Effect of the Aquaretic Tolvaptan on Nitric Oxide System. A Dose-response Study (DOVA)

Study Overview
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Brief Summary
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Tolvaptan is a selective vasopressin receptor antagonist (V2R) that increases free water and sodium excretion. Inhibition of V2R increases vasopressin concentration in plasma, which stimulates V1-receptors in the vascular bed and may change both central and brachial hemodynamics and plasma concentration of vasoactive hormones. The purpose of the study is to measure the effects of tolvaptan on renal handling of water and sodium, systemic hemodynamics and vasoactive hormones at baseline and during nitric oxide (NO)-inhibition with L-NG-monomethyl-arginine (L-NMMA).

Official Title
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The Effects of Tolvaptan on Renal Handling of Water and Sodium, Vasoactive Hormones and Circulatory System, During Basal Conditions and During Inhibition of the Nitric Oxide System in Healthy Subjects. A Dose-response Study.

Conditions
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Nephropathy

Intervention / Treatment
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* Drug: 15 mg tolvaptan
* Drug: 30 mg tolvaptan
* Drug: 45 mg tolvaptan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women, age 18-40 years Body Mass Index (BMI) 18,5-30 kg/m2 Exclusion Criteria: Anamnestic or clinical signs of heart, lung, lever, kidney and brain disease Neoplastic disease Drug abuse Alcohol abuse Medical treatment except peroral anticontraceptive Pregnancy Smoking Abnormal blood and urine sample Abnormal ECG Blood donation within a month before examination Arterial hypertension (>140 mmHg systolic and/or 90 mmHg diastolic)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 15 mg tolvaptan<br>Oral administration of 15 mg tolvaptan on each examination day. | Drug: 15 mg tolvaptan<br>* 15 mg pr day for 1 day<br>* Other names: Samsca;|
| Active Comparator: 30 mg tolvaptan<br>Oral administration of 30 mg tolvaptan on each examination day. | Drug: 30 mg tolvaptan<br>* 30 mg pr day for 1 day<br>* Other names: Samsca;|
| Active Comparator: 45 mg tolvaptan<br>Oral administration of 45 mg tolvaptan on each examination day. | Drug: 45 mg tolvaptan<br>* 45 mg pr day for 1 day<br>* Other names: Samsca;|
| Placebo Comparator: Placebo<br>Oral administration of a Unikalk tablet | Drug: Placebo<br>* 1 tablet Unikalk pr day for 1 day<br>* Other names: Unikalk;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CH2O | Measurement of H2O clearance at baseline, during and after L-NMMA infusion | 5-6 Hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urine biomarkers(Aquaporins and Epithelial Sodium Channels γ) |  | 5-6 Hours | 
| Central and brachial blood pressure |  | 5-6 Hours | 
| Augmentation Index |  | 5-6 Hours | 
| Vasoactive Hormones( Angiotensin II, Aldosterone, Endothelin, Atrial Natriuretic Peptide, Brain Natriuretic Peptide, Arginin Vasopressin) |  | 5-6 Hours | 
| Fractional sodium excretion | Measurement of Sodium excretion at baseline, during and after L-NMMA infusion. | 5-6 Hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tolvaptan, L-NMMA, Healthy subjects, Nephrology