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

• Sponsor: University of Colorado, Boulder (Other)
• Overall Status: Completed
• CT.gov ID: NCT01395329
• Collaborator: Forest Laboratories (Industry)
• Enrollment: 42
• Location: 1
• Arms: 3
• Duration (Months): 67.1
• Patients Per Site Per Month: 0.6

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Prehypertension; Hypertension	Drug: Nebivolol; Drug: Metoprolol; Drug: Placebo; 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	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: Nebivolol and the Endothelin (ET)-1 System
• Study Start Date: May 1, 2011
• Actual Primary Completion Date: Nov 1, 2016
• Actual Study Completion Date: Dec 1, 2016

Arms and Interventions

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.	Drug: Metoprolol; 100 mg tablet to be taken by mouth once per day for 12 weeks; Other Names: Toprol-XL ; 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
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.	Drug: Placebo; gelatin capsule to be taken by mouth once per day for 12 weeks; 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

Outcome Measures

Primary Outcome Measures

1. 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.]

2. 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.]

3. Percent Change in Forearm Blood Flow (FBF) Response to BQ-123 (100 Nmol/Min) [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.]

   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.

4. Percent Change in FBF Response to BQ-123 (100 Nmol/Min) + BQ-788 (50 Nmol/Min) [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.]

   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.

5. FBF Response to Acetylcholine (ACh) [Forearm blood flow was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.]

   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.

6. FBF Response to Sodium Nitroprusside [Forearm blood flow was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.]

   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.

7. FBF Response to ACh in the Absence or Presence of Nonselective Endothelin A/B Blockade (BQ-123+BQ-788) [Forearm blood flow was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UC-Boulder Clinical and Translational Research Center	Boulder	Colorado	United States	80309

Sponsors and Collaborators

• University of Colorado, Boulder
• Forest Laboratories

Investigators

• Principal Investigator: Christopher A DeSouza, Ph.D., University of Colorado at Boulder

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Christopher DeSouza, Professor, University of Colorado, Boulder
• ClinicalTrials.gov Identifier: NCT01395329
• Other Study ID Numbers: BYS-MD-57
• First Posted: Jul 15, 2011
• Last Update Posted: Jan 2, 2019
• Last Verified: Dec 1, 2018

• Additional relevant MeSH terms: Prehypertension; Metoprolol; Nebivolol; Nitroprusside; cyclo(Trp-Asp-Pro-Val-Leu); BQ 788; Acetylcholine

Study Results

Participant Flow

Arm/Group Title	Nebivolol	Metoprolol	Placebo
Arm/Group Description	Nebivolol: 5 mg tablet to be taken by mouth once per day for 12 weeks	Metoprolol: 100 mg tablet to be taken by mouth once per day for 12 weeks	Placebo: gelatin capsule to be taken by mouth once per day for 12 weeks
Period Title: Overall Study
STARTED	14	14	14
COMPLETED	14	14	14
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Nebivolol	Metoprolol	Placebo	Total
Arm/Group Description	Nebivolol: 5 mg tablet to be taken by mouth once per day for 12 weeks	Metoprolol: 100 mg tablet to be taken by mouth once per day for 12 weeks	Placebo: gelatin capsule to be taken by mouth once per day for 12 weeks	Total of all reporting groups
Overall Participants	14	14	14	42
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	14 100%	14 100%	14 100%	42 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57 (5.3)	55 (4.1)	56 (5.9)	56 (5.1)
Sex: Female, Male (Count of Participants)
Female	6 42.9%	5 35.7%	5 35.7%	16 38.1%
Male	8 57.1%	9 64.3%	9 64.3%	26 61.9%
Region of Enrollment (Count of Participants)
United States	14 100%	14 100%	14 100%	42 100%

Outcome Measures

1. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Before Nebivolol	After Nebivolol	Before Metoprolol	After Metoprolol	Before Placebo	After Placebo
Arm/Group Description	Before randomization to Nebivolol	Nebivolol: 5 mg tablet to be taken by mouth once per day for 12 weeks	Before randomization to Metoprolol	Metoprolol: 100 mg tablet to be taken by mouth once per day for 12 weeks	Before randomization to placebo	Placebo: gelatin capsule to be taken by mouth once per day for 12 weeks
Measure Participants	14	14	14	14	14	14
Mean (Standard Error) [mmHg]	144 (6.6)	126 (7.8)	140 (6.1)	125 (9.3)	139 (4.9)	134 (8.3)

2. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Before Nebivolol	After Nebivolol	Before Metoprolol	After Metoprolol	Before Placebo	After Placebo
Arm/Group Description	Before randomization to Nebivolol	Nebivolol: 5 mg tablet to be taken by mouth once per day for 12 weeks	Before randomization to Metoprolol	Metoprolol: 100 mg tablet to be taken by mouth once per day for 12 weeks	Before randomization to placebo	Placebo: gelatin capsule to be taken by mouth once per day for 12 weeks
Measure Participants	14	14	14	14	14	14
Mean (Standard Error) [mmHg]	89 (5.2)	77 (5.3)	90 (7.6)	77 (4.8)	86 (7.7)	83 (7.3)

3. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Before Nebivolol	After Nebivolol	Before Metoprolol	After Metoprolol	Before Placebo	After Placebo
Arm/Group Description	Before randomization to Nebivolol	Nebivolol: 5 mg tablet to be taken by mouth once per day for 12 weeks	Before randomization to Metoprolol	Metoprolol: 100 mg tablet to be taken by mouth once per day for 12 weeks	Before randomization to placebo	Placebo: gelatin capsule to be taken by mouth once per day for 12 weeks
Measure Participants	14	14	14	14	14	14
BQ-123 10 min	10.2 (2.6)	-1.0 (1.7)	10.0 (3.7)	11.1 (2.8)	13.1 (4.6)	15.7 (3.0)
BQ-123 20 min	17.4 (3.3)	6.0 (3.3)	18.0 (4.7)	18.7 (3.2)	20.4 (3.1)	14.7 (3.9)
BQ-123 30 min	22.3 (5.1)	-1.1 (3.3)	23.0 (4.6)	21.1 (4.8)	26.8 (5.1)	23.3 (4.5)
BQ-123 40 min	25.6 (6.3)	3.8 (3.2)	28.4 (4.9)	28.9 (3.8)	23.9 (4.3)	25.7 (3.9)
BQ-123 50 min	25.8 (4.6)	6.1 (3.6)	31.4 (5.9)	27.7 (4.8)	29.0 (5.6)	26.5 (4.5)
BQ-123 60 min	27.0 (6.4)	1.1 (4.5)	34.4 (5.7)	30.6 (5.5)	33.8 (5.3)	30.4 (3.7)

4. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Before Nebivolol	After Nebivolol	Before Metoprolol	After Metoprolol	Before Placebo	After Placebo
Arm/Group Description	Before randomization to Nebivolol	Nebivolol: 5 mg tablet to be taken by mouth once per day for 12 weeks	Before randomization to Metoprolol	Metoprolol: 100 mg tablet to be taken by mouth once per day for 12 weeks	Before randomization to placebo	Placebo: gelatin capsule to be taken by mouth once per day for 12 weeks
Measure Participants	14	14	14	14	14	14
BQ-123 10 min	10.2 (2.6)	-1.0 (1.7)	10.0 (3.7)	11.1 (2.8)	13.1 (4.6)	15.7 (3.0)
BQ-123 20 min	17.4 (3.3)	6.0 (3.3)	18.0 (4.7)	18.7 (3.2)	20.4 (3.1)	14.7 (3.9)
BQ-123 30 min	22.3 (5.1)	-1.1 (3.3)	23.0 (4.6)	21.1 (4.8)	26.8 (5.1)	23.3 (4.5)
BQ-123 40 min	25.6 (6.3)	3.8 (3.2)	28.4 (4.9)	28.9 (3.8)	23.9 (4.3)	25.7 (3.9)
BQ-123 50 min	25.8 (4.6)	6.1 (3.6)	31.4 (5.9)	27.7 (4.8)	29.0 (5.6)	26.5 (4.5)
BQ-123 60 min	27.0 (6.4)	1.1 (4.5)	34.4 (5.7)	30.6 (5.5)	33.8 (5.3)	30.4 (3.7)
BQ-123+BQ-788 70 min	44.0 (6.9)	9.2 (3.7)	33.2 (6.9)	37.8 (5.7)	37.5 (8.3)	38.0 (7.5)
BQ-123+BQ-788 80 min	41.3 (7.0)	16.1 (8.2)	44.7 (7.3)	32.2 (7.3)	42.6 (9.5)	45.0 (7.9)
BQ-123+BQ-788 90 min	39.5 (7.1)	21.8 (9.2)	49.8 (9.5)	47.4 (6.9)	46.4 (8.9)	47.1 (7.4)
BQ-123+BQ-788 100 min	47.4 (7.8)	22.3 (8.5)	47.5 (7.4)	42.0 (7.6)	57.1 (9.5)	53.4 (8.5)
BQ-123+BQ-788 110 min	47.6 (8.5)	18.9 (7.0)	57.8 (10.4)	48.1 (7.6)	57.8 (7.8)	52.8 (9.3)
BQ-123+BQ-788 120 min	57.6 (9.0)	20.4 (7.6)	64.6 (9.8)	55.4 (7.1)	57.9 (9.5)	49.5 (10.3)

5. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Before Nebivolol	After Nebivolol	Before Metoprolol	After Metoprolol	Before Placebo	After Placebo
Arm/Group Description	Before randomization to Nebivolol	Nebivolol: 5 mg tablet to be taken by mouth once per day for 12 weeks	Before randomization to Metoprolol	Metoprolol: 100 mg tablet to be taken by mouth once per day for 12 weeks	Before randomization to placebo	Placebo: gelatin capsule to be taken by mouth once per day for 12 weeks
Measure Participants	14	14	14	14	14	14
Baseline	5.2 (0.3)	4.9 (0.4)	5.3 (0.5)	5.6 (0.5)	4.8 (0.2)	5.1 (0.3)
ACh 4.0	12.1 (0.8)	13.9 (0.9)	12.4 (1.0)	12.0 (1.0)	11.4 (0.6)	13.2 (0.7)
ACh 8.0	12.7 (0.8)	15.0 (0.8)	13.1 (1.1)	13.2 (1.1)	12.0 (0.6)	13.7 (0.6)
ACh 16.0	13.3 (0.8)	16.4 (0.6)	13.8 (1.1)	14.1 (1.1)	12.7 (0.8)	13.9 (0.7)

6. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Before Nebivolol	After Nebivolol	Before Metoprolol	After Metoprolol	Before Placebo	After Placebo
Arm/Group Description	Before randomization to Nebivolol	Nebivolol: 5 mg tablet to be taken by mouth once per day for 12 weeks	Before randomization to Metoprolol	Metoprolol: 100 mg tablet to be taken by mouth once per day for 12 weeks	Before randomization to placebo	Placebo: gelatin capsule to be taken by mouth once per day for 12 weeks
Measure Participants	14	14	14	14	14	14
Baseline	5.2 (0.4)	4.7 (0.3)	4.9 (0.3)	5.7 (0.5)	5.2 (0.3)	5.2 (0.3)
Sodium Nitroprusside 1.0	13.5 (1.2)	13.7 (1.0)	14.1 (1.3)	14.3 (1.2)	12.8 (0.7)	13.7 (0.8)
Sodium Nitroprusside 2.0	15.3 (1.3)	15.2 (1.0)	14.9 (1.3)	15.1 (1.1)	14.4 (0.8)	15.3 (0.8)
Sodium Nitroprusside 4.0	15.9 (1.2)	16.4 (1.1)	15.8 (1.3)	16.0 (1.0)	15.8 (0.8)	16.1 (0.9)

7. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Before Nebivolol	After Nebivolol	Before Metoprolol	After Metoprolol	Before Placebo	After Placebo
Arm/Group Description	Before randomization to Nebivolol	Nebivolol: 5 mg tablet to be taken by mouth once per day for 12 weeks	Before randomization to Metoprolol	Metoprolol: 100 mg tablet to be taken by mouth once per day for 12 weeks	Before randomization to placebo	Placebo: gelatin capsule to be taken by mouth once per day for 12 weeks
Measure Participants	14	14	14	14	14	14
Baseline	5.0 (0.3)	4.7 (0.3)	5.5 (0.4)	6.0 (0.5)	4.9 (0.2)	5.1 (0.3)
ACh 4.0	11.7 (0.8)	13.8 (0.9)	13.1 (1.1)	12.4 (1.1)	11.7 (0.6)	13.3 (0.7)
ACh 8.0	12.3 (0.7)	15.0 (0.7)	13.7 (1.2)	13.7 (1.2)	12.3 (0.7)	13.7 (0.7)
ACh 16.0	12.9 (0.7)	16.1 (0.5)	14.5 (1.2)	14.7 (1.2)	13.0 (0.8)	13.9 (0.8)
Baseline+BQ123/788	6.4 (0.5)	5.8 (0.7)	6.7 (0.4)	7.4 (0.7)	6.1 (0.4)	5.6 (0.4)
ACh 4.0+BQ-123/788	14.6 (0.7)	13.7 (0.9)	16.1 (1.3)	16.5 (1.3)	13.5 (1.0)	15.3 (0.9)
ACh 8.0+BQ-123/788	15.3 (0.7)	14.5 (0.8)	17.1 (1.2)	17.6 (1.2)	15.1 (0.9)	16.5 (0.9)
ACh 16.0+BQ-123/788	15.9 (0.6)	15.0 (0.7)	17.9 (1.3)	18.2 (1.2)	16.2 (0.9)	17.3 (1.0)

Adverse Events

Arm/Group Title	Nebivolol		Metoprolol		Placebo
Arm/Group Description	Nebivolol: 5 mg tablet to be taken by mouth once per day for 12 weeks		Metoprolol: 100 mg tablet to be taken by mouth once per day for 12 weeks		Placebo: gelatin capsule to be taken by mouth once per day for 12 weeks
All Cause Mortality
	Nebivolol		Metoprolol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/14 (0%)		0/14 (0%)
Serious Adverse Events
	Nebivolol		Metoprolol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/14 (0%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	Nebivolol		Metoprolol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/14 (0%)		0/14 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.