Eplerenone and Extracellular Adenosine Formation

Study Overview
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Brief Summary
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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.

Official Title
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Effects of the Selective Mineralocorticoid Receptor Antagonist Eplerenone on Extracellular Adenosine Formation in Humans in Vivo

Conditions
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Pharmacodynamics

Intervention / Treatment
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* Drug: Eplerenone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>fully mimicking placebo 50 mg bid during 8 days | Drug: Placebo<br> <br> |
| Experimental: eplerenone<br>eplerenone 50 mg bid during 8 days | Drug: Eplerenone<br>* 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<br>* Other names: Inspra, RVG 29963;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| forearm blood flow response | 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. | 8 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| forearm blood flow | 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. | 8 days | 
| forearm blood flow | Forearm blood flow to incremental periods of arterial occlusion. The forearm blood flow will be measured by plethysmography. | 8 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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healthy