Tolvaptan Prolongs Blockage of the Vasopressin Type II Receptor Over 24 Hours in Responders With Stage D Heart Failure

Imamura, Teruhiko; Kinugawa, Koichiro; Komuro, Issei

doi:10.1536/ihj.15-297

Cited by 12 publications

(9 citation statements)

References 29 publications

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“…Although tolvaptan has been shown to induce aquaresis, resulting in an amelioration of hyponatraemia in patients with cirrhosis, congestive heart failure and SIAD , to date no direct in vitro evidence has been provided that tolvaptan impairs AQP2 trafficking and insertion to the plasma membrane in collecting duct principal cells in response to vasopressin thus blunting AQP2‐mediated osmotic water permeability. In this respect, a global analysis of the in vitro effect of tolvaptan on rat collecting duct suspension showed that tolvaptan inhibits vasopressin effect on AQP2 phosphorylation at ser256, ser264 and ser269 while inhibiting ser261 .…”

Section: Discussionmentioning

confidence: 99%

The V2 receptor antagonist tolvaptan raises cytosolic calcium and prevents AQP2 trafficking and function: an in vitro and in vivo assessment

Tamma

Mise

Ranieri

et al. 2017

J Cellular Molecular Medi

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Tolvaptan, a selective vasopressin V2 receptor antagonist, is a new generation diuretic. Its clinical efficacy is in principle due to impaired vasopressin‐regulated water reabsorption via aquaporin‐2 (AQP2). Nevertheless, no direct in vitro evidence that tolvaptan prevents AQP2‐mediated water transport, nor that this pathway is targeted in vivo in patients with syndrome of inappropriate antidiuresis (SIAD) has been provided. The effects of tolvaptan on the vasopressin–cAMP/PKA signalling cascade were investigated in MDCK cells expressing endogenous V2R and in mouse kidney. In MDCK, tolvaptan prevented dDAVP‐induced increase in ser256‐AQP2 and osmotic water permeability. A similar effect on ser256‐AQP2 was found in V1aR −/− mice, thus confirming the V2R selectively. Of note, calcium calibration in MDCK showed that tolvaptan per se caused calcium mobilization from the endoplasmic reticulum resulting in a significant increase in basal intracellular calcium. This effect was only observed in cells expressing the V2R, indicating that it requires the tolvaptan–V2R interaction. Consistent with this finding, tolvaptan partially reduced the increase in ser256‐AQP2 and the water permeability in response to forskolin, a direct activator of adenylyl cyclase (AC), suggesting that the increase in intracellular calcium is associated with an inhibition of the calcium‐inhibitable AC type VI. Furthermore, tolvaptan treatment reduced AQP2 excretion in two SIAD patients and normalized plasma sodium concentration. These data represent the first detailed demonstration of the central role of AQP2 blockade in the aquaretic effect of tolvaptan and underscore a novel effect in raising intracellular calcium that can be of significant clinical relevance.

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Section: Discussionmentioning

confidence: 99%

The V2 receptor antagonist tolvaptan raises cytosolic calcium and prevents AQP2 trafficking and function: an in vitro and in vivo assessment

Tamma

Mise

Ranieri

et al. 2017

J Cellular Molecular Medi

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“…Those studies may have missed a considerable amount of urine AQP2. Currently, methods for disrupting EV membranes have been adopted in several studies involving ELISA for urinary AQP2 measurements [10,15]. The localization of the antibody epitope is not unique to AQP2, but also applies to other AQPs where the antibody epitopes are typically at the C-terminus, which are located inside EVs.…”

Section: Discussionmentioning

confidence: 99%

Disruption of Membranes of Extracellular Vesicles Is Necessary for ELISA Determination of Urine AQP2: Proof of Disruption and Epitopes of AQP2 Antibodies

Nameta

Saijo

Ohmoto

et al. 2016

IJMS

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Aquaporin-2 (AQP2) is present in urine extracellular vesicles (EVs) and is a useful biomarker for water balance disorders. We previously found that pre-treatment of urine with alkali/detergent or storage at −25 °C is required for enzyme-linked immunosorbent assay (ELISA) measurement. We speculated that disruptions of EVs membranes are necessary to allow for the direct contact of antibodies with their epitopes. Human urine EVs were prepared using an ultracentrifugation method. Urine EV samples were stored at different temperatures for a week. Electron microscopy showed abundant EVs with diameters of 20–100 nm, consistent with those of exosomes, in normal urine, whereas samples from alkali/detergent pre-treated urine showed fewer EVs with large swollen shapes and frequent membrane disruptions. The abundance and structures of EVs were maintained during storage at −80 °C, but were severely damaged at −25 °C. Binding and competitive inhibition assays showed that epitopes of monoclonal antibody and polyclonal antibody were the hydrophilic Loop D and C-terminus of AQP2, respectively, both of which are present on the inner surface of EVs. Thus, urine storage at −25 °C or pre-treatment with alkali/detergent disrupt EVs membranes and allow AQP2 antibodies to bind to their epitopes located inside EVs.

