Effects of Nebivolol on Skeletal Muscle During Exercise in Hypertensive Patients - Full Text View

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:

MedlinePlus related topics: Exercise and Physical Fitness High Blood Pressure

Drug Information available for: Hydrochlorothiazide Perflutren Succinic acid Metoprolol Metoprolol tartrate Metoprolol succinate Nebivolol Metoprolol fumarate Nebivolol Hydrochloride

U.S. FDA Resources

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.

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

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:

Hamada M, Kazatani Y, Shigematsu Y, Ito T, Kokubu T, Ishise S. Enhanced blood pressure response to isometric handgrip exercise in patients with essential hypertension: effects of propranolol and prazosin. J Hypertens. 1987 Jun;5(3):305-9.

Saitoh M, Miyakoda H, Kitamura H, Kinugawa T, Hisatome I, Kotake H, Mashiba H. Cardiovascular and sympathetic nervous response to dynamic exercise in patients with essential hypertension. Intern Med. 1992 May;31(5):606-10.

Glezer GA, Lediashova GA. Changes in general haemodynamics and renal function during exercise in patients with arterial hypertension. Cor Vasa. 1975;17(1):1-13.

Kazatani Y, Hamada M, Shigematsu Y, Hiwada K, Kokubu T. Beneficial Effect of a Long-Term Antihypertensive Therapy on Blood Pressure Response to Isometric Handgrip Exercise in Patients with Essential Hypertension. Am J Ther. 1995 Mar;2(3):165-169.

Marraccini P, Palombo C, Giaconi S, Michelassi C, Genovesi-Ebert A, Marabotti C, Fommei E, Ghione S, L'Abbate A. Reduced cardiovascular efficiency and increased reactivity during exercise in borderline and established hypertension. Am J Hypertens. 1989 Dec;2(12 Pt 1):913-6.

Kokkinos PF, Andreas PE, Coutoulakis E, Colleran JA, Narayan P, Dotson CO, Choucair W, Farmer C, Fernhall B. Determinants of exercise blood pressure response in normotensive and hypertensive women: role of cardiorespiratory fitness. J Cardiopulm Rehabil. 2002 May-Jun;22(3):178-83.

Schütz W, Hörtnagl H, Magometschnigg D. Function of the autonomic nervous system in young, untreated hypertensive patients. Int J Cardiol. 1986 Feb;10(2):133-40.

Goodman JM, McLaughlin PR, Plyley MJ, Holloway RM, Fell D, Logan AG, Liu PP. Impaired cardiopulmonary response to exercise in moderate hypertension. Can J Cardiol. 1992 May;8(4):363-71.

Lund-Johansen P. Twenty-year follow-up of hemodynamics in essential hypertension during rest and exercise. Hypertension. 1991 Nov;18(5 Suppl):III54-61.

de Champlain J, Petrovich M, Gonzalez M, Lebeau R, Nadeau R. Abnormal cardiovascular reactivity in borderline and mild essential hypertension. Hypertension. 1991 Apr;17(4 Suppl):III22-8.

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.

Bragadeesh T, Sari I, Pascotto M, Micari A, Kaul S, Lindner JR. Detection of peripheral vascular stenosis by assessing skeletal muscle flow reserve. J Am Coll Cardiol. 2005 Mar 1;45(5):780-5.

Lindner JR, Womack L, Barrett EJ, Weltman J, Price W, Harthun NL, Kaul S, Patrie JT. Limb stress-rest perfusion imaging with contrast ultrasound for the assessment of peripheral arterial disease severity. JACC Cardiovasc Imaging. 2008 May;1(3):343-50.

Tzemos N, Lim PO, MacDonald TM. Nebivolol reverses endothelial dysfunction in essential hypertension: a randomized, double-blind, crossover study. Circulation. 2001 Jul 31;104(5):511-4.

Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Deanfield J, Drexler H, Gerhard-Herman M, Herrington D, Vallance P, Vita J, Vogel R; International Brachial Artery Reactivity Task Force. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002 Jan 16;39(2):257-65. Erratum in: J Am Coll Cardiol 2002 Mar 20;39(6):1082.

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.

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. Epub 2009 May 22.

Gavin KM, Seals DR, Silver AE, Moreau KL. Vascular endothelial estrogen receptor alpha is modulated by estrogen status and related to endothelial function and endothelial nitric oxide synthase in healthy women. J Clin Endocrinol Metab. 2009 Sep;94(9):3513-20. Epub 2009 Jun 9.

Colombo PC, Banchs JE, Celaj S, Talreja A, Lachmann J, Malla S, DuBois NB, Ashton AW, Latif F, Jorde UP, Ware JA, LeJemtel TH. Endothelial cell activation in patients with decompensated heart failure. Circulation. 2005 Jan 4;111(1):58-62. Epub 2004 Dec 20.

Pierce GL, Lesniewski LA, Lawson BR, Beske SD, Seals DR. Nuclear factor-{kappa}B activation contributes to vascular endothelial dysfunction via oxidative stress in overweight/obese middle-aged and older humans. Circulation. 2009 Mar 10;119(9):1284-92. Epub 2009 Feb 23.

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
Vascular Diseases
Cardiovascular Diseases
Metoprolol
Nebivolol
Hydrochlorothiazide
Metoprolol succinate
Anti-Arrhythmia Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
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
Diuretics
Natriuretic Agents
Sodium Chloride Symporter Inhibitors
Membrane Transport Modulators
Vasodilator Agents

ClinicalTrials.gov processed this record on June 18, 2013