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

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.

Study Overview

• Status: Completed
• Conditions: Hypertension; Prehypertension
• Intervention / Treatment: Drug: Nebivolol; Other: Forearm Blood Flow (FBF) response to BQ-123 (100 mol/min); Other: FBF response to BQ-123 (100 nmol/min)+BQ-788(50 nmol/min); Other: FBF response to Acetylcholine; Other: FBF response to Sodium Nitroprusside; Other: FBF response to BQ-123+BQ-788+ACh; Drug: Metoprolol; Drug: Placebo

Detailed Description

1. 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.
2. The investigators further hypothesize that reducing ET-1 vasoconstrictor activity contributes to the improvement in endothelial vasodilator function associated with nebivolol.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Boulder, Colorado, United States, 80309
      • UC-Boulder Clinical and Translational Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Nebivolol; 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.	Drug: Nebivolol; 5 mg tablet to be taken by mouth once per day for 12 weeks; Other Names: Bystolic; Other: Forearm Blood Flow (FBF) response to BQ-123 (100 mol/min); 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.; Other Names: BQ-123; Other: FBF response to BQ-123 (100 nmol/min)+BQ-788(50 nmol/min); 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.; Other Names: BQ-123+BQ-788; Other: FBF response to Acetylcholine; The FBF response to the endothelium-dependent vasodilator ACh (4, 8 and 16 ug/100 mL tissue/min) at baseline and at 12 weeks.; Other Names: ACh; Other: FBF response to Sodium Nitroprusside; The FBF response to the endothelium independent vasodilator NTP (1,2 and 4 ug/100 mL tissue/min) at baseline and at 12 weeks.; Other Names: NTP; Other: FBF response to BQ-123+BQ-788+ACh; 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.; Other Names: BQ-123+BQ-788+ACh
ACTIVE_COMPARATOR: Metoprolol; 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.	Other: Forearm Blood Flow (FBF) response to BQ-123 (100 mol/min); 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.; Other Names: BQ-123; Other: FBF response to BQ-123 (100 nmol/min)+BQ-788(50 nmol/min); 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.; Other Names: BQ-123+BQ-788; Other: FBF response to Acetylcholine; The FBF response to the endothelium-dependent vasodilator ACh (4, 8 and 16 ug/100 mL tissue/min) at baseline and at 12 weeks.; Other Names: ACh; Other: FBF response to Sodium Nitroprusside; The FBF response to the endothelium independent vasodilator NTP (1,2 and 4 ug/100 mL tissue/min) at baseline and at 12 weeks.; Other Names: NTP; Other: FBF response to BQ-123+BQ-788+ACh; 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.; Other Names: BQ-123+BQ-788+ACh; Drug: Metoprolol; 100 mg tablet to be taken by mouth once per day for 12 weeks; Other Names: Toprol-XL
PLACEBO_COMPARATOR: Placebo; 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.	Other: Forearm Blood Flow (FBF) response to BQ-123 (100 mol/min); 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.; Other Names: BQ-123; Other: FBF response to BQ-123 (100 nmol/min)+BQ-788(50 nmol/min); 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.; Other Names: BQ-123+BQ-788; Other: FBF response to Acetylcholine; The FBF response to the endothelium-dependent vasodilator ACh (4, 8 and 16 ug/100 mL tissue/min) at baseline and at 12 weeks.; Other Names: ACh; Other: FBF response to Sodium Nitroprusside; The FBF response to the endothelium independent vasodilator NTP (1,2 and 4 ug/100 mL tissue/min) at baseline and at 12 weeks.; Other Names: NTP; Other: FBF response to BQ-123+BQ-788+ACh; 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.; Other Names: BQ-123+BQ-788+ACh; Drug: Placebo; gelatin capsule to be taken by mouth once per day for 12 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Systolic Blood Pressure		Systolic blood pressure was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.
Diastolic Blood Pressure		Diastolic blood pressure was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.
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.	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.
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.	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.
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.	Forearm blood flow was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.
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.	Forearm blood flow was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.
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.	Forearm blood flow was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.

Collaborators and Investigators

• Sponsor: University of Colorado, Boulder
• Collaborators: Forest Laboratories
• Investigators: Principal Investigator: Christopher A DeSouza, Ph.D., University of Colorado at Boulder

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (ACTUAL): November 1, 2016
• Study Completion (ACTUAL): December 1, 2016

Study Registration Dates

• First Submitted: June 9, 2011
• First Submitted That Met QC Criteria: July 13, 2011
• First Posted (ESTIMATE): July 15, 2011

Study Record Updates

• Last Update Posted (ACTUAL): January 2, 2019
• Last Update Submitted That Met QC Criteria: December 5, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Prehypertension; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Agents; Adrenergic Agonists; Cholinergic Agonists; Adrenergic beta-Agonists; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Adrenergic beta-1 Receptor Agonists; Endothelin Receptor Antagonists; Nitric Oxide Donors; Endothelin B Receptor Antagonists; Nebivolol; Metoprolol; Nitroprusside; cyclo(Trp-Asp-Pro-Val-Leu); Acetylcholine; BQ 788
• Other Study ID Numbers: BYS-MD-57