Endothelial Derived Hyperpolarization Factor and Vascular Control

NCT ID: NCT05176379

Last Updated: 2024-07-23

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-02-19
• Study Completion Date: 2025-05-31

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)

Conditions

Healthy

Study Design

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

Study Groups

fluconazole

fluconazole tablet/pill 150 mg, single acute dose

Group Type: EXPERIMENTAL

Fluconazole 150 mg

Intervention Type: DRUG

A single acute 150 mg dose

Placebo

250 mg pill microcrystalline Cellulose, single acute dose

Group Type: PLACEBO_COMPARATOR

Fluconazole 150 mg

Intervention Type: DRUG

A single acute 150 mg dose

Interventions

Fluconazole 150 mg

A single acute 150 mg dose

Intervention Type: DRUG

Other Intervention Names

placebo

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 30 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Oklahoma

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jeremy M Kellawan, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Oklahoma

Locations

Department of Health and Exercise Science

Norman, Oklahoma, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Jeremy M Kellawan, PhD

Role: CONTACT

kellawan@ou.edu

4053259028

Facility Contacts

Michael Bemben, PhD

Role: primary

mgbemben@ou.edu

405-325-5211

Jeremy M Kellawan, PhD

Role: backup

kellawan@ou.edu

(405) 325-9028

Other Identifiers

14056

Identifier Type: -

Identifier Source: org_study_id