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Nebivolol and the Endothelin (ET)-1 System (NETS)

Primary Purpose

Prehypertension, Hypertension

Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Nebivolol
Metoprolol
Placebo
Forearm Blood Flow (FBF) response to BQ-123 (100 mol/min)
FBF response to BQ-123 (100 nmol/min)+BQ-788(50 nmol/min)
FBF response to Acetylcholine
FBF response to Sodium Nitroprusside
FBF response to BQ-123+BQ-788+ACh
Sponsored by
University of Colorado, Boulder
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Prehypertension

Eligibility Criteria

45 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • Subjects will be men and women of all races and ethnic backgrounds aged 45-65 years.
  • Subjects will be prehypertensive/hypertensive defined as resting systolic blood pressure >130 mmHg and < 160 mm Hg and/or diastolic blood pressure >80 mmHg and < 100 mm Hg.
  • All of the women in the study will be postmenopausal (at least 1 year from last menstrual cycle) and not receiving hormone replacement therapy (HRT) currently or in the preceding 3-year period.
  • Lastly, candidates will be sedentary as determined from the Stanford Physical Activity Questionnaire (<35 kcal/wk) and will not have engaged in any program of regular physical activity for at least 1 year prior to the study.

Exclusion Criteria:

  • Candidates who smoke (currently or in the past 7 years), report more than low-risk alcohol consumption as defined as no more than 14 standard drinks/wk and no more than 4 standard drinks/day for men and 7 standard drinks/wk and 3 standard drinks/day for women (a standard drink is defined as 12 ounces of beer, 5 ounces of wine, 1½ ounces of 80-proof distilled spirits)
  • Potential candidates who are taking cardiovascular-acting (i.e. statins, blood pressure medication an aspirin) medications will not be eligible.
  • Fasting plasma glucose >126 mg/dL.
  • Potential candidates with a resting heart rate of < 50 beats/minute will be excluded.
  • Use of hormone replacement therapy.
  • In hypertensive subjects, a seated systolic blood pressure greater than 160 mmHg or a seated diastolic blood pressure greater than 100 mmHg.

Sites / Locations

  • UC-Boulder Clinical and Translational Research Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Placebo Comparator

Arm Label

Nebivolol

Metoprolol

Placebo

Arm Description

Systolic and Diastolic blood pressure will be measured before and after randomization to12 weeks of Nebivolol. Forearm blood flow will be measured in response to 100 nmol/min of BQ-123, BQ-123+BQ788 (50 mol/min), Acetylcholine (4.0, 8.0, 16.0 ug/100 mL tissue/min), Sodium Nitroprusside (1.0, 2.0, 4.0 ug/100 mL tissue/min) and BQ-123+BQ-788+Acetylcholine (same doses as above) will be measured before and after the 12 weeks of nebivolol.

Systolic and Diastolic blood pressure will be measured before and after randomization to12 weeks of Metoprolol. Forearm blood flow will be measured in response to 100 nmol/min of BQ-123, BQ-123+BQ788 (50 mol/min), Acetylcholine (4.0, 8.0, 16.0 ug/100 mL tissue/min), Sodium Nitroprusside (1.0, 2.0, 4.0 ug/100 mL tissue/min) and BQ-123+BQ-788+Acetylcholine (same doses as above) will be measured before and after the 12 weeks of Metoprolol.

Systolic and Diastolic blood pressure will be measured before and after randomization to12 weeks of placebo. Forearm blood flow will be measured in response to 100 nmol/min of BQ-123, BQ-123+BQ788 (50 mol/min), Acetylcholine (4.0, 8.0, 16.0 ug/100 mL tissue/min), Sodium Nitroprusside (1.0, 2.0, 4.0 ug/100 mL tissue/min) and BQ-123+BQ-788+Acetylcholine (same doses as above) will be measured before and after the 12 weeks of placebo.

