Comparison of Nebivolol and Metoprolol With Exercise and Angiotensin II in Hypertensive Patients

• ClinicalTrials.gov Identifier: NCT01502787
• Recruitment Status: Completed
• First Posted: January 2, 2012
• Results First Posted: December 31, 2014
• Last Update Posted: July 7, 2020
• Sponsor: University of Texas Southwestern Medical Center
• Collaborator: Forest Laboratories
• Information provided by (Responsible Party): University of Texas Southwestern Medical Center

Study Description

Brief Summary:

The purpose of this study is to determine if Nebivolol a) attenuates the angiotensin II (Ang II)-induced increase in oxidative stress, thereby attenuating Ang II-induced vasoconstriction; and b) attenuates sympathetic mediated vasoconstriction during exercise, thereby reducing functional skeletal muscle ischemia in hypertensive patients.

Condition or disease	Intervention/treatment	Phase
Hypertension	Drug: Metoprolol succinate; Drug: Nebivolol; Procedure: Forearm blood flow; Procedure: Microneurography; Procedure: Rhythmic handgrip exercise; Procedure: Lower body negative pressure; Drug: Angiotensin II	Phase 4

Detailed Description:

In 40 untreated, stage I hypertensive subjects, Investigators will measure sympathetic nerve activity (microneurography); total forearm blood flow (high-resolution ultrasonography); skeletal muscle oxygenation (Near Infrared spectroscopy); plasma F2-isoprostanes; cardiac output (non-invasive impedance plethysmography); and blood pressure at baseline and after a) rhythmic handgrip exercise at 30% of maximal voluntary contraction alone for 3 minutes, b) rhythmic handgrip at the same intensity of exercise plus lower body negative pressure (LBNP) to activate sympathetic nerve activity (SNA) for 2 minutes, and c) during intravenous infusion of Angiotensin II at the dose of 1, 2, and 3 ng/kg/min for 15 minutes at each dose.

Each subject will then be randomized to receive 12 weeks of Nebivolol (Bystolic, 5-20 mg/day) or Metoprolol Succinate (Toprol XL, 100-300 mg/day), using a randomized crossover design. There will be a 2-week washout period between the two treatment periods. During drug treatment, blood pressure will be monitored every 4 weeks and the doses of Nebivolol and Metoprolol will be titrated to keep BP <140/90 mmHg. SNA, total forearm blood flow, skeletal muscle blood flow, muscle oxygenation, cardiac output, and blood pressure responses to Nebivolol will be compared to responses during Metoprolol in the same subjects.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 46 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Effects of Nebivolol Versus Metoprolol on Blood Flow Responses to Exercise and Angiotensin II in Hypertensive Patients
• Study Start Date: April 2009
• Actual Primary Completion Date: June 2013
• Actual Study Completion Date: June 2013

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 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. There will be a 2-week washout period. Following washout, 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.	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: Forearm blood flow; Using high-resolution ultrasound, investigators will measure skeletal muscle blood flow in the forearm at rest, following handgrip exercise (described below), and following Angiotensin II infusion (described below).; Procedure: Microneurography; Investigators will measure sympathetic nerve activity from the peroneal nerve by inserting a tiny needle directly into the nerve in the leg. Investigators will localize the nerve by electrical stimulation over the skin using a blunt probe. With this stimulation, subject will notice either involuntary twitching or a tingling sensation, which may be annoying but not painful. Investigators will then introduce a tiny, sterile wire needle (an electrode) through the skin at the same location. When the tip of the needle enters the nerve, subjects may again notice involuntary muscle twitches or tingling in the leg. Investigators will then turn the electrical stimulator off and make minor adjustments in the position of the needle until investigators begin to record the nerve signals. The recording needle will remain in position throughout the study.; Other Name: Assessment of sympathetic nerve activity (SNA); Procedure: Rhythmic handgrip exercise; Subjects will perform a rhythmic handgrip exercise at 30% of maximal voluntary contraction for 3 minutes. Investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure, and sympathetic nerve activity (SNA) at baseline and following this handgrip exercise.; Procedure: Lower body negative pressure; Lower body negative pressure increases sympathetic nerve activity. Therefore, investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure and sympathetic nerve activity at baseline and after rhythmic handgrip exercise plus lower body negative pressure (LBNP) for 2 minutes.; Other Name: LBNP; Drug: Angiotensin II; Investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure and sympathetic nerve activity at baseline and during intravenous infusion of Angiotensin II at the dose of 1, 2, and 3 ng/kg/min for 15 minutes at each dose.; Other Name: IND #103,935
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. There will be a 2-week washout period. Following washout, 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.	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: Forearm blood flow; Using high-resolution ultrasound, investigators will measure skeletal muscle blood flow in the forearm at rest, following handgrip exercise (described below), and following Angiotensin II infusion (described below).; Procedure: Microneurography; Investigators will measure sympathetic nerve activity from the peroneal nerve by inserting a tiny needle directly into the nerve in the leg. Investigators will localize the nerve by electrical stimulation over the skin using a blunt probe. With this stimulation, subject will notice either involuntary twitching or a tingling sensation, which may be annoying but not painful. Investigators will then introduce a tiny, sterile wire needle (an electrode) through the skin at the same location. When the tip of the needle enters the nerve, subjects may again notice involuntary muscle twitches or tingling in the leg. Investigators will then turn the electrical stimulator off and make minor adjustments in the position of the needle until investigators begin to record the nerve signals. The recording needle will remain in position throughout the study.; Other Name: Assessment of sympathetic nerve activity (SNA); Procedure: Rhythmic handgrip exercise; Subjects will perform a rhythmic handgrip exercise at 30% of maximal voluntary contraction for 3 minutes. Investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure, and sympathetic nerve activity (SNA) at baseline and following this handgrip exercise.; Procedure: Lower body negative pressure; Lower body negative pressure increases sympathetic nerve activity. Therefore, investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure and sympathetic nerve activity at baseline and after rhythmic handgrip exercise plus lower body negative pressure (LBNP) for 2 minutes.; Other Name: LBNP; Drug: Angiotensin II; Investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure and sympathetic nerve activity at baseline and during intravenous infusion of Angiotensin II at the dose of 1, 2, and 3 ng/kg/min for 15 minutes at each dose.; Other Name: IND #103,935

