Effects of Nebivolol on Skeletal Muscle During Exercise in Hypertensive Patients

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2013 by University of Texas Southwestern Medical Center
Sponsor:
Collaborator:
Forest Laboratories
Information provided by (Responsible Party):
Wanpen Vongpatanasin, University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier:
NCT01501929
First received: November 29, 2011
Last updated: October 16, 2012
Last verified: April 2013
  Purpose

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 Intervention Phase
Hypertension
Drug: Metoprolol succinate
Drug: Nebivolol
Drug: Hydrochlorothiazide
Drug: DEFINITY®
Procedure: Non-invasive measurement of Cardiac Output (CO)
Procedure: Flow mediated vasodilation
Procedure: Endothelial cell collection
Procedure: Microvascular perfusion assessment using Definity
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Official Title: Effects of Nebivolol on Microvascular Perfusion in the Skeletal Muscles During Exercise in Hypertensive Patients

Resource links provided by NLM:


Further study details as provided by University of Texas Southwestern Medical Center:

Primary Outcome Measures:
  • Endothelial cell protein expression [ Time Frame: 12 weeks after initiation of metoprolol ] [ Designated as safety issue: No ]
  • Endothelial cell protein expression [ Time Frame: 12 weeks after initiation of nebivolol ] [ Designated as safety issue: No ]
  • Microvascular blood flow [ Time Frame: 12 weeks after initiation of metoprolol ] [ Designated as safety issue: No ]
  • Microvascular blood flow [ Time Frame: 12 weeks after initiation of nebivolol ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Flow mediated dilation (FMD) [ Time Frame: 12 weeks after initiation of metoprolol ] [ Designated as safety issue: No ]
  • Flow mediated dilation (FMD) [ Time Frame: 12 weeks after initiation of nebivolol ] [ Designated as safety issue: No ]

Estimated Enrollment: 32
Study Start Date: August 2010
Estimated Study Completion Date: August 2013
Estimated Primary Completion Date: August 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: Bystolic
Drug: Hydrochlorothiazide
During the washout period between the two treatments, subjects will be followed after 2 weeks of drug withdrawal. Hydrochlorothiazide (HCTZ) 25 mg once daily will be started in subjects found to have BP > 140/90 mmHg and continued for a 2 week period. The subjects will return in 2 weeks, and at that time HCTZ will be stopped if started in the earlier visit. The subject will then be switched to the remaining treatment (Nebivolol or Metoprolol).
Other Name: HCTZ
Drug: DEFINITY®
The DEFINITY® vial contains components that upon activation yield perflutren lipid microspheres, a diagnostic drug that is intended to be used for contrast enhancement during echocardiographic procedures. The vial contains a clear, colorless, sterile, non-pyrogenic, hypertonic liquid, which upon activation with the aid of a Vialmix®, provides a homogeneous, opaque, milky white injectable suspension of perflutren lipid microspheres. The suspension of activated DEFINITY® will be infused intravenously at a 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.
Other Name: DEFINITY® (IND# 104397)
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: Flow mediated vasodilation
Flow mediated vasodilation (FMD), which is a non-invasive assessment of endothelial function, will be performed on the brachial artery using ultrasound. After a clear picture of the artery 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.
Other Names:
  • FMD
  • Endothelial Dependent Vasodilation
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 Name: 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 Name: Toprol XL
Drug: Hydrochlorothiazide
During the washout period between the two treatments, subjects will be followed after 2 weeks of drug withdrawal. Hydrochlorothiazide (HCTZ) 25 mg once daily will be started in subjects found to have BP > 140/90 mmHg and continued for a 2 week period. The subjects will return in 2 weeks, and at that time HCTZ will be stopped if started in the earlier visit. The subject will then be switched to the remaining treatment (Nebivolol or Metoprolol).
Other Name: HCTZ
Drug: DEFINITY®
The DEFINITY® vial contains components that upon activation yield perflutren lipid microspheres, a diagnostic drug that is intended to be used for contrast enhancement during echocardiographic procedures. The vial contains a clear, colorless, sterile, non-pyrogenic, hypertonic liquid, which upon activation with the aid of a Vialmix®, provides a homogeneous, opaque, milky white injectable suspension of perflutren lipid microspheres. The suspension of activated DEFINITY® will be infused intravenously at a 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.
Other Name: DEFINITY® (IND# 104397)
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: Flow mediated vasodilation
Flow mediated vasodilation (FMD), which is a non-invasive assessment of endothelial function, will be performed on the brachial artery using ultrasound. After a clear picture of the artery 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.
Other Names:
  • FMD
  • Endothelial Dependent Vasodilation
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 Name: 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.

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.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01501929

Contacts
Contact: Debbie Arbique, MS, FNP-C (214) 648-3188 Debbie.Arbique@UTSouthwestern.edu
Contact: Angela L Price, MD (214) 648-3188 Angela.Price@UTSouthwestern.edu

Locations
United States, Texas
UT Southwestern Medical Center Recruiting
Dallas, Texas, United States, 75390-8586
Contact: Debbie Arbique, MS, FNP-C    214-648-3188    Debbie.Arbique@UTSouthwestern.edu   
Contact: Angela L Price, MD    (214) 648-3188    Angela.Price@UTSouthwestern.edu   
Principal Investigator: Wanpen Vongpatanasin, MD         
Sponsors and Collaborators
University of Texas Southwestern Medical Center
Forest Laboratories
Investigators
Principal Investigator: Wanpen Vongpatanasin, MD UT Southwestern Medical Center
  More Information

Publications:

Responsible Party: Wanpen Vongpatanasin, Associate Professor, University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier: NCT01501929     History of Changes
Other Study ID Numbers: Bystolic MD52
Study First Received: November 29, 2011
Last Updated: October 16, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by 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
Cardiovascular Diseases
Vascular Diseases
Definity
Hydrochlorothiazide
Metoprolol
Metoprolol succinate
Nebivolol
Perflutren
Adrenergic Agents
Adrenergic Antagonists
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Anti-Arrhythmia Agents
Antihypertensive Agents
Autonomic Agents
Cardiovascular Agents
Contrast Media
Diagnostic Uses of Chemicals
Diuretics
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Natriuretic Agents
Neurotransmitter Agents
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Sodium Chloride Symporter Inhibitors
Sympatholytics
Therapeutic Uses

ClinicalTrials.gov processed this record on October 29, 2014