Outcomes

Primary Outcome Measures

Systolic Blood Pressure
Diastolic Blood Pressure
Percent Change in Forearm Blood Flow (FBF) Response to BQ-123 (100 Nmol/Min)
Forearm blood flow (FBF) was measured via strain-gauge venous occlusion plethysmography at rest and every 10 minutes thereafter for 60 minutes. The average percent change for before and after either drug or placebo was calculated as the FBF at (each time point-resting value)/resting value and multiplied by 100 to calculate the percent change. The baseline or resting value was measured before the start of each drug infusion.
Percent Change in FBF Response to BQ-123 (100 Nmol/Min) + BQ-788 (50 Nmol/Min)
Forearm blood flow (FBF) was measured via strain-gauge venous occlusion plethysmography at rest and every 10 minutes thereafter for 60 minutes. The average percent change for before and after either drug or placebo was calculated as the FBF at (each time point-resting value)/resting value and multiplied by 100 to calculate the percent change. The baseline or resting value was measured before the start of each drug infusion.
FBF Response to Acetylcholine (ACh)
FBF was measured via strain-gauge occlusion plethysmography at rest and in response to ACh (4.0, 8.0 and 16.0 ug/100 mL tissue/min) for 5 minutes at each dose. Flows during the last minute of rest and each drug dose were measured and the mean value reported.
FBF Response to Sodium Nitroprusside
FBF was measured via strain-gauge occlusion plethysmography at rest and in response to sodium nitroprusside (1.0, 2.0 and 4.0 ug/100 mL tissue/min) for 5 minutes at each dose. Flows during the last minute of rest and each drug dose were measured and the mean value reported.
FBF Response to ACh in the Absence or Presence of Nonselective Endothelin A/B Blockade (BQ-123+BQ-788)
FBF was measured via strain-gauge occlusion plethysmography at rest and in response to BQ-123+BQ-788 +ACh (4.0, 8.0 and 16.0 ug/100 mL tissue/min) for 5 minutes at each dose. Flows during the last minute of rest and each drug dose were measured and the mean value reported.

Secondary Outcome Measures

Full Information

First Posted
June 9, 2011
Last Updated
December 5, 2018
Sponsor
University of Colorado, Boulder
Collaborators
Forest Laboratories
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1. Study Identification

Unique Protocol Identification Number
NCT01395329
Brief Title
Nebivolol and the Endothelin (ET)-1 System
Acronym
NETS
Official Title
Nebivolol and the Endothelin (ET)-1 System
Study Type
Interventional

2. Study Status

Record Verification Date
December 2018
Overall Recruitment Status
Completed
Study Start Date
May 2011 (undefined)
Primary Completion Date
November 2016 (Actual)
Study Completion Date
December 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Colorado, Boulder
Collaborators
Forest Laboratories

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The investigators hypothesize that nebivolol will reduce ET-1-mediated vasoconstrictor tone in adult humans with elevated blood pressure to a greater extent than either metoprolol or placebo.
Detailed Description
The investigators hypothesize that nebivolol will reduce ET-1-mediated vasoconstrictor tone in adult humans with elevated blood pressure to a greater extent than either metoprolol or placebo. The investigators further hypothesize that reducing ET-1 vasoconstrictor activity contributes to the improvement in endothelial vasodilator function associated with nebivolol.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Prehypertension, Hypertension

