The Role of Vasopressin Antagonism on Renal Sodium Handling

Study Overview
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Brief Summary
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Vasopressin has primarily been considered to be a water and osmosis regulating hormone that mediates its effects on renal aquaporin channels. Recent data suggest that vasopressin, through its V2 receptor, may also modulate sodium homeostasis. The purpose of this human physiology study was to test whether antagonism of the V2R alters urine sodium excretion in normal healthy volunteers.

Detailed Description
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Vasopressin's potential roles in maintaining normal volume homeostasis are expanding. While previous data support the concept that vasopressin's primary role is in mediating water homeostasis, recent data suggest that vasopressin, through its V2 receptor, may also modulate sodium homeostasis. This effect occurs via activation of the epithelial sodium channel (ENaC). These studies document that vasopressin via activation of the V2 receptor, not only reduces free water excretion but also sodium excretion. These data suggest that blocking this receptor under the right circumstances and in the right population may be effective in modulating hypertension in humans: specifically a V2 receptor antagonist may be effective in treating some individuals that have salt-sensitive hypertension. The current proposal will test in normal human subjects the proof of principle of the above stated hypothesis, and to assess the best markers to determine such an effect. It is important to perform studies with strict environmental control in a clinical research center because of the variability of environmental factors that can create confusion in interpreting data (dietary sodium, activity, body posture, diurnal variation, ambient temperature, sleep-wake cycle, etc.). The overall program objective is to determine if a vasopressin V2 antagonist will be an effective treatment for salt-sensitive hypertension and if so, what subtype. The object of this specific proposal is to determine the effect of a selective V2 antagonist on sodium handling in normal subjects.

Official Title
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The Role of Vasopressin Antagonism on Renal Sodium Handling

Conditions
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Healthy

Intervention / Treatment
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* Drug: Tolvaptan Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Blood pressure <130/85 mmHg and >100/50 mmHg Normal laboratory values for (see Normal Values table): Complete blood count Serum creatinine, sodium, potassium, glucose, liver enzymes Urinalysis ECG Exclusion Criteria: - Alcohol intake >12 oz per week Tobacco or recreational drug use History of coronary disease, diabetes, hypertension, stroke, kidney disease, or illness requiring overnight hospitalization in the past 6 months Any prescription medication or herbal medication use except oral contraceptive or multivitamin Pregnancy or current breastfeeding First degree relative with hypertension, diabetes, stroke, renal or cardiac disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, placebo-controlled, double-blinded, parallel arm clinical trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo | Drug: Tolvaptan Oral Tablet<br>* Tolvaptan, to block V2R<br>|
| Experimental: 15mg Tolvaptan<br>15mg Tolvaptan | Drug: Tolvaptan Oral Tablet<br>* Tolvaptan, to block V2R<br>|
| Experimental: 30mg Tolvaptan<br>30mg Tolvaptan | Drug: Tolvaptan Oral Tablet<br>* Tolvaptan, to block V2R<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute intravenous saline response | Urine sodium excretion measured in response to saline infusion | 6 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dietary salt response | Cumulative sodium excretion measured in response to dietary salt loading | 6 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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vasopressin receptor, renal sodium excretion