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Effects of Nebivolol on Skeletal Muscle During Exercise in Hypertensive Patients

Sponsor
University of Texas Southwestern Medical Center (Other)
Overall Status
Completed
CT.gov ID
NCT01501929
Collaborator
Forest Laboratories (Industry)
32
Enrollment
1
Location
2
Arms
64
Duration (Months)
0.5
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if Nebivolol improves microvascular perfusion in skeletal muscle during exercise in hypertensive patients and whether this improvement is accompanied by reduction in vascular oxidative stress or increased endothelial nitric oxide synthase (eNOS) expression in humans.

Condition or Disease Intervention/Treatment Phase
  • Drug: Metoprolol succinate
  • Drug: Nebivolol
  • Procedure: Non-invasive measurement of Cardiac Output (CO)
  • Procedure: Endothelial cell collection
  • Procedure: Microvascular perfusion assessment using Definity
 Phase 4

Detailed Description

In 32 untreated stage 1 hypertensive subjects, the investigators will measure blood pressure; noninvasive cardiac output by thoracic electrical bioimpedance (Bioz, Cardio Dynamics); forearm mediated vasodilation (FMD), which is a non-invasive assessment of endothelial function; collect venous endothelial cells; and measure microvascular perfusion using an Octafluoropropane microbubble contrast agent (Definity).

To obtain FMD, the brachial artery will be imaged using ultrasound. After a clear picture has been obtained, the cuff on the same arm will be inflated until it is tight for five minutes. During and following this, the subject's arm will continue to be imaged to monitor maximal increase in the brachial artery diameter.

To collect endothelial cells, a thin wire will be inserted in the vein to collect cells from the inner lining of the vein. The cells collected will be processed and stained for several proteins involved in endothelial cell function, using immunofluorescent technique.

To assess the microvascular perfusion in the skeletal muscle, a contrast agent (Definity) will be administered at baseline and after 5 minutes of rhythmic hand grip exercise at 30% of maximal voluntary contraction.

The investigators will then randomize our subjects to receive 12 weeks of Metoprolol or Nebivolol, using a cross over design. There will be a 4 week washout period between the two treatments. During the washout period, subjects will be followed after 2 weeks of drug withdrawal. Subjects found to have BP > 140/90 mmHg then, will be started on hydrochlorothiazide (HCTZ) at 25 mg once daily. Then subjects will be asked to return in 2 weeks. At that time HCTZ will be stopped if started in the earlier visit, and subject will be switched to the remaining treatment (Nebivolol or Metoprolol). Then, the investigators will assess microvascular perfusion in the skeletal muscle at rest and during handgrip exercise, endothelial function (FMD), and changes in endothelial cell protein expression after 12 weeks of Nebivolol and after 12 weeks of Metoprolol treatment in the same subjects.

Study Design

Study Type:
Interventional
Actual Enrollment :
32 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
None (Open Label)
Primary Purpose:
Diagnostic
Official Title:
Effects of Nebivolol on Microvascular Perfusion in the Skeletal Muscles During Exercise in Hypertensive Patients
Study Start Date :
Aug 1, 2010
Actual Primary Completion Date :
Dec 1, 2015
Actual Study Completion Date :
Dec 1, 2015

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Initial treatment with metoprolol

The subject will be started on metoprolol succinate (Toprol XL) 100-300mg daily, which he/she will continue for a period of 12 weeks. Following the 12-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued. If necessary, 2 weeks after drug withdrawal, subjects will be started on HCTZ if BP > 140/90 mmHg and will continue HCTZ for a 2-week period, after which the subject will be transitioned to nebivolol (Bystolic) 5-20mg daily, which he or she will continue for a period of 12 weeks. Following the 12-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued.

