Clinical trial NCT01837108: Eplerenone and Extracellular Adenosine Formation
Official title: Effects of the Selective Mineralocorticoid Receptor Antagonist Eplerenone on Extracellular Adenosine Formation in Humans in Vivo
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Pharmacodynamics
Keywords: healthy
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
First posted: 2013-04-22
Enrollment: 14
Sex: MALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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.


Eligibility criteria: 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

Primary outcomes:
measure: forearm blood flow response
timeFrame: 8 days
Secondary outcomes:
measure: forearm blood flow
timeFrame: 8 days
measure: forearm blood flow
timeFrame: 8 days
Other outcomes:
measure: 24 hours urine sample
timeFrame: 1 day
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Centre
state: Gelderland
Study officials:
affiliation: Radboud University Medical Centre Nijmegen
name: Niels Riksen, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Radboud University Medical Centre Nijmegen
name: Gerard Rongen, Prof.
role: STUDY_CHAIR
References:
citation: van den Berg TN, Deinum J, Bilos A, Donders AR, Rongen GA, Riksen NP. The effect of eplerenone on adenosine formation in humans in vivo: a double-blinded randomised controlled study. PLoS One. 2014 Oct 30;9(10):e111248. doi: 10.1371/journal.pone.0111248. eCollection 2014.