Genetic Determinants of Response to Beta Blockade

The Aim is to define the contribution of genetic variation to the interindividual variability
in response to β-blockade. The rationale for the study is as follows: Beta-blockers prevent
the activation of β-ARs and thus form the cornerstone of treatment of pathological states
such as congestive heart failure and coronary artery disease. Functional polymorphisms in
cardiac beta-receptors have been shown to determine response to β-blocker therapy. A
physiologic stimulus such as exercise causes sympathetic stimulation and activation of the
cardiac β-ARs and genotypic differences in response to β-blockers are magnified under states
of heightened sympathetic activity. Thus, in addition to measuring the response to β-blockers
at rest, we will also determine the response to β-blockade after sub-maximal exercise on a
supine bicycle ergometer. Genetic variations that may alter sensitivity to a beta blocker
will be sought.

Inclusion Criteria:

- Subject must be willing to give written informed consent and be able to adhere to diet
and study schedules.

- Subjects must be free of any clinically significant disease that requires a
physician's care and/or would interfere with the study evaluations.

- Subjects must have a clinically acceptable physical examination and ECG.

- Laboratory tests (CBC, blood chemistries, and urinalysis) must be within clinically
acceptable limits.

Exclusion Criteria:

- Any subject who has taken any prescription or over-the-counter drugs, other than oral
contraception if female, within one week prior to study drug administration.

- Subjects who are presently, or were formerly, narcotic addicts or alcoholics.

- Active smokers.

- Subjects who have a clinically significant allergy/intolerance to atenolol.

- Females with a positive serum/urine pregnancy test at screening.

- Females who are nursing.

- Subjects with complete heart block/ any other significant cardiovascular disease.

- Subjects with a history of asthma symptoms or medication for it within last 10 years.

- Subjects who have a systolic blood pressure < 90 mm Hg or diastolic blood pressure <
50 mm Hg or heart rate < 50/min at the screening visit or on the baseline pre drug
values on the study day.