Drug: Metoprolol succinate
The subject will be started on metoprolol succinate (Toprol XL) 100-300mg daily, which he or she will continue for a period of 12 weeks. Following the 12-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued.
Other Names:
  • Toprol XL

    • Drug: Nebivolol
    The subject will be started on nebivolol (Bystolic) 5-20mg daily, which he or she will continue for a period of 12 weeks. Following the 12-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued.
    Other Names:
  • Bystolic

    • Procedure: Non-invasive measurement of Cardiac Output (CO)
    Cardiac Output (CO) will be measured non-invasively at rest and during exercise by thoracic electrical bioimpedance. Stroke volume will be derived from change in impedance/time measured during electrical systole. Cardiac output will be determined as the product of stroke volume and heart rate.
    Other Names:
  • Cardiac output by thoracic electrical bioimpedance
  • Bioz, Cardio Dynamics International Corporation

    • Procedure: Endothelial cell collection
    We will collect endothelial cells from a superficial vein, usually in the arm. Following insertion of a peripheral intravenous (IV) catheter, we will collect cells from the inner lining of the vein using a thin, flexible J-tipped wire. The wire will be inserted through the IV into the vein and then removed, along with a sampling of endothelial cells. The cells collected will be processed and stained for several proteins involved in endothelial cell function, using immunofluorescent technique.
    Other Names:
  • Endocell collection

    • Procedure: Microvascular perfusion assessment using Definity
    Using high-resolution ultrasound, we will measure skeletal muscle blood flow during infusion of a solution containing the octafluoropropane microbubble contrast agent, Definity. The solution will be a dilution of 1 vial of Definity to 30 cc of normal saline. The ultrasound probe will be placed over the forearm to obtain images while octafluoropropane microbubbles (Definity) are infused intravenously at the rate of 0.20 to 0.27 ml/min, not to exceed a maximum dose of 2 vials per study subject per day or visit. The microvascular perfusion assessment using Definity be performed at rest as well as during slow and fast handgrip exercises.
    Active Comparator: Initial treatment with nebivolol

    The subject will be started on nebivolol (Bystolic) 5-20mg daily, which he or she will continue for a period of 12 weeks. Following the 12-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued. If necessary, 2 weeks after drug withdrawal, subject will be started on HCTZ if BP > 140/90 mmHg and will continue HCTZ for a 2-week period, after which the subject will be transitioned to metoprolol succinate (Toprol XL) 100-300mg daily, which he or she will continue for a period of 12 weeks. Following the 12-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued.

    Drug: Metoprolol succinate
    The subject will be started on metoprolol succinate (Toprol XL) 100-300mg daily, which he or she will continue for a period of 12 weeks. Following the 12-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued.
    Other Names:
  • Toprol XL

    • Drug: Nebivolol
    The subject will be started on nebivolol (Bystolic) 5-20mg daily, which he or she will continue for a period of 12 weeks. Following the 12-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued.
    Other Names:
  • Bystolic

    • Procedure: Non-invasive measurement of Cardiac Output (CO)
    Cardiac Output (CO) will be measured non-invasively at rest and during exercise by thoracic electrical bioimpedance. Stroke volume will be derived from change in impedance/time measured during electrical systole. Cardiac output will be determined as the product of stroke volume and heart rate.
    Other Names:
  • Cardiac output by thoracic electrical bioimpedance
  • Bioz, Cardio Dynamics International Corporation

    • Procedure: Endothelial cell collection
    We will collect endothelial cells from a superficial vein, usually in the arm. Following insertion of a peripheral intravenous (IV) catheter, we will collect cells from the inner lining of the vein using a thin, flexible J-tipped wire. The wire will be inserted through the IV into the vein and then removed, along with a sampling of endothelial cells. The cells collected will be processed and stained for several proteins involved in endothelial cell function, using immunofluorescent technique.
    Other Names:
  • Endocell collection

    • Procedure: Microvascular perfusion assessment using Definity
    Using high-resolution ultrasound, we will measure skeletal muscle blood flow during infusion of a solution containing the octafluoropropane microbubble contrast agent, Definity. The solution will be a dilution of 1 vial of Definity to 30 cc of normal saline. The ultrasound probe will be placed over the forearm to obtain images while octafluoropropane microbubbles (Definity) are infused intravenously at the rate of 0.20 to 0.27 ml/min, not to exceed a maximum dose of 2 vials per study subject per day or visit. The microvascular perfusion assessment using Definity be performed at rest as well as during slow and fast handgrip exercises.

