Endothelial Derived Hyperpolarization Factor and Vascular Control

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)

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