Pharmacodynamics
Conditions
Keywords
healthy
Brief summary
Various studies have reported cardioprotective effects of mineralocorticoid receptor (MR) antagonists in the setting of an acute myocardial infarction. In a recent animal study, the protective effect of MR antagonists on infarct size was completely abolished in CD73 knock-out and adenosine A2b receptor knock-out mice, and by co-administration of adenosine receptor antagonists in rats. These findings suggest that extracellular formation of adenosine is crucial for this protective effect and that MR antagonists stimulate extracellular adenosine formation by the enzyme CD73. To investigate whether eplerenone promotes adenosine receptor stimulation by activating CD73, the investigators will measure forearm blood flow in response to various dosages of dipyridamole with the use of plethysmography. Dipyridamole increases the extracellular endogenous adenosine concentration by inhibition of the ENT transporter and induces local vasodilation. Therefore, the vasodilator effect of dipyridamole accurately reflects extracellular adenosine formation by the CD73 enzyme.
Interventions
DRUGEplerenone
2 tabs of eplerenone 25 mg will be over-encapsulated and a fully mimicking placebo will be provided by the department of clinical pharmacy of the Radboud University Medical Centre Nijmegen
DRUGPlacebo
Sponsors
Radboud University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
* Male sex * Age 18-40 years * Healthy * Written informed consent
Exclusion criteria
* Smoking * Hypertension (Blood pressure \>140 mmHg and/or \>90 mmHg - SBP/DBP-) * Hypotension (Blood pressure \<100 mmHg and/or \<60 mmHg -SBP/DBP-) * Diabetes Mellitus (fasting glucose \> 6.9 mmol/L or random \> 11.0 mmol/L in venous plasma) * History of any cardiovascular disease * Angina pectoris * History of chronic obstructive pulmonary disease (COPD) or asthma * Alcohol and/or drug abuse * Concomitant use of medication * Renal dysfunction (MDRD \< 60 ml/min/1.73 m2) * Liver enzyme abnormalities (ALAT \> twice upper limit of normality) * Serum potassium ≥ 4.8 mmol/L * Fasting total cholesterol \> 6.0 mmol/L * Second/third degree AV-block on electrocardiography
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| forearm blood flow response | 8 days | Forearm blood flow response to the intrabrachial administration of incremental dosages of dipyridamole, after treatment with eplerenone, compared to placebo. The forearm blood flow will be measured by plethysmography. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| forearm blood flow | 8 days | Forearm blood flow response to the intrabrachial administration of incremental dosages of dipyridamole, with and without caffeine, after eplerenone treatment. The forearm blood flow will be measured by plethysmography. |
Other
| Measure | Time frame | Description |
|---|---|---|
| 24 hours urine sample | 1 day | Twenty-four hours urine samples will be collected and sodium and creatinine will be determined, to ensure that salt intake is approximately the same during both treatment days. |
Countries
Netherlands
Outcome results
None listed