Endothelial Derived Hyperpolarization Factor and Vascular Control

Endothelial Derived Hyperpolarization Factor and Regulation of Cerebral and Muscle Blood Flow

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

Study Overview

• Status: Recruiting
• Conditions: Healthy
• Intervention / Treatment: Drug: Fluconazole 150 mg

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 Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jeremy M Kellawan, PhD; Phone Number: 4053259028; Email: kellawan@ou.edu

Study Locations

• United States
  • Oklahoma
    • Norman, Oklahoma, United States, 73019
      • Recruiting
      • Department of Health and Exercise Science
      • Contact: Michael Bemben, PhD; Phone Number: 405-325-5211; Email: mgbemben@ou.edu
      • Contact: Jeremy M Kellawan, PhD; Phone Number: (405) 325-9028; Email: kellawan@ou.edu
      • Principal Investigator: Jeremy M Kellawan, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 30 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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)

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: fluconazole; fluconazole tablet/pill 150 mg, single acute dose	Drug: Fluconazole 150 mg; A single acute 150 mg dose; Other Names: placebo
Placebo Comparator: Placebo; 250 mg pill microcrystalline Cellulose, single acute dose	Drug: Fluconazole 150 mg; A single acute 150 mg dose; Other Names: placebo

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Wireless electrocardiogram	heart rate	up to 4 hours
Finger photoplethysmography	Mean Arterial Pressure	up to 4 hours

Collaborators and Investigators

• Sponsor: University of Oklahoma
• Investigators: Principal Investigator: Jeremy M Kellawan, PhD, University of Oklahoma

Study record dates

Study Major Dates

• Study Start (Actual): February 19, 2022
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): May 1, 2025

Study Registration Dates

• First Submitted: December 1, 2021
• First Submitted That Met QC Criteria: December 14, 2021
• First Posted (Actual): January 4, 2022

Study Record Updates

• Last Update Posted (Actual): July 23, 2024
• Last Update Submitted That Met QC Criteria: July 19, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: endothelial function; brain blood flow; muscle blood flow
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Fluconazole
• Other Study ID Numbers: 14056

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: We do not plan to share individual participant data

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes