Nebivolol and Endothelial Regulation of Fibrinolysis (NERF)

• ClinicalTrials.gov Identifier: NCT01595516
• Recruitment Status: Completed
• First Posted: May 10, 2012
• Results First Posted: June 25, 2019
• Last Update Posted: June 25, 2019
• Sponsor: University of Colorado, Boulder
• Collaborator: Forest Laboratories
• Information provided by (Responsible Party): Christopher DeSouza, University of Colorado, Boulder

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Prehypertension; Hypertension	Drug: Nebivolol; Drug: Metoprolol; Drug: Placebo; Other: Bradykinin; Other: Saline; Other: Vitamin C	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: Nebivolol and Endothelial Regulation of Fibrinolysis
• Study Start Date: February 2012
• Actual Primary Completion Date: October 2017
• Actual Study Completion Date: October 2017

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Heart Rate [ Time Frame: Heart rate was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention. ]
   Resting heart rate in the seated position
2. 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. ]
3. 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. ]
4. Endothelial t-PA Release in Response to Bradykinin (BDK) Before and After the 12 Week Intervention [ Time Frame: t-PA release was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo 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.
5. Endothelial t-PA Release in Response to Bradykinin (BDK) and Bradykinin+Vitamin C (BDK+C) Before and After 12 Weeks of Nebivolol Therapy. [ Time Frame: t-PA release was measured before the 12 week drug intervention and after the 12 week drug intervention. ]
   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.
6. Endothelial t-PA Release in Response to BDK and BDK+C Before and After 12 Weeks of Metoprolol Therapy. [ Time Frame: t-PA release was measured before the 12 week drug intervention and after the 12 week drug intervention. ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 45 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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.

Contacts and Locations

Locations

United States, Colorado

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 DeSouza, Ph.D.; University of Colorado at Boulder

  Study Documents (Full-Text)

Documents provided by Christopher DeSouza, University of Colorado, Boulder:

Study Protocol and Statistical Analysis Plan  [PDF] August 25, 2015

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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). pii: e007437. doi: 10.1161/JAHA.117.007437.

• Responsible Party: Christopher DeSouza, Professor, University of Colorado, Boulder
• ClinicalTrials.gov Identifier: NCT01595516
• Other Study ID Numbers: BYS-MD-72
• First Posted: May 10, 2012
• Results First Posted: June 25, 2019
• Last Update Posted: June 25, 2019
• Last Verified: June 2019

Additional relevant MeSH terms:

Prehypertension; Vascular Diseases; Cardiovascular Diseases; Ascorbic Acid; Metoprolol; Nebivolol; Bradykinin; Kininogens; Vitamins; Micronutrients; Nutrients; Growth Substances; Physiological Effects of Drugs; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents; Anti-Arrhythmia Agents; Antihypertensive Agents; Sympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic beta-1 Receptor Antagonists; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Vasodilator Agents; Adrenergic beta-1 Receptor Agonists; Adrenergic beta-Agonists; Adrenergic Agonists