Effect of the Aquaretic Tolvaptan on Nitric Oxide System (TORA)

Study Overview
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Brief Summary
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The purpose of this study is to investigate the effect of tolvaptan on renal water, sodium and potassium excretion, plasma concentration of vasoactive hormones,central blood pressure, pulse wave velocity (PWV) and augmentation index, basal and during inhibition of nitric oxide synthesis in healthy subjects.

Detailed Description
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Tolvaptan is a vasopressin antagonist (V2-antagonist) and is used in treatment of hyponatremia. Animal studies have demonstrated that inhibition of V2 receptors in the renal principal cell increases renal free water clearance and renal sodium excretion. Treatment with V2-receptor antagonists increases vasopressin concentration in plasma that stimulates V1-receptors in the vascular bed. This may change both central and peripheral hemodynamics and plasma concentration of vasoactive hormones. Changes in hemodynamics and hormone concentration may consequently change renal sodium and water handling. The nitric oxide system plays a central role in both renal sodium and water handling and regulation of vascular tone and blood pressure. The effects of tolvaptan the circulation and kidneys is investigated by using measurements of biomarkers specific for the sodium/water balance in the urine and by measurements of vasoactive hormones in the blood after administration of tolvaptan and L-NMMA infusion.

Official Title
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Effect of Vasopressin Antagonism on Renal Sodium and Water Handling and Circulation During Inhibition of the Nitric Oxide System in Healthy Subjects

Conditions
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Cardiovascular Diseases, Nephropathy

Intervention / Treatment
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* Drug: 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: Tolvaptan<br>Oral administration of 15 mg Tolvaptan on each examination day. | Drug: Tolvaptan<br>* 15 mg pr day for 1 day<br>* Other names: Samsca;|
| Placebo Comparator: Placebo<br>Oral administration of 15 mg Unikalk tablet on each examination day. | Drug: Placebo<br>* 1 tablet Unikalk 1 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, Epithelial Sodium Channels γ and β, Sodium/Chloride and Sodium/Potassium/Chloride cotransporter) |  | 5-6 Hours | 
| Central blood pressure |  | 5-6 Hours | 
| Pulse wave velocity |  | 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, Cardiology