Effects of Nebivolol on Skeletal Muscle During Exercise in Hypertensive Patients
Effects of Nebivolol on Microvascular Perfusion in the Skeletal Muscles During Exercise in Hypertensive Patients
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.
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.
- Men and women with stage I primary untreated hypertension (BP between 140-159/90-99
- Age 18-65
- 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.