mEq/L in 8 hours) occurred, so that therapy was stopped and restarted 2 days later at a reduced dose (5 mg). This level was effective and well tolerated. To explore the possible pharmacokinetic and pharmacodynamic mechanisms underlying the patient's hyperresponsiveness, the following tests were carried out: (1) in vivo phenotyping of CYP3A4 activity, the cytochrome responsible for tolvaptan metabolism, with two probe...

Vasopressin regulates the growth of the biliary epithelium in polycystic liver disease

The neurohypophysial hormone arginine vasopressin (AVP) acts by three distinct receptor subtypes: V1a, V1b, and V2. In the liver, AVP is involved in ureogenesis, glycogenolysis, neoglucogenesis and regeneration. No data exist about the presence of AVP in the biliary epithelium. Cholangiocytes are the target cells in a number of animal models of cholestasis, including bile duct ligation (BDL), and in several human pathologies, such as polycystic liver disease characterized by the presence of cysts that bud from the biliary epithelium. In vivo, liver fragments from normal and BDL mice and rats as well as liver samples from normal and ADPKD patients were collected to evaluate: (i) intrahepatic bile duct mass by immunohistochemistry for cytokeratin-19; and (ii) expression of V1a, V1b and V2 by immunohistochemistry, immunofluorescence and real-time PCR. In vitro, small and large mouse cholangiocytes, H69 (non-malignant human cholangiocytes) and LCDE (human cholangiocytes from the cystic epithelium) were stimulated with vasopressin in the absence/presence of AVP antagonists such as OPC-31260 and Tolvaptan, before assessing cellular growth by MTT assay and cAMP levels. Cholangiocytes express V2 receptor that was upregulated following BDL and in ADPKD liver samples. Administration of AVP increased proliferation and cAMP levels of small cholangiocytes and LCDE cells. We found no effect in the proliferation of large mouse cholangiocytes and H69 cells. Increases were blocked by preincubation with the AVP antagonists. These results showed that AVP and its receptors may be important in the modulation of the proliferation rate of the biliary epithelium.

PILOT STUDY OF THE RELATIONSHIP OF AMBIENT COPEPTIN TO THE AQUARETIC EFFECTS OF TOLVAPTAN IN PATIENTS WITH HEART FAILURE

Tolvaptan, an arginine vasopressin (AVP) antagonist, may be a novel therapy for congestive heart failure (CHF) but AVP activation is not uniform and results have been variable in previous trials of unselected CHF patients. Copeptin, c-terminal pre-provasopressin, reflects AVP activation. We

Use of "Vaptans" in treatment of hyponatremia

Hyponatremia is the most prevalent electrolyte imbalance, and may be present in up to 30% of hospitalized patients. It is an important predictor of in-hospital mortality. Irrespective of the reason underlying hyponatremia, water metabolism plays an important role. Arginine-vasopressin, which has cardiovascular effects and plays a role in water metabolism, is released from the posterior hypothalamus in response to an increase in plasma osmolality or a drop in the blood pressure, which are detected by osmoreceptors and baroreceptors respectively. Arginine-vasopressin has receptors located on vascular smooth muscle cells, the heart (V1a), the collecting ducts of the renal medulla (V2), the anterior pituitary gland (V1b) and many other organs. Arginine-vasopressin antagonists, known as "vaptans", have recently attracted attention for the treatment of chronic hypotonic hyponatremia. In this review, we focus on the diagnosis and classification of hyponatremia, current trends in its treatment in the light of guidelines, and the rationale of using vaptans in treating hyponatremia. We also briefly review cornerstone studies in the literature regarding vaptans, and the correct indications, contraindications and cautions in the use of "tolvaptan" and "conivaptan", two approved vaptans for this indication.

Review of Tolvaptan's Pharmacokinetic and Pharmacodynamic Properties and Drug Interactions.

Tolvaptan is an arginine vasopressin (AVP) antagonist that acts to increase excretion of free water (aquaresis) in patients without introducing electrolyte abnormalities or worsening renal function. It works via blockade of vasopressin-2 receptors at the renal collecting duct. Since the approval of tolvaptan for the treatment of hypervolemic and euvolemic hyponatremia in 2009, new studies have been reported to better characterize its pharmacokinetic and pharmacodynamic profile of tolvaptan. This paper is a review of both these clinical studies, as well as previous literature, in order to help guide appropriate clinical use of tolvaptan in patients. With appropriate monitoring of serum sodium, tolvaptan may be safely dose escalated from 15 mg once daily to a maximum effective dose of 60 mg once daily for multiple days, to achieve optimal aqauretic effects. In terms of drug interactions, co-administration of moderate to potent CYP3A4 inhibitors and inducers should be avoided. Tolvaptan should also be co-administered with caution and proper monitoring in the presence of P-glycoprotein substrate and strong inhibitors. Co-administration of tolvaptan with diuretic therapy did not appear to alter the aquaretic effect of tolvaptan; and was shown to be safe and well tolerated.