Nebivolol and Endothelial Regulation of Fibrinolysis (NERF)

Nebivolol and Endothelial Regulation of Fibrinolysis

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.

Study Overview

• Status: Completed
• Conditions: Hypertension; Prehypertension
• Intervention / Treatment: Drug: Nebivolol; Drug: Metoprolol; Drug: Placebo; Other: Bradykinin; Other: Saline; Other: Vitamin C

• Study Type: Interventional
• Enrollment (Actual): 44
• 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 >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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Gelatin capsule to be taken by mouth once per day for 12 weeks
Active Comparator: Metoprolol	Drug: Metoprolol; 100 mg tablet to be taken by mouth once per day for 12 weeks; Other Names: Toprol-XL
Active Comparator: Nebivolol	Drug: Nebivolol; 5 mg tablet to be taken by mouth once per day for 12 weeks; Other Names: Bystolic
Other: Bradykinin	Drug: Nebivolol; 5 mg tablet to be taken by mouth once per day for 12 weeks; Other Names: Bystolic; Drug: Metoprolol; 100 mg tablet to be taken by mouth once per day for 12 weeks; Other Names: Toprol-XL; Drug: Placebo; Gelatin capsule to be taken by mouth once per day for 12 weeks; Other: Bradykinin; 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.; Other Names: BDK
Other: Saline	Drug: Nebivolol; 5 mg tablet to be taken by mouth once per day for 12 weeks; Other Names: Bystolic; Drug: Metoprolol; 100 mg tablet to be taken by mouth once per day for 12 weeks; Other Names: Toprol-XL; Drug: Placebo; Gelatin capsule to be taken by mouth once per day for 12 weeks; Other: Bradykinin; 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.; Other Names: BDK; Other: Saline; 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.; Other: Vitamin C; 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.
Other: Vitamin C	Drug: Nebivolol; 5 mg tablet to be taken by mouth once per day for 12 weeks; Other Names: Bystolic; Drug: Metoprolol; 100 mg tablet to be taken by mouth once per day for 12 weeks; Other Names: Toprol-XL; Other: Bradykinin; 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.; Other Names: BDK; Other: Saline; 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.; Other: Vitamin C; 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.

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.
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.
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.

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Stauffer BL, Dow CA, Diehl KJ, Bammert TD, Greiner JJ, DeSouza CA. Nebivolol, But Not Metoprolol, Treatment Improves Endothelial Fibrinolytic Capacity in Adults With Elevated Blood Pressure. J Am Heart Assoc. 2017 Nov 9;6(11):e007437. doi: 10.1161/JAHA.117.007437.

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): October 1, 2017
• Study Completion (Actual): October 1, 2017

Study Registration Dates

• First Submitted: March 5, 2012
• First Submitted That Met QC Criteria: May 8, 2012
• First Posted (Estimate): May 10, 2012

Study Record Updates

• Last Update Posted (Actual): June 25, 2019
• Last Update Submitted That Met QC Criteria: June 5, 2019
• Last Verified: June 1, 2019

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; Enzyme Inhibitors; Protease Inhibitors; Protective Agents; Adrenergic Agonists; Micronutrients; Vitamins; Antioxidants; Adrenergic beta-Agonists; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Adrenergic beta-1 Receptor Agonists; Cysteine Proteinase Inhibitors; Nebivolol; Metoprolol; Ascorbic Acid; Bradykinin; Kininogens
• Other Study ID Numbers: BYS-MD-72