Nebivolol and the Endothelin (ET)-1 System

Study Overview
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Brief Summary
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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
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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.

Official Title
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Nebivolol and the Endothelin (ET)-1 System

Conditions
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Prehypertension, Hypertension

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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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. |