Nebivolol and Endothelial Regulation of Fibrinolysis (NERF)

Study Overview
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Brief Summary
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The investigators hypothesize that nebivolol will improve endothelial t-PA release in adult humans with elevated blood pressure to a greater extent than either metoprolol or placebo. The investigators further hypothesize that the improvement in the capacity of the vascular endothelium to release t-PA with nebivolol is mediated, in part, by the compound's antioxidant properties.

Official Title
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Nebivolol and Endothelial Regulation of Fibrinolysis

Conditions
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Prehypertension, Hypertension

Intervention / Treatment
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* Drug: Nebivolol
* Drug: Metoprolol
* Drug: Placebo
* Other: Bradykinin
* Other: Saline
* Other: Vitamin C


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 >125 mmHg and <160 mmHg and/or diastolic >80 mmHg and <100 mmHg. All of the women in the study will be postmenopausal and not receiving hormone replacement therapy (HRT) currently or in the preceding 3-year period. 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 and 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 >160 mmHg or a seated diastolic blood pressure >100 mmHg will be excluded.

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> | Drug: Nebivolol<br>* 5 mg tablet to be taken by mouth once per day for 12 weeks<br>* Other names: Bystolic;|
| Active Comparator: Metoprolol<br> | Drug: Metoprolol<br>* 100 mg tablet to be taken by mouth once per day for 12 weeks<br>* Other names: Toprol-XL;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Gelatin capsule to be taken by mouth once per day for 12 weeks<br>|
| Other: Bradykinin<br> | Drug: Nebivolol<br>* 5 mg tablet to be taken by mouth once per day for 12 weeks<br>* Other names: Bystolic;Drug: Metoprolol<br>* 100 mg tablet to be taken by mouth once per day for 12 weeks<br>* Other names: Toprol-XL;Drug: Placebo<br>* Gelatin capsule to be taken by mouth once per day for 12 weeks<br>Other: Bradykinin<br>* Bradykinin is infused into the brachial artery at doses of 12.5, 25.0 and 50.0 ng/100 mL of forearm tissue /min. BDK stimulates the endothelial cells to release tissue type plasminogen activator (t-PA). Blood flow in mL/100 mL tissue/min is also measured to BDK.<br>* Other names: BDK;|
| Other: Saline<br> | Drug: Nebivolol<br>* 5 mg tablet to be taken by mouth once per day for 12 weeks<br>* Other names: Bystolic;Drug: Metoprolol<br>* 100 mg tablet to be taken by mouth once per day for 12 weeks<br>* Other names: Toprol-XL;Drug: Placebo<br>* Gelatin capsule to be taken by mouth once per day for 12 weeks<br>Other: Bradykinin<br>* Bradykinin is infused into the brachial artery at doses of 12.5, 25.0 and 50.0 ng/100 mL of forearm tissue /min. BDK stimulates the endothelial cells to release tissue type plasminogen activator (t-PA). Blood flow in mL/100 mL tissue/min is also measured to BDK.<br>* Other names: BDK;Other: Saline<br>* Baseline or resting forearm blood flow is measured in response to saline for 5 minutes before each drug infusion. t-PA release in response to the saline is also measured.<br>Other: Vitamin C<br>* The acute effects of into-arterial vitamin C on the ability of the endothelium to release t-PA was determined before and after the nebivolol and metoprolol intervention. After allowing sufficient time ( 20 minutes) for FBF and plasma t-PA concentrations to return to baseline following the initial infusion of BDK, vitamin C (24 mg/min) was infused at a constant rate while the BDK dose-response curves were repeated. t-PA and FBF were measured.<br>|
| Other: Vitamin C<br> | Drug: Nebivolol<br>* 5 mg tablet to be taken by mouth once per day for 12 weeks<br>* Other names: Bystolic;Drug: Metoprolol<br>* 100 mg tablet to be taken by mouth once per day for 12 weeks<br>* Other names: Toprol-XL;Other: Bradykinin<br>* Bradykinin is infused into the brachial artery at doses of 12.5, 25.0 and 50.0 ng/100 mL of forearm tissue /min. BDK stimulates the endothelial cells to release tissue type plasminogen activator (t-PA). Blood flow in mL/100 mL tissue/min is also measured to BDK.<br>* Other names: BDK;Other: Saline<br>* Baseline or resting forearm blood flow is measured in response to saline for 5 minutes before each drug infusion. t-PA release in response to the saline is also measured.<br>Other: Vitamin C<br>* The acute effects of into-arterial vitamin C on the ability of the endothelium to release t-PA was determined before and after the nebivolol and metoprolol intervention. After allowing sufficient time ( 20 minutes) for FBF and plasma t-PA concentrations to return to baseline following the initial infusion of BDK, vitamin C (24 mg/min) was infused at a constant rate while the BDK dose-response curves were repeated. t-PA and FBF were measured.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Heart Rate | Resting heart rate in the seated position | Heart rate was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention. | 
| 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. | 
| Endothelial t-PA Release in Response to Bradykinin (BDK) Before and After the 12 Week Intervention | Net endothelial release of t-PA antigen in response to bradykinin (BDK) was calculated using the following equation: Net Release of t-PA Antigen=(Cv-Ca) x (FBF x [101-hematocrit/100]) where Cv and Ca represent the concentration of t-PA in the vein and artery respectively. A positive difference indicates a net release and a negative difference net uptake. Arterial and venous blood samples are collected simultaneously at baseline and each dose of the drug (BDK). t-PA concentration were determined by enzyme immunoassay. Hematocrit was measured in triplicate using the standard microhematocrit technique and corrected for trapped plasma volume within the trapped red blood cells. | t-PA release was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention. | 
| Endothelial t-PA Release in Response to Bradykinin (BDK) and Bradykinin+Vitamin C (BDK+C) Before and After 12 Weeks of Nebivolol Therapy. | Net endothelial release of t-PA antigen in response to bradykinin (BDK) and bradykinin+vitamin C (BDK+C) was calculated using the following equation: Net Release of t-PA Antigen=(Cv-Ca) x (FBF x [101-hematocrit/100]) where Cv and Ca represent the concentration of t-PA in the vein and artery respectively. A positive difference indicates a net release and a negative difference net uptake. Arterial and venous blood samples are collected simultaneously at baseline and each dose of the drug (BDK) and BDK+Vit C. t-PA concentration were determined by enzyme immunoassay. Hematocrit was measured in triplicate using the standard microhematocrit technique and corrected for trapped plasma volume within the trapped red blood cells. | t-PA release was measured before the 12 week drug intervention and after the 12 week drug intervention. | 
| Endothelial t-PA Release in Response to BDK and BDK+C Before and After 12 Weeks of Metoprolol Therapy. | Net endothelial release of t-PA antigen in response to BDK and BDK+C was calculated using the following equation: Net Release of t-PA Antigen=(Cv-Ca) x (FBF x [101-hematocrit/100]) where Cv and Ca represent the concentration of t-PA in the vein and artery respectively. A positive difference indicates a net release and a negative difference net uptake. Arterial and venous blood samples are collected simultaneously at baseline and each dose of the drug (BDK) and BDK+Vit C. t-PA concentration were determined by enzyme immunoassay. Hematocrit was measured in triplicate using the standard microhematocrit technique and corrected for trapped plasma volume within the trapped red blood cells. | t-PA release was measured before the 12 week drug intervention and after the 12 week drug intervention. |