title: The effect of eplerenone on adenosine formation in humans in vivo: a double-blinded randomised controlled study.
abstract: BACKGROUND
  It has been suggested that mineralocorticoid receptor antagonists have direct cardioprotective properties, because these drugs reduce mortality in patients with heart failure. In murine models of myocardial infarction, mineralocorticoid receptor antagonists reduce infarct size. Using gene deletion and pharmacological approaches, it has been shown that extracellular formation of the endogenous nucleoside adenosine is crucial for this protective effect. We now aim to translate this finding to humans, by investigating the effects of the selective mineralocorticoid receptor antagonist eplerenone on the vasodilator effect of the adenosine uptake inhibitor dipyridamole, which is a well-validated surrogate marker for extracellular adenosine formation.
  
  
  RESULTS
  In a randomised, double-blinded, placebo-controlled, cross-over study we measured the forearm blood flow response to the intrabrachial administration of dipyridamole in 14 healthy male subjects before and after treatment with placebo or eplerenone (50 mg bid for 8 days). The forearm blood flow during administration of dipyridamole (10, 30 and 100 µg·min(-1)·dl(-1)) was 1.63 (0.60), 2.13 (1.51) and 2.71 (1.32) ml·dl(-1)·min(-1) during placebo use, versus 2.00 (1.45), 2.68 (1.87) and 3.22 (1.94) ml·dl(-1)·min(-1) during eplerenone treatment (median (interquartile range); P = 0.51). Concomitant administration of the adenosine receptor antagonist caffeine attenuated dipyridamole-induced vasodilation to a similar extent in both groups. The forearm blood flow response to forearm ischemia, as a stimulus for increased formation of adenosine, was similar during both conditions.
  
  
  CONCLUSIONS
  In a dosage of 50 mg bid, eplerenone does not augment extracellular adenosine formation in healthy human subjects. Therefore, it is unlikely that an increased extracellular adenosine formation contributes to the cardioprotective effect of mineralocorticoid receptor antagonists.
  
  
  BACKGROUND
  ClinicalTrials.gov, NCT01837108.
authors.affiliation: Department of Pharmacology-Toxicology, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: T N A
authors.initials: TN
authors.lastname: van den Berg
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Deinum
authors.affiliation: Department of Pharmacology-Toxicology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Bilos
authors.affiliation: Department for Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: A Rogier T
authors.initials: AR
authors.lastname: Donders
authors.affiliation: Department of Pharmacology-Toxicology, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Rongen
authors.affiliation: Department of Pharmacology-Toxicology, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Niels P
authors.initials: NP
authors.lastname: Riksen
mesh_terms: D000241:Adenosine / Q000096:biosynthesis*; D002110:Caffeine / Q000494:pharmacology; D004176:Dipyridamole / Q000494:pharmacology; D004311:Double-Blind Method; D000077545:Eplerenone; D005542:Forearm / Q000098:blood supply; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006940:Hyperemia / Q000503:physiopathology; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D013148:Spironolactone / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D009599:Nitroprusside; D013148:Spironolactone; D002110:Caffeine; D004176:Dipyridamole; D000077545:Eplerenone; D000241:Adenosine