Central Sodium Sensing: Implications for Blood Pressure Regulation

November 20, 2025 updated by: William Farquhar, University of Delaware
The ability of the brain to sense changing sodium levels in the blood is critical in mediating the neurohumoral responses to hypernatremia, however, the mechanisms underlying sodium sensing in humans is poorly understood. The purpose of this study is to identify key sodium-sensing regions of the human brain in older adults and determine if the Na-K-2Cl co-transporter mediates the neurohumoral response to acute hypernatremia. Completion of this project will increase our understanding of blood pressure regulation, which has major public health implications.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

The prevalence of hypertension is very high in older adults, and a major factor in hypertension is salt sensitivity of blood pressure (BP) and elevated sympathetic nerve activity (SNA). However, we know very little about how the human brain 'senses' sodium, and what molecular mechanisms are involved. Rodent studies have identified specialized sodium chloride (NaCl)-sensing neurons in the circumventricular organs (CVOs), which mediate NaCl-induced changes in SNA, arginine vasopressin (AVP), and BP. Recent data suggest the Na-K-2Cl co-transporter (NKCC2) is not kidney specific but is also expressed in brain regions that regulate whole body NaCl and water homeostasis. In addition, NKCC2 is accessible by drugs in the circulation since the CVOs lack a complete blood brain barrier. The objective of this R21 is to identify key NaCl-sensing regions of the brain in older adults and determine if NKCC2 mediates the neurohumoral response to acute hypernatremia. We seek to translate the prior rodent findings to humans by assessing neuronal activation (using blood oxygen level dependent functional magnetic resonance imaging, BOLD fMRI) as well as thirst, AVP, SNA and BP during an acute hypernatremic stimulus, with and without an NKCC2 antagonist (furosemide). This will enable us to assess the role of NKCC2 in NaCl sensing. The overall hypothesis is that acute hypernatremia will elicit detectable changes in the BOLD fMRI signal and increase thirst, AVP, SNA, and BP largely through NKCC2 in healthy older adults. Accordingly, the first specific aim is to identify the areas of the human brain that respond to acute hypernatremia and determine the role of NKCC2 in central NaCl- sensing. Acute hypernatremia will be induced with a 30-minute infusion of 3% NaCl delivered intravenously. Brain activity during the hypertonic saline infusion will be measured in regions such as the organum vasculosum laminae terminalis, subfornical organ, anterior cingulate cortex, hypothalamus, and insular cortex. The second specific aim is to determine the effect of acute hypernatremia on thirst, AVP, SNA, and BP, and determine the role of NKCC2 in mediating these responses. Salt sensitivity of BP will be individually assessed and comparisons will be made between those with a salt resistant and salt sensitive phenotype; we anticipate that acute hypernatremia will elicit changes in the BOLD fMRI signal and SNA & AVP in all subjects, but the responses will be greater in those who are classified as salt sensitive. This would represent the first trial in healthy human subjects to identify a putative brain NaCl-sensing co-transporter, and we think the scope and innovative approaches are ideal for the R21 funding mechanism. Older adults are prone to hypertension, so it is critically important to understand how normotensive older adults centrally sense sodium, to provide a needed foundation for exploring the mechanistic underpinning of salt sensitive hypertension.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
29

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.
  • Name: William B Farquhar, PhD
  • Phone Number: 302-831-6178
  • Email: wbf@udel.edu

Study Contact Backup

Study Locations

  • United States
    • Delaware
      • Newark, Delaware, United States, 19713
        • William B Farquhar

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 45 years (Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • Age: 18 - 45 years
  • Blood pressure: >100/60 mmHg and <130/80 mmHg
  • BMI: 18.5 kg/m2 - 30 kg/m2
  • Serum potassium: 3.5 mmol/L - 5.5 mmol/L

Exclusion Criteria:

