Nebivolol and the Endothelin (ET)-1 System

1. The investigators hypothesize that nebivolol will reduce ET-1-mediated vasoconstrictor
tone in adult humans with elevated blood pressure to a greater extent than either
metoprolol or placebo.

2. The investigators further hypothesize that reducing ET-1 vasoconstrictor activity
contributes to the improvement in endothelial vasodilator function associated with
nebivolol.

Inclusion Criteria:

- Subjects will be men and women of all races and ethnic backgrounds aged 45-65 years.

- Subjects will be prehypertensive/hypertensive defined as resting systolic blood
pressure >130 mmHg and < 160 mm Hg and/or diastolic blood pressure >80 mmHg and < 100
mm Hg.

- All of the women in the study will be postmenopausal (at least 1 year from last
menstrual cycle) and not receiving hormone replacement therapy (HRT) currently or in
the preceding 3-year period.

- Lastly, candidates will be sedentary as determined from the Stanford Physical Activity
Questionnaire (<35 kcal/wk) and will not have engaged in any program of regular
physical activity for at least 1 year prior to the study.

Exclusion Criteria:

- Candidates who smoke (currently or in the past 7 years), report more than low-risk
alcohol consumption as defined as no more than 14 standard drinks/wk and no more than
4 standard drinks/day for men and 7 standard drinks/wk and 3 standard drinks/day for
women (a standard drink is defined as 12 ounces of beer, 5 ounces of wine, 1½ ounces
of 80-proof distilled spirits)

- Potential candidates who are taking cardiovascular-acting (i.e. statins, blood
pressure medication an aspirin) medications will not be eligible.

- Fasting plasma glucose >126 mg/dL.

- Potential candidates with a resting heart rate of < 50 beats/minute will be excluded.

- Use of hormone replacement therapy.

- In hypertensive subjects, a seated systolic blood pressure greater than 160 mmHg or a
seated diastolic blood pressure greater than 100 mmHg.