Nebivolol and the Endothelin (ET)-1 System

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.

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

Primary outcomes

• 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 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.
• 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.
• 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.
• 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.
• 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.

Sex: All, ages: 45 Years to 65 Years, accepts 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.

Participant flow

Outcome results

• Systolic Blood Pressure (Primary), Mean, mmHg: Before Nebivolol 144 +/- 6.6; After Nebivolol 126 +/- 7.8; Before Metoprolol 140 +/- 6.1; After Metoprolol 125 +/- 9.3; Before Placebo 139 +/- 4.9; After Placebo 134 +/- 8.3
• Diastolic Blood Pressure (Primary), Mean, mmHg: Before Nebivolol 89 +/- 5.2; After Nebivolol 77 +/- 5.3; Before Metoprolol 90 +/- 7.6; After Metoprolol 77 +/- 4.8; Before Placebo 86 +/- 7.7; After Placebo 83 +/- 7.3
• Percent Change in Forearm Blood Flow (FBF) Response to BQ-123 (100 Nmol/Min) (Primary), Mean, percent change from baseline: Before Nebivolol 10.2 +/- 2.6; After Nebivolol -1.0 +/- 1.7; Before Metoprolol 10.0 +/- 3.7; After Metoprolol 11.1 +/- 2.8; Before Placebo 13.1 +/- 4.6; After Placebo 15.7 +/- 3.0
• Percent Change in FBF Response to BQ-123 (100 Nmol/Min) + BQ-788 (50 Nmol/Min) (Primary), Mean, Percent change from baseline: Before Nebivolol 10.2 +/- 2.6; After Nebivolol -1.0 +/- 1.7; Before Metoprolol 10.0 +/- 3.7; After Metoprolol 11.1 +/- 2.8; Before Placebo 13.1 +/- 4.6; After Placebo 15.7 +/- 3.0
• FBF Response to Acetylcholine (ACh) (Primary), Mean, mL/100 mL tissue/min: Before Nebivolol 5.2 +/- 0.3; After Nebivolol 4.9 +/- 0.4; Before Metoprolol 5.3 +/- 0.5; After Metoprolol 5.6 +/- 0.5; Before Placebo 4.8 +/- 0.2; After Placebo 5.1 +/- 0.3
• FBF Response to Sodium Nitroprusside (Primary), Mean, mL/100 mL tissue/min: Before Nebivolol 5.2 +/- 0.4; After Nebivolol 4.7 +/- 0.3; Before Metoprolol 4.9 +/- 0.3; After Metoprolol 5.7 +/- 0.5; Before Placebo 5.2 +/- 0.3; After Placebo 5.2 +/- 0.3
• FBF Response to ACh in the Absence or Presence of Nonselective Endothelin A/B Blockade (BQ-123+BQ-788) (Primary), Mean, mL/100 mL tissue/min: Before Nebivolol 5.0 +/- 0.3; After Nebivolol 4.7 +/- 0.3; Before Metoprolol 5.5 +/- 0.4; After Metoprolol 6.0 +/- 0.5; Before Placebo 4.9 +/- 0.2; After Placebo 5.1 +/- 0.3

Adverse events

• Results publication: 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. PMID 27113048

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