Sex Differences in the Dilatory Response of Compound 21

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.

Study Overview

• Status: Completed
• Conditions: Sex Differences
• Intervention / Treatment: Drug: Compound 21 + losartan; Drug: Compound 21

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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 Progesterone and Testosterone	plasma measurement of circulating progesterone and testosterone; measured by ELISA in plasma samples	at the start of the experimental visit, immediately prior to local losartan treatment
Circulating Estradiol	plasma measurement of circulating estradiol, measured by ELISA in plasma samples	at the start of the experimental visit, immediately prior to local losartan treatment

Collaborators and Investigators

• Sponsor: Anna Stanhewicz, PhD
• Investigators: Principal Investigator: Anna Stanhewicz, PhD, University of Iowa

Study record dates

Study Major Dates

• Study Start (Actual): October 3, 2022
• Primary Completion (Actual): February 23, 2023
• Study Completion (Actual): February 23, 2023

Study Registration Dates

• First Submitted: October 7, 2022
• First Submitted That Met QC Criteria: October 7, 2022
• First Posted (Actual): October 12, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 19, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Anti-Arrhythmia Agents; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Compound 21; Losartan
• Other Study ID Numbers: 202206519

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No