Endothelin Receptor Function and Acute Stress

Study Overview
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Brief Summary
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Our bodies respond differently to stress. Animal studies by the investigators have found that endothelin-1 plays a role in regulating blood pressure in response to stress. This study is an extension of the investigators previous animal work to evaluate the role of endothelin-1 during stress in humans.

Detailed Description
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Using a salt sensitive animal model of prehypertension, the Dahl S rat,the investigators have previously published that acute stress elicits a pressor response that is accompanied by an increase in 8 isoprostane and endothelin-1. However, the pressor response is suppressed by endothelin A/B receptor antagonism. Moreover, the investigators have identified that the increase in 8-isoprostane occurs downstream of endothelin receptor activation. These data indicate that endothelin receptor activation is a main player In the pressor response to acute stress in pre-hypertensive animals; however, this phenomenon has yet to be elucidated in humans.

Official Title
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Endothelin Receptor Function and Acute Stress (End-Stress)

Conditions
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Hypertension

Intervention / Treatment
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* Drug: Bosentan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and premenopausal women (Ages 18-50 years old) Self-reported Black and White adults Lean adults (BMl <25 kg/m^) Obese adults (BMl > 30 kg/m^) Exclusion Criteria: Having a BMI less than 16 kg/m2 (severely and very severely underweight) or that is greater than 40 kg/m2 (Class III obesity) Having evidence of cardiovascular, pulmonary, renal, hepatic, cerebral, or metabolic disease Having evidence of pregnancy Using medications that affect vascular tone (i.e., nitrates, etc.) Postmenopausal women Uncontrolled hypertension Individuals who are on a restricted salt diet Having a history of chronic pain Having a history of rheumatoid arthritis Using medications that are contraindicated with bosentan (i.e. glyburide, cyclosporine) Liver dysfunction (which may be identified with the blood sample we take)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bosentan<br>Sub-Chronic (3 days) Bosentan 250mg/day. | Drug: Bosentan<br>* Stress response and vascular function will be assessed 3 days following 125 mg twice per day of Bosentan<br>* Other names: Tracleer;|
| Placebo Comparator: Placebo<br>Stress response and endothelial function will be determined following a three day treatment of placebo | Drug: Placebo<br>* Stress response and vascular function will be assessed 3 days following twice per day placebo<br>* Other names: lactose capsule;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Flow-Mediated Dilation (FMD) | Brachial artery FMD induced by reactive hyperemia will be used to assess vascular endothelial function. | Baseline and 3 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Arterial Stiffness Evaluation (PWV) | A tonometer will be gently applied on the carotid artery and then the femoral artery and the radial artery to record how fast blood flows between each of the points. | Baseline and 3 days | 
| Physio Flow | Six surface electrodes will be placed on the body. 2 on the neck, 2 on the chest, and 2 on the back in order to measure parameters of the heart during exercise. | Baseline and 3 days | 
| Femoral blood flow | Though ultrasound assessment; resistance of the blood flow, blood flow, blood velocity, and arterial diameter will all be measured in the femoral artery during the physically induced stress test which involves submerging the subjects hand in ice water for 3 minutes. | Baseline and 3 days | 
| Blood Pressure | Blood pressure will measured in response to the physically induced stress test which involves submerging the subjects hand in ice water for 3 minutes. | Baseline and 3 days | 
| Resting Energy Expenditure | REE will be assessed before and following treatment | Baseline and 3 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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arterial stiffness, flow-mediated dilation, endothelial function, pulse wave velocity, inflammation, oxidative stress, Nitric Oxide, Cold Pressor Test, physio flow, Bosentan, Endothelin Receptor, Endothelin-1, BMI, stress, blood pressure