    Outcome Measures

    Primary Outcome Measures

    1. Endothelial Cell Protein Expression p47phox From Endothelial Cell Collection [12 weeks]

      Endothelial cell (EC) was collected after a 20-guage angiocatheter was inserted into the contralateral forearm vein under sterile conditions. Three J-shaped vascular guidewires (St. Jude, St. Paul, MN) were advanced sequentially into the vein up to 10 cm. Endothelial cells were collected by gentle abrasion and placed into a dissociation buffer (0.5% bovine serum albumin, 2mM EDTA, and 100 ug/ml heparin in PBS). Endothelial cells were recovered from the tips of guide wires by repeated washing into collection tubes and subsequent centrifugation. EC were incubated with monoclonal antibodies against the polyclonal antibodies against NADPH oxidase p47 subunit. The intensity of staining was measured using fluorescence microscopy.

    2. Microvascular Blood Flow [12 weeks]

      Microvascular perfusion of skeletal muscle were measured during handgrip at 20 cycle per minute after 12 weeks of metoprolol, and after 12 weeks of nebivolol

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    Inclusion Criteria:

    • Men and women with stage I primary untreated hypertension (BP between 140-159/90-99 mmHg)

    • Age 18-65

    Exclusion Criteria:

    • Congestive heart failure

    • Coronary artery disease

    • Left ventricular hypertrophy by echocardiography or ECG

    • History of stroke

    • Average blood pressure >159/99 mmHg

    • Bradycardia with a resting heart rate <55 bpm

    • Chronic kidney disease with a serum creatinine > 1.4 mg/dL

    • Asthma or chronic obstructive pulmonary disease

    • Women who are pregnant or planning to become pregnant

    • Hypersensitivity to beta blockers, hydrochlorothiazide, or Definity

    • Any history of substance abuse (other than tobacco)

    • Concomitant drug treatment which raises endogenous nitric oxide levels, including nitrates or phosphodiesterase V inhibitors (Viagra, Levitra)

    • History of symptomatic bradycardia or heart block

    • Patients with Right-to-left, bidirectional, or transient right-to-left cardiac shunts

    • Hypersensitivity to perflutren, blood, blood products or albumin.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 UT Southwestern Medical Center Dallas Texas United States 75390-8586

    Sponsors and Collaborators

    • University of Texas Southwestern Medical Center
    • Forest Laboratories

    Investigators

    • Principal Investigator: Wanpen Vongpatanasin, MD, UT Southwestern Medical Center

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Wanpen Vongpatanasin, Associate Professor, University of Texas Southwestern Medical Center
    ClinicalTrials.gov Identifier:
    NCT01501929
    Other Study ID Numbers:
    • Bystolic MD52
    First Posted:
    Dec 30, 2011
    Last Update Posted:
    Nov 6, 2018
    Last Verified:
    May 1, 2018
    Keywords provided by Wanpen Vongpatanasin, Associate Professor, University of Texas Southwestern Medical Center
    hypertension
    blood pressure
    blood pressure medications
    metoprolol
    nebivolol
    vascular oxidative stress
    nitric oxide
    nitric oxide synthase (eNOS)
    endothelium
    endothelial dysfunction
    endothelial cell protein expression
    microvascular blood flow
    flow mediated dilation
    handgrip exercise
    endothelial cell collection
    microbubbles
    Definity
    Additional relevant MeSH terms:
    Hypertension
    Metoprolol
    Nebivolol

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail 32 subjects were enrolled in the study and 7 were subsequently excluded sure to various reasons, including pregnancy, normal BP of < 120/80 mmHg after the washout period of 3 week, inability to participate, and diagnosis with cancer.
    Arm/Group Title Metoprolol First, Then Nebivolol Nebivolol First, Then Metoprolol
    Arm/Group Description The subject will be started on metoprolol succinate (Toprol XL) 100-300mg daily, which he/she will continue for a period of 12 weeks. Then the subject will be switched to nebivolol (5-20 mg daily) for a period of 12 weeks. The subject will be started on nebivolol (5-20 mg daily), which he/she will continue for a period of 12 weeks. Then the subject will be switched to metoprolol succinate (Toprol XL) 100-300mg daily for a period of 12 weeks.
    Period Title: First Intervention
    STARTED 8 17
    COMPLETED 8 17
    NOT COMPLETED 0 0
    Period Title: First Intervention
    STARTED 8 17
    COMPLETED 8 17
    NOT COMPLETED 0 0

