Effect of tolvaptan on renal handling of water and sodium, GFR and central hemodynamics in autosomal dominant polycystic kidney disease during inhibition of the nitric oxide system:a randomized, placebo-controlled, double blind, crossover study
| Autor: | Jeppe Bakkestroem Rosenbaek, Jesper Noergaard Bech, Safa Al Therwani, Erling B. Pedersen, My Emma Sofie Malmberg |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
030232 urology & nephrology Tolvaptan 030204 cardiovascular system & hematology lcsh:RC870-923 chemistry.chemical_compound 0302 clinical medicine Cross-Over Studies Aldosterone Middle Aged Polycystic Kidney Autosomal Dominant Treatment Outcome Nephrology Blood pressure Female Antidiuretic Hormone Receptor Antagonists Research Article Glomerular Filtration Rate medicine.drug Adult medicine.medical_specialty Fractional excretion of sodium Metabolic Clearance Rate ENaC Autosomal dominant polycystic kidney disease Diuresis Nitric Oxide Natriuresis Young Adult 03 medical and health sciences Double-Blind Method Internal medicine medicine Journal Article Humans Epithelial Sodium Channels ADPKD Aquaporin 2 business.industry urogenital system Sodium Hemodynamics Water Vasoactive hormones Nitric oxide Benzazepines AQP2 lcsh:Diseases of the genitourinary system. Urology medicine.disease Free water clearance Endocrinology chemistry business Antidiuretic |
| Zdroj: | Therwani, S, Malmberg, M E S, Rosenbaek, J B, Bech, J N & Pedersen, E B 2017, ' Effect of tolvaptan on renal handling of water and sodium, GFR and central hemodynamics in autosomal dominant polycystic kidney disease during inhibition of the nitric oxide system : a randomized, placebo-controlled, double blind, crossover study ', B M C Nephrology, vol. 18, no. 1, 268 . https://doi.org/10.1186/s12882-017-0686-3 BMC Nephrology BMC Nephrology, Vol 18, Iss 1, Pp 1-13 (2017) |
| ISSN: | 0252-7863 |
| DOI: | 10.1186/s12882-017-0686-3 |
| Popis: | Background: Tolvaptan slows progression of autosomal dominant polycystic kidney disease (ADPKD) by antagonizing the vasopressin-cAMP axis. Nitric oxide (NO) stimulates natriuresis and diuresis, but its role is unknown during tolvaptan treatment in ADPKD.Methods: Eighteen patients with ADPKD received tolvaptan 60 mg or placebo in a randomized, placebo-controlled, double blind, crossover study. L-NMMA (L-NG-monomethyl-arginine) was given as a bolus followed by continuous infusion during 60 min. We measured: GFR, urine output (UO), free water clearance (CH2O), fractional excretion of sodium (FENa), urinary excretion of aquaporin-2 channels (u-AQP2) and epithelial sodium channels (u-ENaCγ), plasma concentrations of vasopressin (p-AVP), renin (PRC), angiotensinII (p-AngII), aldosterone (p-Aldo), and central blood pressure (cBP).Results: During tolvaptan with NO-inhibition, a more pronounced decrease was measured in UO, CH2O (61% vs 43%) and FENa (46% vs 41%) after placebo than after tolvaptan; GFR and u-AQP2 decreased to the same extent; p-AVP increased three fold, whereas u-ENaCγ, PRC, p-AngII, and p-Aldo remained unchanged. After NO-inhibition, GFR increased after placebo and remained unchanged after tolvaptan (5% vs −6%). Central diastolic BP (CDBP) increased to a higher level after placebo than tolvaptan. Body weight fell during tolvaptan treatment.Conclusions: During NO inhibition, tolvaptan antagonized both the antidiuretic and the antinatriuretic effect of L-NMMA, partly via an AVP-dependent mechanism. U-AQP2 was not changed by tolvaptan, presumeably due to a counteracting effect of elevated p-AVP. The reduced GFR during tolvaptan most likely is caused by the reduction in extracellular fluid volume and blood pressure.Trial registration: Clinical Trial no: NCT02527863. Registered 18 February 2015. BACKGROUND: Tolvaptan slows progression of autosomal dominant polycystic kidney disease (ADPKD) by antagonizing the vasopressin-cAMP axis. Nitric oxide (NO) stimulates natriuresis and diuresis, but its role is unknown during tolvaptan treatment in ADPKD.METHODS: Eighteen patients with ADPKD received tolvaptan 60 mg or placebo in a randomized, placebo-controlled, double blind, crossover study. L-NMMA (L-NG-monomethyl-arginine) was given as a bolus followed by continuous infusion during 60 min. We measured: GFR, urine output (UO), free water clearance (CH2O), fractional excretion of sodium (FENa), urinary excretion of aquaporin-2 channels (u-AQP2) and epithelial sodium channels (u-ENaCγ), plasma concentrations of vasopressin (p-AVP), renin (PRC), angiotensinII (p-AngII), aldosterone (p-Aldo), and central blood pressure (cBP).RESULTS: During tolvaptan with NO-inhibition, a more pronounced decrease was measured in UO, CH2O (61% vs 43%) and FENa (46% vs 41%) after placebo than after tolvaptan; GFR and u-AQP2 decreased to the same extent; p-AVP increased three fold, whereas u-ENaCγ, PRC, p-AngII, and p-Aldo remained unchanged. After NO-inhibition, GFR increased after placebo and remained unchanged after tolvaptan (5% vs -6%). Central diastolic BP (CDBP) increased to a higher level after placebo than tolvaptan. Body weight fell during tolvaptan treatment.CONCLUSIONS: During NO inhibition, tolvaptan antagonized both the antidiuretic and the antinatriuretic effect of L-NMMA, partly via an AVP-dependent mechanism. U-AQP2 was not changed by tolvaptan, presumeably due to a counteracting effect of elevated p-AVP. The reduced GFR during tolvaptan most likely is caused by the reduction in extracellular fluid volume and blood pressure.TRIAL REGISTRATION: Clinical Trial no: NCT02527863 . Registered 18 February 2015. |
| Databáze: | OpenAIRE |
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