Vascular Dysfunction in Hypertensive Postmenopausal Women

NCT03371823 | Terminated Phase 4 Results DMC FDA Drug

• 1 other identifier: 1009297
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to investigate the role of ET-1 in mediating vasoconstrictor tone in hypertensive postmenopausal women (PMW) alone and in combination with a commonly prescribed Angiotensin II (ANG II) antagonist. The long term goal is to understand the mechanisms contributing to hypertension (HTN) in PMW. This study is the first step in reaching our goal.

Conditions

Cardiovascular Diseases; Hypertension

Keywords

Hypertension; Endothelin-1 receptor

Outcome Measures

Primary Outcomes (1)

• ET-1 Mediated Constriction

  Cutaneous blood flow is measured via laser Doppler flowmetry during cutaneous microdialysis perfusions of ET-A and ET-B receptor antagonists as previously described by Wenner MM in 2017(see reference list).

  Each participant was assessed at baseline and 2 weeks later.

Secondary Outcomes (1)

• Endothelin Receptor A and B Expression

  Baseline and 2 weeks later

Study Arms (2)

Normotensive

OTHER

Normotensive PMW will complete an experimental visit to assess vascular function. All women will wear an ambulatory BP monitor during the 24 hours preceding the experimental visit to confirm BP classification. Large blood vessel function will be assessed using two non-invasive techniques: 1. Flow Mediated Dilation (FMD) 2. Pulse Wave Analysis and Pulse Wave Velocity. ET-1 mediated vasoconstrictor tone is assessed by measuring the cutaneous blood flow during microdialysis perfusions of ET-A and ET-B receptor antagonist. ET-1 production, ET-A and ET-B receptor expression is assessed from antecubital vein endothelial cells and skin punch biopsy samples.

Other: Normotensive

Hypertensives

EXPERIMENTAL

Hypertensive women will be tested at baseline and then administered Losartan 50 mg once a day at night for 14 days. Vascular function is measured at baseline and again after 2 weeks of losartan. All women will wear an ambulatory BP monitor during the 24 hours preceding the experimental visits to confirm BP classification. Large blood vessel function will be assessed using two non-invasive techniques: 1. Flow Mediated Dilation (FMD) 2. Pulse Wave Analysis and Pulse Wave Velocity. ET-1 mediated vasoconstrictor tone is assessed by measuring the cutaneous blood flow during microdialysis perfusions of ET-A and ET-B receptor antagonist. ET-1 production, ET-A and ET-B receptor expression is assessed from antecubital vein endothelial cells and skin punch biopsy samples.

Drug: Hypertensives

Interventions

Normotensive OTHER

FMD is a measure of endothelial function by assessing the degree to which vessel dilates in response to increased flow. Pulse Wave Analysis and Pulse Wave Velocity assesses arterial stiffness and wave reflection in all women. Laser Doppler flowmetry is used in combination with cutaneous microdialysis as a minimally invasive technique to examine mechanisms of vascular function. ET-B and ET-A receptor antagonists will be perfused via intradermal microdialysis fibers while measuring cutaneous blood flow. ET-1 production and ET-B receptor expression in endothelial cells collected from an antecubital vein will also be assessed. Immunohistochemistry will be performed on skin punch biopsy samples to assess for protein expression of ET-A and ET-B receptors.

Normotensive

Hypertensives DRUG

ANG II increases the synthesis of ET-1 and alters ET-A/B receptor expression, thus affecting ET-1 bioavailability. Losartan is an ANG II receptor antagonist which attenuates ET-1 production. Losartan 50 mg daily is administered for 14 days to hypertensive women. FMD is used to measure endothelial function. Pulse Wave Analysis and Pulse Wave Velocity assesses arterial stiffness and wave reflection. Laser Doppler flowmetry with cutaneous microdialysis is used to examine vascular function when ET-A and ET-B receptor antagonists is perfused via intradermal microdialysis fibers. ET-1 production and ET-B receptor expression in endothelial cells collected from an antecubital vein will be assessed. Skin punch biopsy samples will be used to assess for protein expression of ET-A and ET-B receptors.

Hypertensives

Eligibility Criteria

• Age: 50 Years - 70 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \> 1year post menopausal.
• Age range 50-70 years
• Resting ECG in normal limits
• Standard blood chemistry within normal limits
• Systolic blood pressure: \<130mm Hg for normotensives; \>130mm Hg for hypertensives.
• Diastolic blood pressure: \< 80mm Hg for normotensives; \> 80mm Hg for hypertensives.

You may not qualify if:

• History of cardiovascular disease
• Blood clots or stroke
• Cancer
• Diabetes
• Kidney or Liver disease
• Obesity (BMI\>35kg/m2)
• Pregnant/Breast feeding
• Current use of hormone therapy
• Current use of tobacco products
• High cholesterol
• Current use of anti-hypertensive meds

Sponsors & Collaborators

• University of Delaware: lead
• National Institutes of Health (NIH): collaborator

Study Sites (1)

University of Delaware

Newark, Delaware, 19716, United States

Location

Related Publications (25)

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• Wenner MM, Sebzda KN, Kuczmarski AV, Pohlig RT, Edwards DG. ETB receptor contribution to vascular dysfunction in postmenopausal women. Am J Physiol Regul Integr Comp Physiol. 2017 Jul 1;313(1):R51-R57. doi: 10.1152/ajpregu.00410.2016. Epub 2017 Apr 24.

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MeSH Terms

Conditions

Cardiovascular Diseases; Hypertension

Interventions

Antihypertensive Agents

Condition Hierarchy (Ancestors)

Vascular Diseases

Intervention Hierarchy (Ancestors)

Cardiovascular Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses

Limitations and Caveats

We were not able to enroll naive to therapy hypertensive women for the Losartan arm of the trial and do not have data on this arm of the study.

Results Point of Contact

• Title: Dr. Megan Wenner
• Organization: University of Delaware

mwenner@udel.edu

302-831-7343

Study Officials

• Megan Wenner, Ph.D

  University of Delaware

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant professor

Study Record Dates

• First Submitted: November 22, 2017
• First Posted: December 13, 2017
• Study Start: September 1, 2017
• Primary Completion: December 31, 2019
• Study Completion: December 31, 2019
• Last Updated: January 19, 2022
• Results First Posted: January 19, 2022

Record last verified: 2022-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)