Healthy
Conditions
Keywords
Atenolol, Exercise, Genotype, Healthy volunteers
Brief summary
The overall goal of this project is to determine the genetic factors contributing to interindividual differences in response to beta-blockade.
Detailed description
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.
Interventions
DRUGAtenolol (β-blocker)
25 mg tablet
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
National Center for Research Resources (NCRR)
Vanderbilt University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Reduction in Heart Rate | 2 exercise periods of 6 minutes each. 6 minutes of exercise before taking atenolol, and 6 minutes of exercise starting 2.5 hours after taking 25 mg of atenolol (2.5 hours + 6 minutes) | Reduction in heart rate based upon genotype while exercising. Participants exercised on a recumbent bike for 2 minutes at 25W, 2 minutes at 50W, and 2 minutes at 75W twice, once before taking atenolol, and once 2.5 hours after oral administration of 25 mg of atenolol. Data points represent unadjusted mean reduction in heart rate in the 3 genotype groups. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| White Participants--Atenolol Unrelated black and white American subjects were eligible to participate if they were between 18 and 50 years old and had no clinically significant abnormality based on medical history, physical exam, electrocardiogram and routine laboratory testing. Subjects were free of medications for at least 1 week. They also received an alcohol and caffeine free diet for 6 days prior to the study. | 85 |
| Black Participants-Atenolol Unrelated black and white American subjects were eligible to participate if they were between 18 and 50 years old and had no clinically significant abnormality based on medical history, physical exam, electrocardiogram and routine laboratory testing. Subjects were free of medications for at least 1 week. They also received an alcohol and caffeine free diet for 6 days prior to the study | 69 |
| Total | 154 |
Baseline characteristics
| Characteristic | White Participants--Atenolol | Black Participants-Atenolol | Total |
|---|---|---|---|
| Age, Continuous | 27.0 years STANDARD_DEVIATION 6.4 | 25.9 years STANDARD_DEVIATION 6 | 26.5 years STANDARD_DEVIATION 6.2 |
| diastolic blood pressure | 64.0 mmHg STANDARD_DEVIATION 6.8 | 66.2 mmHg STANDARD_DEVIATION 7.5 | 65.0 mmHg STANDARD_DEVIATION 7.1 |
| GRK5 Genotype GLN/GLN | 85 Participants | 29 Participants | 114 Participants |
| GRK5 Genotype GLN/LEU | 0 Participants | 35 Participants | 35 Participants |
| GRK5 Genotype LEU/LEU | 0 Participants | 5 Participants | 5 Participants |
| Region of Enrollment United States | 85 participants | 69 participants | 154 participants |
| Sex: Female, Male Female | 40 Participants | 47 Participants | 87 Participants |
| Sex: Female, Male Male | 45 Participants | 22 Participants | 67 Participants |
| systolic blood pressure | 109.9 mmHg STANDARD_DEVIATION 11.4 | 112.5 mmHg STANDARD_DEVIATION 12.1 | 111.1 mmHg STANDARD_DEVIATION 11.8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 85 | 0 / 69 |
| other Total, other adverse events | 0 / 85 | 0 / 69 |
| serious Total, serious adverse events | 0 / 85 | 0 / 69 |
Outcome results
Primary
Reduction in Heart Rate
Reduction in heart rate based upon genotype while exercising. Participants exercised on a recumbent bike for 2 minutes at 25W, 2 minutes at 50W, and 2 minutes at 75W twice, once before taking atenolol, and once 2.5 hours after oral administration of 25 mg of atenolol. Data points represent unadjusted mean reduction in heart rate in the 3 genotype groups.
Time frame: 2 exercise periods of 6 minutes each. 6 minutes of exercise before taking atenolol, and 6 minutes of exercise starting 2.5 hours after taking 25 mg of atenolol (2.5 hours + 6 minutes)
Population: There are 3 genotypes for GRK5, GLN/GLN, GLN/LEU, and LEU/LEU. A priori analysis plan was to compare reduction in heart rate among the 3 genotypes..
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GLN/GLN | Reduction in Heart Rate | 4 minutes from baseline, 2 minutes exercise at 50W | 11.7 beats per minute | Standard Deviation 7 |
| GLN/GLN | Reduction in Heart Rate | 6 minutes from baseline, 2 minutes exercise at 75W | 14 beats per minute | Standard Deviation 8 |
| GLN/GLN | Reduction in Heart Rate | 0, baseline | 7.9 beats per minute | Standard Deviation 7 |
| GLN/GLN | Reduction in Heart Rate | 2 minutes from baseline, 2 minutes exercise at 25W | 9.6 beats per minute | Standard Deviation 8.2 |
| GLN/LEU | Reduction in Heart Rate | 4 minutes from baseline, 2 minutes exercise at 50W | 10.9 beats per minute | Standard Deviation 7.2 |
| GLN/LEU | Reduction in Heart Rate | 2 minutes from baseline, 2 minutes exercise at 25W | 8.4 beats per minute | Standard Deviation 7.7 |
| GLN/LEU | Reduction in Heart Rate | 6 minutes from baseline, 2 minutes exercise at 75W | 12.4 beats per minute | Standard Deviation 9.1 |
| GLN/LEU | Reduction in Heart Rate | 0, baseline | 6 beats per minute | Standard Deviation 5.9 |
| LEU/LEU | Reduction in Heart Rate | 6 minutes from baseline, 2 minutes exercise at 75W | 10 beats per minute | Standard Deviation 6.1 |
| LEU/LEU | Reduction in Heart Rate | 0, baseline | 3.3 beats per minute | Standard Deviation 5.4 |
| LEU/LEU | Reduction in Heart Rate | 2 minutes from baseline, 2 minutes exercise at 25W | 7.4 beats per minute | Standard Deviation 4.4 |
| LEU/LEU | Reduction in Heart Rate | 4 minutes from baseline, 2 minutes exercise at 50W | 9.1 beats per minute | Standard Deviation 3.4 |