Central Sodium Sensing: Implications for Blood Pressure Regulation

NCT ID: NCT05480722

Last Updated: 2025-12-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 29 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-06-01
• Study Completion Date: 2025-01-31

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.

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.

Conditions

Salt Sensitivity of Blood Pressure

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: SINGLE

Study Groups

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.

Group Type: EXPERIMENTAL

Hypertonic Saline with furosemide

Intervention Type: OTHER

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.

Hypertonic Saline without furosemide

Intervention Type: OTHER

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.

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.

Group Type: EXPERIMENTAL

Hypertonic Saline with furosemide

Intervention Type: OTHER

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.

Hypertonic Saline without furosemide

Intervention Type: OTHER

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: OTHER

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Delaware

OTHER

Sponsor Role: lead

Responsible Party

William Farquhar

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

William B Farquhar, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Delaware

Locations

William B Farquhar

Newark, Delaware, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

1808532

Identifier Type: -

Identifier Source: org_study_id