V2 Receptor Effects on Fluid Regulation and Performance

Revisiting the Human Sweat Gland - Does Arginine Vasopressin Modulate Sweat Sodium Concentration Via the V2 Receptor?

This primary aim of this study was to critically assess whether or not sweat water content and sodium concentration were acutely regulated by dynamic changes in antidiuretic hormone (arginine vasopressin or AVP) acting on the Vasopressin 2 receptor (V2R) during exercise. Secondary aims were to evaluate running performance and core temperature to further characterize the role of AVP in the coordinated balance of fluid and temperature homeostasis during exercise. The primary hypothesis was that activation of the V2R in sweat glands would result in water reabsorption and fluid conservation during endurance exercise.

Study Overview

• Status: Completed
• Conditions: Hyponatremia; Hypernatremia; Electrolyte Imbalance
• Intervention / Treatment: Drug: V2R (Vasopressin 2 receptor)

Detailed Description

Ten healthy habitual runners (> 50km running per week) between 18-60 years of age participated in this double blind randomized control trial. Each subject presented to the exercise lab on four separate occasions. Trial 1 was a familiarization trial to determine each subject's maximal aerobic capacity and peak treadmill running speak (VO2 Peak test). Trials 2, 3 and 4 utilized the same exact protocol, differing only in pharmacological intervention. In a randomized, double-blind order (both participant and investigator blinded to the intervention), either a placebo pill, the V2 receptor antagonist tolvaptan (Samsca™, 30mg tablet), or the V2 receptor agonist desmopressin (DDAVP™, 0.2mg tablet) was ingested along with the CorTemp™ Core Temperature Sensor two hours before commencement of the Exercise Trial with 240mL of bottled water. The exercise protocol consisted of 60 minutes of treadmill running at 60% of peak speed (steady-state) followed by a performance test (the VO2 Peak test). Blood, saliva and urine, were collected before the exercise trial (baseline) and again after both the steady-state run and performance runs. Sweat was obtained from sweat patches after both the steady-state and performance runs. Core temperature, fluid intake, performance time, body weight, thirst and sodium palatability ratings were also assessed. Free access to water was allowed during the trial and all urine produced during the trial was measured and collected. The main outcome measure was sweat sodium concentration.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Rochester, Michigan, United States, 48309
      • Oakland University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy (no acute or chronic medical conditions or regular prescription medication use), habitual (>50km/week)
• Distance runners between the ages of 18-60 years.

Exclusion Criteria:

• Individuals with chronic medical problems which require regular prescription medication
• Runners with pre-existing kidney problems
• Unable to sense thirst
• Difficulty swallowing
• Gastrointestinal disorders
• History of fainting associated with blood draw.

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: all study participants; All study participants received all interventions. V2R Antagonist: 30mg Tolvaptan tablet ingested 2 hours before exercise. V2R agonist: 0.2mg DDAVP tablet ingested 2 hours before exercise Placebo	Drug: V2R (Vasopressin 2 receptor); All ten subjects were used as their own controls in this double-blind, randomized controlled trial assessing the effect of the V2R on sweat sodium concentration via use of a V2R blocker (antagonist), stimulator (agonist), against a placebo (drug naive state).; Other Names: V2R antagonist: tolvaptan (30mg tablet); V2R agonist: desmopressin (0.2mg tablet)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sweat Sodium Concentration Obtained After the Steady-state Portion of the Trial	Changes in sweat sodium concentration will parallel changes in urine sodium concentration with use of the V2R antagonist, agonist and placebo if the primary hypothesis is true (sweat sodium is regulated by the V2R, similar to how urine sodium is regulated by principle cells located within in the kidney collecting duct)	4 study trials (4 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urine Sodium Concentration After the Steady-state Portion of the Trial	Changes in urine sodium concentration after use of the V2R antagonist, agonist and placebo interventions will verify whether or not pharmacologic activation or inhibition was successfully induced.	4 study trials (4 weeks)
Blood Sodium Concentration	Measurement of blood sodium concentration will determine if normonatremia (blood sodium concentrations within the normal physiological range of 135-145mmol/L) were maintained throughout the trial with appropriate fluid intake during the V2R antagonist, agonist and placebo intervention trials.	4 study trials (4 weeks)
Saliva Sodium Concentration	Measurement of salivary sodium concentration will allow us to determine if the V2R antagonist, agonist and placebo interventions activate aquaporin-5 (AQP5) water channels that are also located in sweat glands. If the V2R acts on the sweat glands through AQP5, there should be parallel changes in sweat, urine and saliva sodium concentrations with each pharmaceutical intervention.	4 trials (4 weeks)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body Weight	Changes in body weight during the V2R antagonist, agonist and placebo conditions will provide researchers with an additional measure of overall fluid balance (fluid in versus fluid out) as well as an estimate of overall sweat water losses.	4 trials (4 weeks)
Core Temperature	Measurement of core temperature using an ingestible CorTemp sensor during the V2R antagonist, agonist and placebo trials will allow researchers to assess if fluid homeostasis and thermoregulation were intertwined in response to each pharmacological intervention.	4 trials (4 weeks)
Thirst Rating	To determine if fluid intake behaviors were appropriately regulated in response to the V2R antagonist, agonist and placebo conditions during exercise.	4 trials (4 weeks)
Sodium Palatability Ratings	To determine if sodium preference ratings were appropriately regulated in response to the V2R antagonist, agonist and placebo conditions during exercise.	4 weeks (4 trials)
Performance	To determine if exercise performance, as determined by overall exercise time, was affected in response to the V2R antagonist, agonist and placebo conditions.	4 trials (4 weeks)
Fluid Intake	To determine if fluid intake behaviors were appropriately regulated in response to the V2R antagonist, agonist and placebo conditions during exercise.	4 weeks (4 trials)

Collaborators and Investigators

• Sponsor: Oakland University
• Collaborators: Georgetown University
• Investigators: Principal Investigator: Tamara D Hew-Butler, PhD, Oakland University; Study Director: Joseph G Verbalis, MD, Georgetown University

Publications and helpful links

General Publications

• Hew-Butler T, Hummel J, Rider BC, Verbalis JG. Characterization of the effects of the vasopressin V2 receptor on sweating, fluid balance, and performance during exercise. Am J Physiol Regul Integr Comp Physiol. 2014 Aug 15;307(4):R366-75. doi: 10.1152/ajpregu.00120.2014. Epub 2014 Jun 18.

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (Actual): October 1, 2011
• Study Completion (Actual): October 1, 2012

Study Registration Dates

• First Submitted: March 10, 2014
• First Submitted That Met QC Criteria: March 11, 2014
• First Posted (Estimate): March 12, 2014

Study Record Updates

• Last Update Posted (Estimate): May 12, 2016
• Last Update Submitted That Met QC Criteria: April 6, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Keywords: running; arginine vasopressin; sweat sodium; V2 antagonist
• Additional Relevant MeSH Terms: Metabolic Diseases; Water-Electrolyte Imbalance; Hyponatremia; Hypernatremia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Hemostatics; Coagulants; Vasoconstrictor Agents; Antidiuretic Hormone Receptor Antagonists; Antidiuretic Agents; Tolvaptan; Vasopressins; Arginine Vasopressin
• Other Study ID Numbers: RAM#4713