  • Age: < 18 years or > 45 years
  • Blood pressure: < 100/60 mmHg or > 130/80 mmHg
  • BMI: < 18.5 kg/m2 or > 30 kg/m2
  • Serum potassium: < 3.5 mmol/L or > 5.5 mmol/L
  • Abnormal ECG
  • History of - cardiovascular, cancer, metabolic, respiratory, renal disease
  • Hormone replacement therapy
  • Current tobacco or nicotine use
  • Pregnant or nursing mothers
  • Major brain injury (concussions do not count)
  • Clinically diagnosed psychiatric or neurological disorder
  • Clinically diagnosed anxiety or depression
  • Psychiatric, neurological, anxiety or depression medications
  • Hypertension medications
  • Sulfonamide drug allergy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Non-Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Hypernatremia + Furosemide first, then Hypernatremia without Furosemide
Participants in this arm will undergo blood-oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) on two separate days. On the first testing day, participants will receive a hypertonic saline infusion with NKCC2 antagonism (furosemide). On the second testing day, participants will receive a hypertonic saline infusion without NKCC2 antagonism (furosemide). This will enable us to examine sodium sensing mechanisms. The two conditions will be separated by at least 1 week washout. The hypertonic saline will be a 3% NaCl solution infused intravenously at a rate of 0.15 ml/kg/min for 30 minutes; the furosemide will be infused intravenously as a 40 mg bolus in 4mL of isotonic saline (0.9% NaCl) immediately prior to the hypertonic saline infusion.
Other: Hypertonic Saline with furosemide
Subjects will undergo MRI with a hypertonic saline infusion with NKCC2 antagonism (furosemide). The hypertonic saline will be a 3% NaCl solution infused intravenously at a rate of 0.15 ml/kg/min for 30 minutes; the furosemide will be infused intravenously as a 40 mg bolus in 4mL of isotonic saline (0.9% NaCl) immediately prior to the hypertonic saline infusion.
Other: Hypertonic Saline without furosemide
Subjects will undergo MRI with a hypertonic saline infusion. The hypertonic saline will be a 3% NaCl solution infused intravenously at a rate of 0.15 ml/kg/min for 30 minutes.
Experimental: Hypernatremia without Furosemide first, then Hypernatremia + Furosemide
Participants in this arm will undergo blood-oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) on two separate days. On the first testing day, participants will receive a hypertonic saline infusion without NKCC2 antagonism (furosemide). On the second testing day, participants will receive a hypertonic saline infusion with NKCC2 antagonism (furosemide). This will enable us to examine sodium sensing mechanisms. The two conditions will be separated by at least 1 week washout. The hypertonic saline will be a 3% NaCl solution infused intravenously at a rate of 0.15 ml/kg/min for 30 minutes; the furosemide will be infused intravenously as a 40 mg bolus in 4mL of isotonic saline (0.9% NaCl) immediately prior to the hypertonic saline infusion.
Other: Hypertonic Saline with furosemide
Subjects will undergo MRI with a hypertonic saline infusion with NKCC2 antagonism (furosemide). The hypertonic saline will be a 3% NaCl solution infused intravenously at a rate of 0.15 ml/kg/min for 30 minutes; the furosemide will be infused intravenously as a 40 mg bolus in 4mL of isotonic saline (0.9% NaCl) immediately prior to the hypertonic saline infusion.
Other: Hypertonic Saline without furosemide
Subjects will undergo MRI with a hypertonic saline infusion. The hypertonic saline will be a 3% NaCl solution infused intravenously at a rate of 0.15 ml/kg/min for 30 minutes.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Functional Connectivity Between the Subfornical Organ and Organum Vasculosum of the Lamina Terminalis (Z-score)
Time Frame: Functional connectivity (FC) was calculated at baseline (~10 min). Then, participants received a 30-minute hypertonic saline infusion (HSI) with or without furosemide before. FC was calculated during the early (0-15 min) and late phase (15-30 min) of HSI.
Functional connectivity between sodium sensing circumventricular organs (subfornical organ (SFO) and organum vasculosum of the lamina terminalis(OVLT)) was calculated (expressed as the z-score). Functional connectivity is a measure of the the correlation (or synchronization) of the blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal time course between two brain regions. Pearson correlations were computed between the BOLD fMRI signal in the SFO and OVLT in a seed-to-seed functional connectivity analysis. Pearson correlations were converted to Z-scores using a Fisher's transform. A Z-score of 0 indicates no correlation between the BOLD fMRI signal between these 2 brain regions; a higher score indicates a greater, positive correlation between the BOLD fMRI signal in these 2 brain regions; a lower score indicates a greater, negative correlation between the fMRI signal in these 2 brain regions. This data does not have any clinical thresholds.
Functional connectivity (FC) was calculated at baseline (~10 min). Then, participants received a 30-minute hypertonic saline infusion (HSI) with or without furosemide before. FC was calculated during the early (0-15 min) and late phase (15-30 min) of HSI.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Delaware

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: William B Farquhar, PhD, University of Delaware

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 1, 2022

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
January 31, 2025

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
January 31, 2025

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 27, 2022

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 27, 2022

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 29, 2022

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
December 8, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
November 20, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
November 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 1808532

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Data will be shared upon reasonable request.

IPD Sharing Time Frame

Immediately

IPD Sharing Access Criteria

Upon reasonable request

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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