Hypertension
Conditions
Keywords
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
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.
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.
Interventions
DRUGMetoprolol 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.
DRUGNebivolol
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.
PROCEDUREForearm 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).
PROCEDUREMicroneurography
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.
PROCEDURERhythmic 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.
PROCEDURELower 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.
DRUGAngiotensin 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.
Sponsors
Forest Laboratories
University of Texas Southwestern Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Forearm Blood Flow | 12 weeks after each specified medication |
Secondary
| Measure | Time frame |
|---|---|
| Blood Pressure During Exercise | 12 weeks |
| Blood Pressure During Angiotensin II Infusion | 12 weeks after initiation of metoprolol |
Countries
United States
Participant flow
Recruitment details
25 subjects were screened but failed to meet inclusion criteria and were not included in treatment groups
Participants by arm
| Arm | Count |
|---|---|
| All Participants 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 , 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. | 21 |
| Total | 21 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 54 years STANDARD_DEVIATION 13.74 |
| Region of Enrollment United States | 21 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 21 | 0 / 21 |
| serious Total, serious adverse events | 0 / 21 | 0 / 21 |
Outcome results
Primary
Forearm Blood Flow
Time frame: 12 weeks after each specified medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| First Intervention Metoprolol: 12 Weeks | Forearm Blood Flow | 96 ml/min | Standard Deviation 1 |
| Second Intervention Nebivolol: 24 Weeks | Forearm Blood Flow | 105 ml/min | Standard Deviation 13 |
Secondary
Blood Pressure During Angiotensin II Infusion
Time frame: 12 weeks after initiation of metoprolol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| First Intervention Metoprolol: 12 Weeks | Blood Pressure During Angiotensin II Infusion | 114 mmHg | Standard Error 3 |
| Second Intervention Nebivolol: 24 Weeks | Blood Pressure During Angiotensin II Infusion | 113 mmHg | Standard Error 3 |
Secondary
Blood Pressure During Exercise
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| First Intervention Metoprolol: 12 Weeks | Blood Pressure During Exercise | 101 mmHg | Standard Error 3 |
| Second Intervention Nebivolol: 24 Weeks | Blood Pressure During Exercise | 103 mmHg | Standard Error 3 |