Effects of Nebivolol on Skeletal Muscle During Exercise in Hypertensive Patients

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.

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.