Endothelial Derived Hyperpolarization Factor and Vascular Control

Phase 4

Recruiting

• Conditions: Healthy
• Interventions: Drug: Fluconazole 150 mg

• Registration Number: NCT05176379
• Lead Sponsor: University of Oklahoma

Brief Summary

Most cardiometabolic diseases are characterized by increased muscle sympathetic nerve activity (MSNA) during rest and exercise which contributes to poor health outcomes. In healthy humans during muscle contraction, there is a blunting of skeletal muscle vascular responsiveness to increases in MSNA. However, the exact mechanisms involved are unknown although, best evidence suggests that the mechanism is endothelium derived, but nitric oxide (NO) and prostaglandin (PG) independent. Endothelium-derived hyperpolarizing factor (EDHF) is a NO and PG independent vasodilator in both cerebral and skeletal muscle circulations, however, it is unknown if EDHF contributes to vascular responsiveness during elevated MSNA. The application of lower body negative pressure (LBNP) is a safe and non-invasive manipulation that can be used to increase MSNA causing vasoconstriction in humans. Therefore, the purpose of this experiment is to determine if acute inhibition of EDHF alters central and peripheral vascular responses to LBNP at rest and during dynamic exercise. Thereby, providing evidence by which EDHF contributes to vascular control in healthy humans and identify it's potential as a therapeutic target for cardiometabolic diseases that are characterized by elevated MSNA

Detailed Description

The purpose of this study is to investigate the importance of the endothelium-derived hyperpolarizing factor (EDHF) in regulation of muscle and brain blood flow during rest, sympathetic activation via lower body negative pressure (LBNP), and during rhythmic exercise. We hypothesize that acute inhibition of EDHF will blunt cardiovascular responses and decrease peripheral tissue oxygenation (specifically in the brain and muscle) in response to LBNP during rest and during exercise. This work will provide evidence that EDHF counter acts sympathetic nervous activity in healthy humans, thereby highlighting EDHF as a potentially crucial mechanism in human vascular control. Ultimately this work will provide basic knowledge need to open longer treatment windows and potentially novel therapies for cardiovascular complications from cardiometabolic diseases.

To test these hypotheses, we will complete two specific aims:

I) To test the hypothesis whether EDHF inhibition alters sympathetic restraint muscle vasculature (termed, sympatholysis), we will compare changes in oxygenated hemoglobin (O2Hb), deoxygenated hemoglobin (HHb), Cardiac Output (CO) and Mean Arterial Pressure (MAP), Total Peripheral Resistance (TPR), Tissue Oxygen Saturation Index (TSI) during sympathetic activation (LBNP) and Handgrip exercise in two conditions: placebo vs. acute EDHF inhibition (Fluconazole).

II) To test the hypothesis whether EDHF inhibition alters regulation of cerebral blood flow during rest and sympathetic activation (LBNP), we will compare changes in cerebral vascular conductance index (CVCi), cerebral TSI as well as gain, coherence, and phase in transfer functional analysis during the exposure to Lower Body Negative Pressure (LBNP) in two conditions: placebo vs. acute EDHF inhibition (Fluconazole)

Study Timeline

• Study First Submitted: 2021-12-01
• Study First Submitted QC: 2021-12-14
• Study First Posted: 2022-01-04
• Study Start: 2022-02-19
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-19
• Last Update Posted: 2024-07-23
• Primary Completion: 2024-12
• Study Completion: 2025-05

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

• Normotensive (systolic blood pressure < 130 mmHg and/or diastolic blood pressure < 85 mmHg) individuals
• Individuals free of cardiovascular disease and metabolic disease
• Individuals free of any form of autonomic dysfunction
• Individuals with a BMI under 30 kg/m²
• Women that are premenopausal with a regular menstrual cycle (26-30 days)

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Exclusion Criteria

• Smokers, tobacco users (regular use in the last 6 months)
• Individuals with a blood pressure greater than 130/85
• Subjects who use Amiodarone, Sulphaphenazole
• Subjects who use S-warfarin, Tolbutamine, Phenytoin, Lonafarnib
• Cardiometabolic medication use (e.g. anti-hypertensives, insulin-sensitizing, statins)
• Sex hormone replacement medical use (e.g. testosterone, estrogen, progesterone)
• Pregnancy

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo	Fluconazole 150 mg	250 mg pill microcrystalline Cellulose, single acute dose
fluconazole	Fluconazole 150 mg	fluconazole tablet/pill 150 mg, single acute dose

Primary Outcome Measures

Name	Time	Method
Transcranial Doppler Ultrasound	up to 4 hours	middle cerebral artery blood velocity
Near-Infrared Spectroscopy	up to 4 hours	Concentrations of Oxygen, deoxy, and Total Hemoglobin (micro molar)

Secondary Outcome Measures

Name	Time	Method
Finger photoplethysmography	up to 4 hours	Mean Arterial Pressure
Wireless electrocardiogram	up to 4 hours	heart rate

Trial Locations

Locations (1)

Department of Health and Exercise Science; 🇺🇸 Norman, Oklahoma, United States