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“…Urine osmolality is invariably decreased after the administration of tolvaptan in patients with HF who respond to tolvaptan, 8) and the depressed osmolality sustains for over 24 hours since blood concentration of tolvaptan is often detectable at the trough, especially in cases with renal dysfunction. 9) Therefore, the level of urine osmolality was not changed by marked aquaresis of tolvaptan, even under the significant existence of glycosuria induced by SGLT2i. In other words, diuretic benefit by SGLT2i cannot be simply attributable to glycosuria but also to ameliorating resistance to other diuretic/aquaretic agents, possibly by way of improving renal congestion.…”

Section: Discussionmentioning

confidence: 89%

Successful Withdrawal from Dobutamine by Canagliflozin in a Diabetic Patient with Stage D Heart Failure

et al. 2017

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SummaryPatients with stage D heart failure (HF) frequently become dependent on high doses of diuretics and inotropic agents. Recently, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), an oral antidiabetic agent, has been demonstrated to have favorable effects in preventing HF. However, it remains unknown whether SGLT2i is reliable for patients with decompensated HF. We experienced a case of a patient with stage D HF for whom attempting intravenous dobutamine withdrawal was difficult even after the administration of all conventional pharmacological treatment. Administration of canagliflozin produced an additive diuretic action and correction of volume overload in combination with azosemide and tolvaptan, and resulted in successful withdrawal of dobutamine. Thus, SGLT2i might be promising for the treatment of patients with congestive HF who are refractory to conventional diuretic treatment.(Int Heart J 2017; 58: 978-981) Key words: Diabetes mellitus, Sodium-glucose cotransporter 2 inhibitor, Diuretics, Inotropic agents S odium-glucose cotransporter 2 inhibitors (SGLT2i-s) are novel antidiabetic agents with multiple effects such as a glucose-lowering effect, osmotic diuretic action, and others. 1) Recently, empagliflozin, an SGLT2i, has been demonstrated to reduce death from cardiovascular causes and hospitalization for heart failure (HF) in the EMPA-REG OUTCOME trial.2) Importantly, this significant reduction of both mortality and HF emerged after only a couple of months of treatment, which might be attributable to the favorable effects of SGLT2i on hemodynamics, such as osmotic diuretic action, reduction of preload and afterload, and inhibitions of neurohumoral system. The EMPA-REG OUTCOME study supports the concept that SGLT2i is also effective for decompensated HF, but it remains unknown whether SGLT2i is actually effective in such patients. Here we describe a case of successful HF treatment with canagliflozin, one of the SGLT2i-s, in a patient with stage D HF and diabetes mellitus. Administration of canagliflozin produced an additive diuretic action and correction of volume overload in combination with azosemide and tolvaptan, and resulted in successful withdrawal of dobutamine. Case ReportThe patient was a 67-year-old woman with ischemic cardiomyopathy (Table) who had received coronary artery bypass in October 2015. In the patient, signs of HF worsened even after introduction of standard medical therapy, and the patient needed pimobendan with high doses of loop diuretics and tolvaptan. The patient soon became dependent upon intravenous infusion of inotropes, including dobutamine and olprinone and received intra-aortic balloon pumping (IABP). The patient was transferred to our hospital in January 2016. On admission, serum levels of creatinine 0.99 mg/dL, total bilirubin 0.8 mg/dL, and HbA 1C 7.4% were assayed, and the plasma B-type natriuretic peptide (BNP) was 2,679 pg/mL. Transthoracic echocardiography showed left ventricular ejection fraction of 15% along with dilatation of left ventricle (diastolic dia...

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Tolvaptan Prolongs Blockage of the Vasopressin Type II Receptor Over 24 Hours in Responders With Stage D Heart Failure

Cited by 12 publications

References 29 publications

The V2 receptor antagonist tolvaptan raises cytosolic calcium and prevents AQP2 trafficking and function: an in vitro and in vivo assessment

The V2 receptor antagonist tolvaptan raises cytosolic calcium and prevents AQP2 trafficking and function: an in vitro and in vivo assessment

Disruption of Membranes of Extracellular Vesicles Is Necessary for ELISA Determination of Urine AQP2: Proof of Disruption and Epitopes of AQP2 Antibodies

Successful Withdrawal from Dobutamine by Canagliflozin in a Diabetic Patient with Stage D Heart Failure

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