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

This study has been completed.
Sponsor:
Collaborator:
Forest Laboratories
Information provided by (Responsible Party):
Wanpen Vongpatanasin, University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier:
NCT01502787
First received: November 1, 2011
Last updated: May 27, 2014
Last verified: May 2014
  Purpose

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 Intervention 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

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 Versus Metoprolol on Blood Flow Responses to Exercise and Angiotensin II in Hypertensive Patients

Resource links provided by NLM:


Further study details as provided by University of Texas Southwestern Medical Center:

Primary Outcome Measures:
  • Forearm blood flow [ Time Frame: 12 weeks after initiation of metoprolol ] [ Designated as safety issue: No ]
  • Forearm blood flow [ Time Frame: 12 weeks after initiation of nebivolol ] [ Designated as safety issue: No ]
  • Sympathetic nerve activity (SNA) during exercise [ Time Frame: 12 weeks after initiation of metoprolol ] [ Designated as safety issue: No ]
  • Sympathetic nerve activity (SNA) during exercise [ Time Frame: 12 weeks after initiation of nebivolol ] [ Designated as safety issue: No ]
  • Sympathetic nerve activity (SNA) during Angiotensin II infusion [ Time Frame: 12 weeks after initiation of metoprolol ] [ Designated as safety issue: No ]
  • Sympathetic nerve activity (SNA) during Angiotensin II infusion [ Time Frame: 12 weeks after initiation of nebivolol ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Blood pressure during exercise [ Time Frame: 12 weeks after initiation of metoprolol ] [ Designated as safety issue: No ]
  • Blood pressure during exercise [ Time Frame: 12 weeks after initiation of nebivolol ] [ Designated as safety issue: No ]
  • Blood pressure during Angiotensin II infusion [ Time Frame: 12 weeks after initiation of metoprolol ] [ Designated as safety issue: No ]
  • Blood pressure during Angiotensin II infusion [ Time Frame: 12 weeks after initiation of nebivolol ] [ Designated as safety issue: No ]

Enrollment: 46
Study Start Date: April 2009
Study Completion Date: June 2013
Primary Completion Date: June 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 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

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.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
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
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01502787

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
  More Information

Publications:

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Wanpen Vongpatanasin, Associate Professor, University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier: NCT01502787     History of Changes
Other Study ID Numbers: Bystolic MD19
Study First Received: November 1, 2011
Last Updated: May 27, 2014
Health Authority: United States: Institutional Review Board

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
Angiotensin II
Metoprolol
Nebivolol
Metoprolol succinate
Vasoconstrictor Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
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

ClinicalTrials.gov processed this record on August 27, 2014