Genetic Determinants of Response to Beta Blockade

The overall goal of this project is to determine the genetic factors contributing to interindividual differences in 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.