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Trial record 2 of 232 for:    EDN1

Vascular Dysfunction in Hypertensive Postmenopausal Women

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ClinicalTrials.gov Identifier: NCT03371823
Recruitment Status : Recruiting
First Posted : December 13, 2017
Last Update Posted : May 9, 2019
Sponsor:
Collaborator:
National Institutes of Health (NIH)
Information provided by (Responsible Party):
Megan M. Wenner, University of Delaware

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.

Condition or disease Intervention/treatment Phase
Cardiovascular Diseases Hypertension Other: Normotensive Drug: Hypertensives Phase 4

Detailed Description:

Cardiovascular disease (CVD) is the leading cause of death in women, and mortality from CVD is higher in PMW compared to age-matched men. PMW are at a greater risk for developing HTN, a major risk factor for CVD. They are also more likely to have uncontrolled or resistant HTN despite medication.

ANG II is a common therapeutic target for the treatment HTN. ANG II blockade is highly effective in normalizing blood pressure (BP) in hypertensive male rats, but does not reduce BP to the same degree in hypertensive post menopausal female rats. Endothelin-1 (ET-1) receptor antagonists reduce BP in hypertensive postmenopausal female rats, but have no effect on males. Thus the mechanisms contributing to HTN in female rats and likely women, particularly after menopause, are complex, multifactorial and not completely understood.

After menopause, the vasoconstrictor effects of both ANG II and ET-1 are amplified in animal models. As such, these two predominant pathways may contribute to the high incidence of HTN in PMW. ET-1 is a potent vasoconstrictor produced and released by endothelial cells that binds to two receptor subtypes, ET-A and ET-B. While both receptors are located on vascular smooth muscle (VSM) and mediate vasoconstriction, ET-B receptors are also located on the endothelium and mediate vasodilation via nitric oxide.

Importantly, the production of ET-1 and expression of ET-A and B receptors can be modulated by hormones such as estradiol and ANG II. Estradiol attenuates ET-1 production, and reduces ET-1 mediated vasoconstriction via an ET-B receptor mechanism in vitro. Thus, decline in estradiol after menopause may enhance vasoconstrictor tone via ET-1 and lead to HTN. ET-1 also potentiates the vasoconstrictor effects of ANG II since the vasoconstrictor and hypertensive effects of ANG II are ameliorated by ET-1 receptor blockade. Additionally, ANG II stimulates the synthesis of ET-1 and upregulates ET-A and ET-B receptor expression on VSM. The ANG II receptor antagonist Losartan reduces ET-A and ET-B receptor expression and attenuates the constrictor effects of ET-1 in a diabetic rat model. Therefore, ET-1 is an important independent factor contributing to HTN in PMW, but therapeutic agents targeting both ANG II and ET-1 may have greater efficacy given their interactions.

The investigators propose a comprehensive assessment of vascular function by measuring blood flow responses in the cutaneous circulation during perfusion of ET-1 receptor antagonists via microdialysis, combined with measures of intracellular protein and receptor expression of endothelial cells and skin punch biopsies collected from normotensive and hypertensive PMW. Investigators central hypothesis is that hypertensive PMW have greater ET-1 mediated vasoconstrictor tone due to increased ET-1 expression, down-regulation of ET-B receptors on endothelial cells and up-regulation of both ET-A and ET-B receptors on VSM leading to increased vasoconstriction and HTN. Investigators further hypothesize that ANG II exacerbates the increase in ET-1, and ET-A and ET-B receptor expression contributing to exaggerated constriction with HTN in PMW.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Losartan and ET-1 Mediated Constriction in Postmenopausal Women With High Blood Pressure
Actual Study Start Date : September 1, 2017
Estimated Primary Completion Date : December 31, 2019
Estimated Study Completion Date : December 31, 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Losartan

Arm Intervention/treatment
Normotensive
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
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.

Experimental: Hypertensives
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
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.




Primary Outcome Measures :
  1. ET-1 mediated constriction [ Time Frame: 18 month ]
    Blood flow responses during blockade of ET-A and ET-B receptors


Secondary Outcome Measures :
  1. Endothelin Receptor A and B expression [ Time Frame: 18 months ]
    ET-A and ET-B receptors will be examined from skin punch biopsy samples in women pre/post losartan administration



Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria: - Women.

  • > 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.

Exclusion Criteria:

  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03371823


Contacts
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Contact: Megan Wenner, Ph.D 3028317343 mwenner@udel.edu
Contact: Joshua C Hobson, MS 302-831-8137 jhobson@udel.edu

Locations
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United States, Delaware
University of Delaware Recruiting
Newark, Delaware, United States, 19716
Contact: Megan Wenner, PhD    302-831-7343    mwenner@udel.edu   
Contact: Joshua C Hobson, MS    302-831-8137    jhobson@udel.edu   
Sponsors and Collaborators
University of Delaware
National Institutes of Health (NIH)
Investigators
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Principal Investigator: Megan Wenner, Ph.D University of Delaware

Publications:

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Responsible Party: Megan M. Wenner, Assistant professor, University of Delaware
ClinicalTrials.gov Identifier: NCT03371823     History of Changes
Other Study ID Numbers: 1009297
First Posted: December 13, 2017    Key Record Dates
Last Update Posted: May 9, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Megan M. Wenner, University of Delaware:
Hypertension
Endothelin-1 receptor
Additional relevant MeSH terms:
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Hypertension
Cardiovascular Diseases
Vascular Diseases
Losartan
Anti-Arrhythmia Agents
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action