Effects of Nebivolol on Skeletal Muscle During Exercise in Hypertensive Patients

NCT01501929 | Completed Phase 4 Results DMC

• 1 other identifier: Bystolic MD52
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

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.

Conditions

Hypertension

Keywords

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

Outcome Measures

Primary Outcomes (2)

• Endothelial Cell Protein Expression p47phox From Endothelial Cell Collection

  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.

  12 weeks

• Microvascular Blood Flow

  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

  12 weeks

Study Arms (2)

Initial treatment with metoprolol

ACTIVE COMPARATOR

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; Drug: Nebivolol; Procedure: Non-invasive measurement of Cardiac Output (CO); Procedure: Endothelial cell collection; Procedure: Microvascular perfusion assessment using Definity

Initial treatment with nebivolol

ACTIVE COMPARATOR

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; Drug: Nebivolol; Procedure: Non-invasive measurement of Cardiac Output (CO); Procedure: Endothelial cell collection; Procedure: Microvascular perfusion assessment using Definity

Interventions

Metoprolol succinate DRUG

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.

Also known as: Toprol XL

Initial treatment with metoprolol; Initial treatment with nebivolol

Nebivolol DRUG

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.

Also known as: Bystolic

Initial treatment with metoprolol; Initial treatment with nebivolol

Non-invasive measurement of Cardiac Output (CO) PROCEDURE

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.

Also known as: Cardiac output by thoracic electrical bioimpedance, Bioz, Cardio Dynamics International Corporation

Initial treatment with metoprolol; Initial treatment with nebivolol

Endothelial cell collection PROCEDURE

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.

Also known as: Endocell collection

Initial treatment with metoprolol; Initial treatment with nebivolol

Microvascular perfusion assessment using Definity PROCEDURE

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.

Initial treatment with metoprolol; Initial treatment with nebivolol

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and women with stage I primary untreated hypertension (BP between 140-159/90-99 mmHg)
• Age 18-65

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Texas Southwestern Medical Center: lead
• Forest Laboratories: collaborator

Study Sites (1)

UT Southwestern Medical Center

Dallas, Texas, 75390-8586, United States

Location

Related Publications (24)

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MeSH Terms

Conditions

Hypertension

Interventions

Metoprolol; Nebivolol

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Ethanolamines; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Wanpen Vongpatanasin
• Organization: University of Texas Southwestern

Wanpen.Vongpatanasin@UTSouthwestern.edu

2146482103

Study Officials

• Wanpen Vongpatanasin, MD

  University of Texas Southwestern Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: November 29, 2011
• First Posted: December 30, 2011
• Study Start: August 1, 2010
• Primary Completion: December 1, 2015
• Study Completion: December 1, 2015
• Last Updated: November 6, 2018
• Results First Posted: November 6, 2018

Record last verified: 2018-05

Locations

US (1)