Central Sodium Sensing: Implications for Blood Pressure Regulation

Sponsor
University of Delaware (Other)
Overall Status
Recruiting
CT.gov ID
NCT05480722
Collaborator
(none)
40
1
2
32
1.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
  • Other: Dietary Intervention
  • Other: Hypertonic Saline
N/A

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 Design

Study Type:
Interventional
Anticipated Enrollment :
40 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Intervention Model Description:
double blinded randomized crossover designdouble blinded randomized crossover design
Masking:
Double (Participant, Investigator)
Masking Description:
double blinded
Primary Purpose:
Basic Science
Official Title:
Central Sodium Sensing: Implications for Blood Pressure Regulation
Actual Study Start Date :
Jun 1, 2022
Anticipated Primary Completion Date :
Jan 31, 2025
Anticipated Study Completion Date :
Jan 31, 2025

Arms and Interventions

Arm Intervention/Treatment
Experimental: Salt Sensitivity Assessment

1 week high salt diet and 1 week low salt diet

Other: Dietary Intervention
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

Other: Hypertonic Saline
Subjects will undergo MRI with a hypertonic saline infusion with and without NKCC2 antagonism (furosemide)

Outcome Measures

Primary Outcome Measures

  1. Functional MRI [1 hour]

    Functional connectivity between sodium sensing regions the brain

  2. Hormone [1 hour]

    Arginine Vasopressin

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years to 45 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
Yes
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

Contacts and Locations

Locations

Site City State Country Postal Code
1 William B Farquhar Newark Delaware United States 19713

Sponsors and Collaborators

  • University of Delaware

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
William Farquhar, Professor, University of Delaware
ClinicalTrials.gov Identifier:
NCT05480722
Other Study ID Numbers:
  • 1808532
First Posted:
Jul 29, 2022
Last Update Posted:
Jul 29, 2022
Last Verified:
Jul 1, 2022
Individual Participant Data (IPD) Sharing Statement:
Undecided
Plan to Share IPD:
Undecided
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
Additional relevant MeSH terms:

Study Results

No Results Posted as of Jul 29, 2022