    Baseline Characteristics

    Arm/Group Title All Study Participants
    Arm/Group Description After the baseline measurement, all subjects were randomized to receive either nebivolol at the dose of 5 mg once daily or Metoprolol succinate 100 mg once daily, using a double-blind crossover design. If BP remained above 140/90 mmHg during the first follow-up visit, the dose of Nebivolol was increased up to 20 mg once daily and Metoprolol was increased up to 300 mg once daily.
    Overall Participants 25
    Age (Count of Participants)
    <=18 years
    0
    0%
    Between 18 and 65 years
    25
    100%
    >=65 years
    0
    0%
    Sex: Female, Male (Count of Participants)
    Female
    14
    56%
    Male
    11
    44%
    Region of Enrollment (participants) [Number]
    United States
    25
    100%

    Outcome Measures

    1. Primary Outcome
    Title Endothelial Cell Protein Expression p47phox From Endothelial Cell Collection
    Description Endothelial cell (EC) was collected after a 20-guage angiocatheter was inserted into the contralateral forearm vein under sterile conditions. Three J-shaped vascular guidewires (St. Jude, St. Paul, MN) were advanced sequentially into the vein up to 10 cm. Endothelial cells were collected by gentle abrasion and placed into a dissociation buffer (0.5% bovine serum albumin, 2mM EDTA, and 100 ug/ml heparin in PBS). Endothelial cells were recovered from the tips of guide wires by repeated washing into collection tubes and subsequent centrifugation. EC were incubated with monoclonal antibodies against the polyclonal antibodies against NADPH oxidase p47 subunit. The intensity of staining was measured using fluorescence microscopy.
    Time Frame 12 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Metoprolol Nebivolol
    Arm/Group Description The subject will be started on metoprolol succinate (Toprol XL) 100-300mg daily, which he/she will continue for a period of 12 weeks. The subject will be started on metoprolol succinate (Toprol XL) 100-300mg daily, which he or she will continue for a period of 12 weeks. The subject will be started on nebivolol (Bystolic) 5-20mg daily, which he or she will continue for a period of 12 weeks.
    Measure Participants 25 25
    Mean (Standard Error) [Ratio human to HUVEC p47Phox expression]
    0.47
    (0.12)
    0.44
    (0.07)
    2. Primary Outcome
    Title Microvascular Blood Flow
    Description Microvascular perfusion of skeletal muscle were measured during handgrip at 20 cycle per minute after 12 weeks of metoprolol, and after 12 weeks of nebivolol
    Time Frame 12 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Metoprolol Nebivolol
    Arm/Group Description The subject will be started on metoprolol succinate (Toprol XL) 100-300mg daily, which he/she will continue for a period of 12 weeks. The subject will be started on metoprolol succinate (Toprol XL) 100-300mg daily, which he or she will continue for a period of 12 weeks. The subject will be started on nebivolol (Bystolic) 5-20mg daily, which he or she will continue for a period of 12 weeks.
    Measure Participants 25 25
    Median (Inter-Quartile Range) [video intensity units/ second]
    43.938
    74.584

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Initial Treatment With Metoprolol Initial Treatment With Nebivolol
    Arm/Group Description The subject will be started on metoprolol succinate (Toprol XL) 100-300mg daily, which he/she will continue for a period of 12 weeks. The subject will be started on metoprolol succinate (Toprol XL) 100-300mg daily, which he or she will continue for a period of 12 weeks. The subject will be started on nebivolol (Bystolic) 5-20mg daily, which he or she will continue for a period of 12 weeks.
    All Cause Mortality
    Initial Treatment With Metoprolol Initial Treatment With Nebivolol
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/25 (0%) 0/25 (0%)
    Serious Adverse Events
    Initial Treatment With Metoprolol Initial Treatment With Nebivolol
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/25 (0%) 0/25 (0%)
    Other (Not Including Serious) Adverse Events
    Initial Treatment With Metoprolol Initial Treatment With Nebivolol
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/25 (0%) 0/25 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Wanpen Vongpatanasin
    Organization University of Texas Southwestern
    Phone 2146482103
    Email Wanpen.Vongpatanasin@UTSouthwestern.edu
    Responsible Party:
    Wanpen Vongpatanasin, Associate Professor, University of Texas Southwestern Medical Center
    ClinicalTrials.gov Identifier:
    NCT01501929
    Other Study ID Numbers:
    • Bystolic MD52
    First Posted:
    Dec 30, 2011
    Last Update Posted:
    Nov 6, 2018
    Last Verified:
    May 1, 2018