Electrolyte Imbalance, Hypernatremia, Hyponatremia
Conditions
Keywords
arginine vasopressin, sweat sodium, V2 antagonist, running
Brief summary
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.
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.
Interventions
DRUGV2R (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).
Sponsors
Georgetown University
Oakland University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sweat Sodium Concentration Obtained After the Steady-state Portion of the Trial | 4 study trials (4 weeks) | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Urine Sodium Concentration After the Steady-state Portion of the Trial | 4 study trials (4 weeks) | 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. |
| Blood Sodium Concentration | 4 study trials (4 weeks) | 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. |
| Saliva Sodium Concentration | 4 trials (4 weeks) | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Performance | 4 trials (4 weeks) | To determine if exercise performance, as determined by overall exercise time, was affected in response to the V2R antagonist, agonist and placebo conditions. |
| Body Weight | 4 trials (4 weeks) | 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. |
| Fluid Intake | 4 weeks (4 trials) | To determine if fluid intake behaviors were appropriately regulated in response to the V2R antagonist, agonist and placebo conditions during exercise. |
| Core Temperature | 4 trials (4 weeks) | 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. |
| Thirst Rating | 4 trials (4 weeks) | To determine if fluid intake behaviors were appropriately regulated in response to the V2R antagonist, agonist and placebo conditions during exercise. |
| Sodium Palatability Ratings | 4 weeks (4 trials) | To determine if sodium preference ratings were appropriately regulated in response to the V2R antagonist, agonist and placebo conditions during exercise. |
Countries
United States
Participant flow
Pre-assignment details
Participants received all three interventions in randomized fashion.
Participants by arm
| Arm | Count |
|---|---|
| 1/Placebo, V2R Agonist, V2R Antagonist This study was a double-blind randomized controlled trial in which all ten subjects participated in three trials under three separate pharmacological interventions: V2R antagonist, agonist and placebo conditions. A standardized exercise protocol was performed in the laboratory, separated by one week. Each subject served as his or her own control and the key which identified which intervention was utilized in the exact order (all tablets customized to appear identical) was unlocked only after data collection was completed. Therefore, all ten subjects participated in a total of thirty intervention exercise trials after the initial treadmill familiarization trial was completed.
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). | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | 1/Placebo, V2R Agonist, V2R Antagonist |
|---|---|
| Age, Continuous | 35.5 years STANDARD_DEVIATION 13.1 |
| BMI | 22.5 kg/m2 STANDARD_DEVIATION 3.3 |
| Peak treadmill running speed | 11.0 mph STANDARD_DEVIATION 1.4 |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 8 Participants |
| VO2 Peak | 58.7 ml/kg/minute STANDARD_DEVIATION 6.2 |
| years of running experience | 8.8 years STANDARD_DEVIATION 8.7 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 |
Outcome results
Primary
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)
Time frame: 4 study trials (4 weeks)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1/Placebo, V2R Agonist, V2R Antagonist | Sweat Sodium Concentration Obtained After the Steady-state Portion of the Trial | Placebo | 80.1 mEq/L | Standard Deviation 21.6 |
| 1/Placebo, V2R Agonist, V2R Antagonist | Sweat Sodium Concentration Obtained After the Steady-state Portion of the Trial | V2R Agonist | 76.8 mEq/L | Standard Deviation 24.5 |
| 1/Placebo, V2R Agonist, V2R Antagonist | Sweat Sodium Concentration Obtained After the Steady-state Portion of the Trial | V2R Antagonist | 84.7 mEq/L | Standard Deviation 25.7 |
Secondary
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.
Time frame: 4 study trials (4 weeks)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1/Placebo, V2R Agonist, V2R Antagonist | Blood Sodium Concentration | Placebo | 143.6 mEq/L | Standard Deviation 1.5 |
| 1/Placebo, V2R Agonist, V2R Antagonist | Blood Sodium Concentration | V2R Agonist | 144.3 mEq/L | Standard Deviation 2.3 |
| 1/Placebo, V2R Agonist, V2R Antagonist | Blood Sodium Concentration | V2R Antagonist | 145.9 mEq/L | Standard Deviation 2 |
Secondary
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.
Time frame: 4 trials (4 weeks)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1/Placebo, V2R Agonist, V2R Antagonist | Saliva Sodium Concentration | V2R Antagonist | 31.0 mEq/L | Standard Deviation 13.3 |
| 1/Placebo, V2R Agonist, V2R Antagonist | Saliva Sodium Concentration | Placebo | 20.5 mEq/L | Standard Deviation 11 |
| 1/Placebo, V2R Agonist, V2R Antagonist | Saliva Sodium Concentration | V2R Agonist | 28.1 mEq/L | Standard Deviation 9.5 |
Secondary
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.
Time frame: 4 study trials (4 weeks)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1/Placebo, V2R Agonist, V2R Antagonist | Urine Sodium Concentration After the Steady-state Portion of the Trial | Placebo | 82.0 mEq/L | Standard Deviation 48.5 |
| 1/Placebo, V2R Agonist, V2R Antagonist | Urine Sodium Concentration After the Steady-state Portion of the Trial | V2R Agonist | 89.3 mEq/L | Standard Deviation 21.5 |
| 1/Placebo, V2R Agonist, V2R Antagonist | Urine Sodium Concentration After the Steady-state Portion of the Trial | V2R Antagonist | 16.4 mEq/L | Standard Deviation 5 |
Other Pre-specified
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.
Time frame: 4 trials (4 weeks)
Other Pre-specified
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.
Time frame: 4 trials (4 weeks)
Other Pre-specified
Fluid Intake
To determine if fluid intake behaviors were appropriately regulated in response to the V2R antagonist, agonist and placebo conditions during exercise.
Time frame: 4 weeks (4 trials)
Other Pre-specified
Performance
To determine if exercise performance, as determined by overall exercise time, was affected in response to the V2R antagonist, agonist and placebo conditions.
Time frame: 4 trials (4 weeks)
Other Pre-specified
Sodium Palatability Ratings
To determine if sodium preference ratings were appropriately regulated in response to the V2R antagonist, agonist and placebo conditions during exercise.
Time frame: 4 weeks (4 trials)
Other Pre-specified
Thirst Rating
To determine if fluid intake behaviors were appropriately regulated in response to the V2R antagonist, agonist and placebo conditions during exercise.
Time frame: 4 trials (4 weeks)