- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05480722
Central Sodium Sensing: Implications for Blood Pressure Regulation
December 7, 2023 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
Recruiting
Conditions
Intervention / Treatment
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
Interventional
Enrollment (Estimated)
40
Phase
- 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
- Name: William B Farquhar, PhD
- Phone Number: 302-831-6178
- Email: wbf@udel.edu
Study Contact Backup
- Name: Joseph M Stock, PhD
- Phone Number: 610-331-6553
- Email: jmstock@udel.edu
Study Locations
-
-
Delaware
-
Newark, Delaware, United States, 19713
- Recruiting
- William B Farquhar
-
Contact:
- William B Farquhar, PhD
- Phone Number: 302-831-6178
- Email: wbf@udel.edu
-
Contact:
- Joseph M Stock, PhD
- Phone Number: 610-331-6553
- Email: jmstock@udel.edu
-
-
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
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: Randomized
- Interventional Model: Crossover Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Salt Sensitivity Assessment
1 week high salt diet and 1 week low salt diet
|
Subjects will consume a low salt diet for 1 week and a high salt diet for 1 week to determine sodium sensitivity
|
Experimental: Functional Magnetic Resonance Imaging
Hypertonic saline infusion perturbation with and without NKCC2 antagonism (furosemide) to examine sodium sensing mechanisms
|
Subjects will undergo MRI with a hypertonic saline infusion with and without NKCC2 antagonism (furosemide)
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
fMRI to assess SFO-OLVT functional connectivity (z-score)
Time Frame: 1 hour
|
Functional connectivity between sodium sensing regions the brain (subfornical organ and organum vasculosum of the lamina terminalis)
|
1 hour
|
Plasma arginine vasopressin concentration (pg/mL)
Time Frame: 1 hour
|
hormone circulating in the blood
|
1 hour
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
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)
June 1, 2022
Primary Completion (Estimated)
January 31, 2025
Study Completion (Estimated)
January 31, 2025
Study Registration Dates
First Submitted
July 27, 2022
First Submitted That Met QC Criteria
July 27, 2022
First Posted (Actual)
July 29, 2022
Study Record Updates
Last Update Posted (Estimated)
December 14, 2023
Last Update Submitted That Met QC Criteria
December 7, 2023
Last Verified
December 1, 2023
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 1808532
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
UNDECIDED
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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