7. Study Design

Primary Purpose
Other
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
42 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Nebivolol
Arm Type
Active Comparator
Arm Description
Systolic and Diastolic blood pressure will be measured before and after randomization to12 weeks of Nebivolol. Forearm blood flow will be measured in response to 100 nmol/min of BQ-123, BQ-123+BQ788 (50 mol/min), Acetylcholine (4.0, 8.0, 16.0 ug/100 mL tissue/min), Sodium Nitroprusside (1.0, 2.0, 4.0 ug/100 mL tissue/min) and BQ-123+BQ-788+Acetylcholine (same doses as above) will be measured before and after the 12 weeks of nebivolol.
Arm Title
Metoprolol
Arm Type
Active Comparator
Arm Description
Systolic and Diastolic blood pressure will be measured before and after randomization to12 weeks of Metoprolol. Forearm blood flow will be measured in response to 100 nmol/min of BQ-123, BQ-123+BQ788 (50 mol/min), Acetylcholine (4.0, 8.0, 16.0 ug/100 mL tissue/min), Sodium Nitroprusside (1.0, 2.0, 4.0 ug/100 mL tissue/min) and BQ-123+BQ-788+Acetylcholine (same doses as above) will be measured before and after the 12 weeks of Metoprolol.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Systolic and Diastolic blood pressure will be measured before and after randomization to12 weeks of placebo. Forearm blood flow will be measured in response to 100 nmol/min of BQ-123, BQ-123+BQ788 (50 mol/min), Acetylcholine (4.0, 8.0, 16.0 ug/100 mL tissue/min), Sodium Nitroprusside (1.0, 2.0, 4.0 ug/100 mL tissue/min) and BQ-123+BQ-788+Acetylcholine (same doses as above) will be measured before and after the 12 weeks of placebo.
Intervention Type
Drug
Intervention Name(s)
Nebivolol
Other Intervention Name(s)
Bystolic
Intervention Description
5 mg tablet to be taken by mouth once per day for 12 weeks
Intervention Type
Drug
Intervention Name(s)
Metoprolol
Other Intervention Name(s)
Toprol-XL
Intervention Description
100 mg tablet to be taken by mouth once per day for 12 weeks
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
gelatin capsule to be taken by mouth once per day for 12 weeks
Intervention Type
Other
Intervention Name(s)
Forearm Blood Flow (FBF) response to BQ-123 (100 mol/min)
Other Intervention Name(s)
BQ-123
Intervention Description
The forearm blood flow response to the endothelin (ET) -1 A receptor blocker BQ-123 (100 nmol/min) for 60 minutes at baseline and at 12 weeks.
Intervention Type
Other
Intervention Name(s)
FBF response to BQ-123 (100 nmol/min)+BQ-788(50 nmol/min)
Other Intervention Name(s)
BQ-123+BQ-788
Intervention Description
The FBF response to the nonselective endothelin (ET) -1 receptor blockade BQ-123 (100 nmol/min) + BQ-788 (50 nmol/min)for 60 minutes at baseline and at 12 weeks.
Intervention Type
Other
Intervention Name(s)
FBF response to Acetylcholine
Other Intervention Name(s)
ACh
Intervention Description
The FBF response to the endothelium-dependent vasodilator ACh (4, 8 and 16 ug/100 mL tissue/min) at baseline and at 12 weeks.
Intervention Type
Other
Intervention Name(s)
FBF response to Sodium Nitroprusside
Other Intervention Name(s)
NTP
Intervention Description
The FBF response to the endothelium independent vasodilator NTP (1,2 and 4 ug/100 mL tissue/min) at baseline and at 12 weeks.
Intervention Type
Other
Intervention Name(s)
FBF response to BQ-123+BQ-788+ACh
Other Intervention Name(s)
BQ-123+BQ-788+ACh
Intervention Description
The FBF response to the nonselective endothelin (ET) -1 receptor blockade BQ-123 (100 nmol/min) + BQ-788 (50 nmol/min)for 60 minutes at baseline and at 12 weeks.
Primary Outcome Measure Information:
Title
Systolic Blood Pressure
Time Frame
Systolic blood pressure was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.
Title
Diastolic Blood Pressure
Time Frame
Diastolic blood pressure was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.
Title
Percent Change in Forearm Blood Flow (FBF) Response to BQ-123 (100 Nmol/Min)
Description
Forearm blood flow (FBF) was measured via strain-gauge venous occlusion plethysmography at rest and every 10 minutes thereafter for 60 minutes. The average percent change for before and after either drug or placebo was calculated as the FBF at (each time point-resting value)/resting value and multiplied by 100 to calculate the percent change. The baseline or resting value was measured before the start of each drug infusion.
Time Frame
Forearm blood flow was measured at 0-60 minutes before the 12 week drug or placebo intervention and 0-60 minutes after the 12 week drug or placebo intervention.
