Effects of Nebivolol on Skeletal Muscle During Exercise in Hypertensive Patients

Phase 4

Completed

• Conditions: Hypertension
• Interventions: Drug: Metoprolol succinate; Drug: Nebivolol; Procedure: Non-invasive measurement of Cardiac Output (CO); Procedure: Endothelial cell collection; Procedure: Microvascular perfusion assessment using Definity

• Registration Number: NCT01501929
• Lead Sponsor: University of Texas Southwestern Medical Center

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.

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 Timeline

• Study Start: 2010-08
• Study First Submitted: 2011-11-29
• Study First Submitted QC: 2011-12-29
• Study First Posted: 2011-12-30
• Primary Completion: 2015-12
• Study Completion: 2015-12
• Status Verified: 2018-05
• Results First Submitted: 2018-05-11
• Results First Submitted QC: 2018-10-09
• Last Update Submitted: 2018-10-09
• Results First Posted: 2018-11-06
• Last Update Posted: 2018-11-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 32

Inclusion Criteria

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

Read More

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.

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Initial treatment with nebivolol	Metoprolol succinate	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.
Initial treatment with metoprolol	Metoprolol succinate	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.
Initial treatment with metoprolol	Non-invasive measurement of Cardiac Output (CO)	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.
Initial treatment with metoprolol	Endothelial cell collection	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.
Initial treatment with metoprolol	Microvascular perfusion assessment using Definity	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.
Initial treatment with nebivolol	Non-invasive measurement of Cardiac Output (CO)	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.
Initial treatment with nebivolol	Endothelial cell collection	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.
Initial treatment with nebivolol	Microvascular perfusion assessment using Definity	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.
Initial treatment with metoprolol	Nebivolol	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.
Initial treatment with nebivolol	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.

Primary Outcome Measures

Name	Time	Method
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.
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

Trial Locations

Locations (1)

UT Southwestern Medical Center; 🇺🇸 Dallas, Texas, United States