Sex Differences in the Dilatory Response of Compound 21

Study Overview
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Brief Summary
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When blood pressure changes, Angiotensin II is produced and released into the bloodstream. This substance can make blood vessels smaller (i.e., vasoconstriction) by acting through Angiotensin II type I receptors (AT1R) to increase blood pressure. Or it can increase the diameter of vessels (i.e., vasodilation) through Angiotensin II type II receptors (AT2R) to decrease blood pressure. These two receptors normally work in balance to maintain blood pressure. However, excess Angiotensin II released in the bloodstream may reduce the sensitivity of AT2Rs, leading to excessive activation of AT1Rs. This results in increased constriction which plays a major role in diseases such as high blood pressure, hardening of the arteries, and heart failure. In the body, Angiotensin II production is reduced in the presence of estrogen, as seen in pre-menopausal women. Pre-menopausal women have a greater protection against cardiovascular diseases compared to age-matched males, likely due to the protective effects of estrogen. However, the extent that estrogen may impact the sensitivity of Angiotensin II receptors in pre-menopausal is unknown. In this study, the investigators use the blood vessels in the skin as a representative vascular bed for examining mechanisms of microvascular dysfunction in humans. Using a minimally invasive technique (intradermal microdialysis for the local delivery of pharmaceutical agents), the blood vessels in a dime-sized area of the skin are studied in healthy young women and men. As a compliment to these measurements, blood is drawn from the subjects and circulating factors that may contribute to cardiovascular health are measured.

Official Title
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Sex Differences in the Dilatory Response of Compound 21

Conditions
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Sex Differences

Intervention / Treatment
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* Drug: Compound 21
* Drug: Compound 21 + losartan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Young women or men, 18-35 years old, Body mass index between 18 and 30 kg/m2, Systolic blood pressure <140, Diastolic blood pressure <90 mmHg. Exclusion Criteria: Skin allergies, skin disorders, or skin diseases such as Raynaud's phenomenon or other history of cold intolerance, History of metabolic or cardiovascular disease, Taking medications that could alter vascular function, including antidepressants, anxiety medications, or cholesterol or blood pressure lowering drugs, Women with oligo- or amenorrhea, Women that are pregnant or nursing current tobacco use, Allergy to materials used during the experiment (e.g. latex).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 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: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Local losartan perfusion<br> 1 hour of losartan is perfused through an intradermal microdialysis fiber | Drug: Compound 21 + losartan<br>* Compound 21 + losartan (43 µM) is perfused at 10 doses increasing serially for 10 minutes each from 10^-12 M to 10^-3 M.<br>|
| Other: Local lactated Ringer's (control) perfusion<br> 1 hour of lactated Ringer's is perfused through an intradermal microdialysis fiber | Drug: Compound 21<br>* Compound 21 + Ringer's is perfused at 10 doses increasing serially for 10 minutes each from 10^-12 M to 10^-3 M<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Microvascular AT2R sensitivity following local control treatment | cutaneous vascular vasodilator response to exogenous Compound 21 perfusion; measured with laser-Doppler flowmetry coupled with intradermal microdialysis delivery of Compound 21 in young men and women | post 1 hour of local control treatment | 
| Microvascular AT2R sensitivity following local AT1R inhibition | cutaneous vascular vasodilator response to exogenous Compound 21 perfusion; measured with laser-Doppler flowmetry coupled with intradermal microdialysis delivery of Compound 21 co-infused with losartan young men and women | post 1 hour of local losartan treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| circulating hormones | plasma measurement of circulating estradiol, progesterone, and testosterone; measured by ELISA in plasma samples | a total of 1 time during the experiment |