Title
Percent Change in FBF Response to BQ-123 (100 Nmol/Min) + BQ-788 (50 Nmol/Min)
Description
Forearm blood flow (FBF) was measured via strain-gauge venous occlusion plethysmography at rest and every 10 minutes thereafter for 60 minutes. The average percent change for before and after either drug or placebo was calculated as the FBF at (each time point-resting value)/resting value and multiplied by 100 to calculate the percent change. The baseline or resting value was measured before the start of each drug infusion.
Time Frame
Forearm blood flow was measured 0-120 minutes before the 12 week drug or placebo intervention and 0-120 minutes after the 12 week drug or placebo intervention.
Title
FBF Response to Acetylcholine (ACh)
Description
FBF was measured via strain-gauge occlusion plethysmography at rest and in response to ACh (4.0, 8.0 and 16.0 ug/100 mL tissue/min) for 5 minutes at each dose. Flows during the last minute of rest and each drug dose were measured and the mean value reported.
Time Frame
Forearm blood flow was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.
Title
FBF Response to Sodium Nitroprusside
Description
FBF was measured via strain-gauge occlusion plethysmography at rest and in response to sodium nitroprusside (1.0, 2.0 and 4.0 ug/100 mL tissue/min) for 5 minutes at each dose. Flows during the last minute of rest and each drug dose were measured and the mean value reported.
Time Frame
Forearm blood flow was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.
Title
FBF Response to ACh in the Absence or Presence of Nonselective Endothelin A/B Blockade (BQ-123+BQ-788)
Description
FBF was measured via strain-gauge occlusion plethysmography at rest and in response to BQ-123+BQ-788 +ACh (4.0, 8.0 and 16.0 ug/100 mL tissue/min) for 5 minutes at each dose. Flows during the last minute of rest and each drug dose were measured and the mean value reported.
Time Frame
Forearm blood flow was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
45 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Subjects will be men and women of all races and ethnic backgrounds aged 45-65 years. Subjects will be prehypertensive/hypertensive defined as resting systolic blood pressure >130 mmHg and < 160 mm Hg and/or diastolic blood pressure >80 mmHg and < 100 mm Hg. All of the women in the study will be postmenopausal (at least 1 year from last menstrual cycle) and not receiving hormone replacement therapy (HRT) currently or in the preceding 3-year period. Lastly, candidates will be sedentary as determined from the Stanford Physical Activity Questionnaire (<35 kcal/wk) and will not have engaged in any program of regular physical activity for at least 1 year prior to the study. Exclusion Criteria: Candidates who smoke (currently or in the past 7 years), report more than low-risk alcohol consumption as defined as no more than 14 standard drinks/wk and no more than 4 standard drinks/day for men and 7 standard drinks/wk and 3 standard drinks/day for women (a standard drink is defined as 12 ounces of beer, 5 ounces of wine, 1½ ounces of 80-proof distilled spirits) Potential candidates who are taking cardiovascular-acting (i.e. statins, blood pressure medication an aspirin) medications will not be eligible. Fasting plasma glucose >126 mg/dL. Potential candidates with a resting heart rate of < 50 beats/minute will be excluded. Use of hormone replacement therapy. In hypertensive subjects, a seated systolic blood pressure greater than 160 mmHg or a seated diastolic blood pressure greater than 100 mmHg.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christopher A DeSouza, Ph.D.
Organizational Affiliation
University of Colorado at Boulder
Official's Role
Principal Investigator
Facility Information:
Facility Name
UC-Boulder Clinical and Translational Research Center
City
Boulder
State/Province
Colorado
ZIP/Postal Code
80309
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
27113048
Citation
Diehl KJ, Stauffer BL, Dow CA, Bammert TD, Brunjes DL, Greiner JJ, DeSouza CA. Chronic Nebivolol Treatment Suppresses Endothelin-1-Mediated Vasoconstrictor Tone in Adults With Elevated Blood Pressure. Hypertension. 2016 Jun;67(6):1196-204. doi: 10.1161/HYPERTENSIONAHA.115.06979. Epub 2016 Apr 25.
Results Reference
derived

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Nebivolol and the Endothelin (ET)-1 System

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