Eplerenone and Extracellular Adenosine Formation (eplerenone01)

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

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.

Study Overview

• Status: Completed
• Conditions: Pharmacodynamics
• Intervention / Treatment: Drug: Placebo; Drug: Eplerenone

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525EZ
      • Radboud University Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; fully mimicking placebo 50 mg bid during 8 days	Drug: Placebo
Experimental: eplerenone; eplerenone 50 mg bid during 8 days	Drug: Eplerenone; 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; Other Names: Inspra, RVG 29963

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
24 hours urine sample	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.	1 day

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: Niels Riksen, Dr., Radboud University Medical Centre Nijmegen; Study Chair: Gerard Rongen, Prof., Radboud University Medical Centre Nijmegen

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): January 1, 2014

Study Registration Dates

• First Submitted: April 12, 2013
• First Submitted That Met QC Criteria: April 17, 2013
• First Posted (Estimate): April 22, 2013

Study Record Updates

• Last Update Posted (Estimate): January 9, 2014
• Last Update Submitted That Met QC Criteria: January 8, 2014
• Last Verified: April 1, 2013

More Information

Terms related to this study

• Keywords: healthy
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Antihypertensive Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Eplerenone
• Other Study ID Numbers: NL43234.091.13