Outcome Measures

Primary Outcome Measures :

1. Forearm Blood Flow [ Time Frame: 12 weeks after each specified medication ]

Secondary Outcome Measures :

1. Blood Pressure During Exercise [ Time Frame: 12 weeks ]
2. Blood Pressure During Angiotensin II Infusion [ Time Frame: 12 weeks after initiation of metoprolol ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Stage I hypertension (140-159/90-99 mmHg)
• Men and women age 18-65

Exclusion Criteria:

• Congestive heart failure or coronary artery disease
• Blood pressure averaging >159/99 mmHg or resting heart rate < 55 bpm
• Serum creatinine > 1.4 mg/dL
• Asthma or chronic obstructive pulmonary diseases
• Left ventricular hypertrophy by echocardiography or ECG
• Pregnancy
• Hypersensitivity to beta blockers, microbubble contrast agents, or angiotensin
• Any history of substance abuse (other than tobacco)
• Concomitant drug treatment which raises endogenous nitric oxide levels such as nitrates or phosphodiesterase V inhibitors (Viagra, Levitra, or Cialis)
• History of symptomatic bradycardia or heart block

Contacts and Locations

Locations

United States, Texas

UT Southwestern Medical Center

Dallas, Texas, United States, 75390

Sponsors and Collaborators

University of Texas Southwestern Medical Center

Forest Laboratories

Investigators

• Principal Investigator: Wanpen Vongpatanasin, MD; UT Southwestern Medical Center

  Study Documents (Full-Text)

Documents provided by University of Texas Southwestern Medical Center:

Study Protocol and Statistical Analysis Plan  [PDF] July 25, 2008

More Information

Publications:

Rosenmeier JB, Dinenno FA, Fritzlar SJ, Joyner MJ. alpha1- and alpha2-adrenergic vasoconstriction is blunted in contracting human muscle. J Physiol. 2003 Mar 15;547(Pt 3):971-6. Epub 2003 Feb 14.

Hansen J, Sander M, Thomas GD. Metabolic modulation of sympathetic vasoconstriction in exercising skeletal muscle. Acta Physiol Scand. 2000 Apr;168(4):489-503. Review.

Thomas GD, Sander M, Lau KS, Huang PL, Stull JT, Victor RG. Impaired metabolic modulation of alpha-adrenergic vasoconstriction in dystrophin-deficient skeletal muscle. Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):15090-5.

Thomas GD, Zhang W, Victor RG. Impaired modulation of sympathetic vasoconstriction in contracting skeletal muscle of rats with chronic myocardial infarctions: role of oxidative stress. Circ Res. 2001 Apr 27;88(8):816-23.

Chavoshan B, Sander M, Sybert TE, Hansen J, Victor RG, Thomas GD. Nitric oxide-dependent modulation of sympathetic neural control of oxygenation in exercising human skeletal muscle. J Physiol. 2002 Apr 1;540(Pt 1):377-86.

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.

