Effects of Nebivolol on Skeletal Muscle During Exercise in Hypertensive Patients

• ClinicalTrials.gov Identifier: NCT01501929
• Recruitment Status: Completed
• First Posted: December 30, 2011
• Results First Posted: November 6, 2018
• Last Update Posted: November 6, 2018
• Sponsor: University of Texas Southwestern Medical Center
• Collaborator: Forest Laboratories
• Information provided by (Responsible Party): Wanpen Vongpatanasin, University of Texas Southwestern Medical Center

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
Hypertension	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 (Clinical Trial)
• 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: August 2010
• Actual Primary Completion Date: December 2015
• Actual Study Completion Date: December 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 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; 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 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: 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; 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 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.

Outcome Measures

Primary Outcome Measures :

1. Endothelial Cell Protein Expression p47phox From Endothelial Cell Collection [ Time Frame: 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 [ Time Frame: 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

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• 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

Locations

United States, Texas

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

More Information

Publications:

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Zhao W, Swanson SA, Ye J, Li X, Shelton JM, Zhang W, Thomas GD. Reactive oxygen species impair sympathetic vasoregulation in skeletal muscle in angiotensin II-dependent hypertension. Hypertension. 2006 Oct;48(4):637-43. Epub 2006 Aug 28.

Ladage D, Brixius K, Hoyer H, Steingen C, Wesseling A, Malan D, Bloch W, Schwinger RH. Mechanisms underlying nebivolol-induced endothelial nitric oxide synthase activation in human umbilical vein endothelial cells. Clin Exp Pharmacol Physiol. 2006 Aug;33(8):720-4.

Reidenbach C, Schwinger RH, Steinritz D, Kehe K, Thiermann H, Klotz T, Sommer F, Bloch W, Brixius K. Nebivolol induces eNOS activation and NO-liberation in murine corpus cavernosum. Life Sci. 2007 Jun 6;80(26):2421-7. Epub 2007 Apr 25.

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Clerk LH, Vincent MA, Jahn LA, Liu Z, Lindner JR, Barrett EJ. Obesity blunts insulin-mediated microvascular recruitment in human forearm muscle. Diabetes. 2006 May;55(5):1436-42.

Womack L, Peters D, Barrett EJ, Kaul S, Price W, Lindner JR. Abnormal skeletal muscle capillary recruitment during exercise in patients with type 2 diabetes mellitus and microvascular complications. J Am Coll Cardiol. 2009 Jun 9;53(23):2175-83. doi: 10.1016/j.jacc.2009.02.042.

Donato AJ, Gano LB, Eskurza I, Silver AE, Gates PE, Jablonski K, Seals DR. Vascular endothelial dysfunction with aging: endothelin-1 and endothelial nitric oxide synthase. Am J Physiol Heart Circ Physiol. 2009 Jul;297(1):H425-32. doi: 10.1152/ajpheart.00689.2008. Epub 2009 May 22.

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

Velasco A, Solow E, Price A, Wang Z, Arbique D, Arbique G, Adams-Huet B, Schwedhelm E, Lindner JR, Vongpatanasin W. Differential effects of nebivolol vs. metoprolol on microvascular function in hypertensive humans. Am J Physiol Heart Circ Physiol. 2016 Jul 1;311(1):H118-24. doi: 10.1152/ajpheart.00237.2016. Epub 2016 May 13.

• Responsible Party: Wanpen Vongpatanasin, Associate Professor, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT01501929
• Other Study ID Numbers: Bystolic MD52
• First Posted: December 30, 2011
• Results First Posted: November 6, 2018
• Last Update Posted: November 6, 2018
• Last Verified: May 2018

Keywords provided by Wanpen Vongpatanasin, 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; Vascular Diseases; Cardiovascular Diseases; Metoprolol; Nebivolol; Anti-Arrhythmia Agents; Antihypertensive Agents; Sympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Adrenergic beta-1 Receptor Antagonists; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Adrenergic beta-1 Receptor Agonists; Adrenergic beta-Agonists; Adrenergic Agonists