Murphey LJ, Morrow JD, Sawathiparnich P, Williams GH, Vaughan DE, Brown NJ. Acute angiotensin II increases plasma F2-isoprostanes in salt-replete human hypertensives. Free Radic Biol Med. 2003 Oct 1;35(7):711-8.

Dijkhorst-Oei LT, Stroes ES, Koomans HA, Rabelink TJ. Acute simultaneous stimulation of nitric oxide and oxygen radicals by angiotensin II in humans in vivo. J Cardiovasc Pharmacol. 1999 Mar;33(3):420-4.

Vittorio TJ, Lang CC, Katz SD, Packer M, Mancini DM, Jorde UP. Vasopressor response to angiotensin II infusion in patients with chronic heart failure receiving beta-blockers. Circulation. 2003 Jan 21;107(2):290-3.

Oelze M, Daiber A, Brandes RP, Hortmann M, Wenzel P, Hink U, Schulz E, Mollnau H, von Sandersleben A, Kleschyov AL, Mülsch A, Li H, Förstermann U, Münzel T. Nebivolol inhibits superoxide formation by NADPH oxidase and endothelial dysfunction in angiotensin II-treated rats. Hypertension. 2006 Oct;48(4):677-84. Epub 2006 Aug 28.

Fratta Pasini A, Garbin U, Nava MC, Stranieri C, Davoli A, Sawamura T, Lo Cascio V, Cominacini L. Nebivolol decreases oxidative stress in essential hypertensive patients and increases nitric oxide by reducing its oxidative inactivation. J Hypertens. 2005 Mar;23(3):589-96.

Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003 May 21;289(19):2560-72. Epub 2003 May 14. Erratum in: JAMA. 2003 Jul 9;290(2):197.

Klingbeil AU, Schobel H, Langenfeld MR, Hilgers K, Schäufele T, Schmieder RE. Hyper-responsiveness to angiotensin II is related to cardiac structural adaptation in hypertensive subjects. J Hypertens. 1999 Jun;17(6):825-33.

Hopkins PN, Hunt SC, Jeunemaitre X, Smith B, Solorio D, Fisher ND, Hollenberg NK, Williams GH. Angiotensinogen genotype affects renal and adrenal responses to angiotensin II in essential hypertension. Circulation. 2002 Apr 23;105(16):1921-7.

Vuagnat A, Giacché M, Hopkins PN, Azizi M, Hunt SC, Vedie B, Corvol P, Williams GH, Jeunemaitre X. Blood pressure response to angiotensin II, low-density lipoprotein cholesterol and polymorphisms of the angiotensin II type 1 receptor gene in hypertensive sibling pairs. J Mol Med (Berl). 2001 May;79(4):175-83.

Matsukawa T, Miyamoto T. Does infusion of ANG II increase muscle sympathetic nerve activity in patients with primary aldosteronism? Am J Physiol Regul Integr Comp Physiol. 2008 Jun;294(6):R1873-9. doi: 10.1152/ajpregu.00471.2007. Epub 2008 Mar 26.

Nodari S, Metra M, Dei Cas L. Beta-blocker treatment of patients with diastolic heart failure and arterial hypertension. A prospective, randomized, comparison of the long-term effects of atenolol vs. nebivolol. Eur J Heart Fail. 2003 Oct;5(5):621-7.

Van Bortel LM, van Baak MA. Exercise tolerance with nebivolol and atenolol. Cardiovasc Drugs Ther. 1992 Jun;6(3):239-47.

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

Price A, Raheja P, Wang Z, Arbique D, Adams-Huet B, Mitchell JH, Victor RG, Thomas GD, Vongpatanasin W. Differential effects of nebivolol versus metoprolol on functional sympatholysis in hypertensive humans. Hypertension. 2013 Jun;61(6):1263-9. doi: 10.1161/HYPERTENSIONAHA.113.01302. Epub 2013 Apr 1.

• Responsible Party: University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT01502787
• Other Study ID Numbers: STU 062011-072
• First Posted: January 2, 2012
• Results First Posted: December 31, 2014
• Last Update Posted: July 7, 2020
• Last Verified: July 2020

Keywords provided by University of Texas Southwestern Medical Center:

hypertension; blood pressure; blood pressure medications; metoprolol; nebivolol; handgrip exercise; lower body negative pressure; angiotensin II; sympathetic nerve activity; flow mediated dilation; nitric oxide; microneurography

Additional relevant MeSH terms:

Hypertension; Vascular Diseases; Cardiovascular Diseases; Metoprolol; Nebivolol; Angiotensin II; Giapreza; Angiotensinogen; 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; Vasoconstrictor Agents; Serine Proteinase Inhibitors; Protease Inhibitors; Enzyme Inhibitors