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The effect of eplerenone on adenosine formation in humans in vivo: a double-blinded randomised controlled study.

van den Berg TN, Deinum J, Bilos A, Donders AR, Rongen GA, Riksen NP - PLoS ONE (2014)

Bottom Line: Using gene deletion and pharmacological approaches, it has been shown that extracellular formation of the endogenous nucleoside adenosine is crucial for this protective effect.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology-Toxicology, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.

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.

Methods and 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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov, NCT01837108.

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Related in: MedlinePlus

FBF response to dipyridamole, without and with caffeine.FBF response to A dipyridamole and B dipyridamole (D) in incremental dosages during concomitant administration of caffeine (C) in a constant dosage of 90 µg·dL−1·min−1, during placebo (grey) and eplerenone (black) treatment in the experimental (filled squares) and non-experimental (open squares) arm.
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pone-0111248-g003: FBF response to dipyridamole, without and with caffeine.FBF response to A dipyridamole and B dipyridamole (D) in incremental dosages during concomitant administration of caffeine (C) in a constant dosage of 90 µg·dL−1·min−1, during placebo (grey) and eplerenone (black) treatment in the experimental (filled squares) and non-experimental (open squares) arm.

Mentions: Baseline FBF before intra-arterial infusion of dipyridamole was 1.34 (0.82) ml·dl−1·min−1 during placebo and 1.47 (1.05) ml·dl−1·min−1 during eplerenone treatment. The incremental dosages of dipyridamole increased FBF in the experimental arm to 1.63 (0.60), 2.13 (1.51) and 2.71 (1.32) ml·dl−1·min−1, and 2.00 (1.45), 2.68 (1.87) and 3.22 (1.94) ml·dl−1·min−1 during placebo and eplerenone treatment, respectively. There was no significant increase in FBF response to dipyridamole during eplerenone treatment compared to the placebo experiment (Figure 3A; p = 0.51). Similarly, the FBF ratio did not differ between placebo and eplerenone treatment (p = 0.79). In none of the experiments changes in FBF in the non-experimental arm were observed.


The effect of eplerenone on adenosine formation in humans in vivo: a double-blinded randomised controlled study.

van den Berg TN, Deinum J, Bilos A, Donders AR, Rongen GA, Riksen NP - PLoS ONE (2014)

FBF response to dipyridamole, without and with caffeine.FBF response to A dipyridamole and B dipyridamole (D) in incremental dosages during concomitant administration of caffeine (C) in a constant dosage of 90 µg·dL−1·min−1, during placebo (grey) and eplerenone (black) treatment in the experimental (filled squares) and non-experimental (open squares) arm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214740&req=5

pone-0111248-g003: FBF response to dipyridamole, without and with caffeine.FBF response to A dipyridamole and B dipyridamole (D) in incremental dosages during concomitant administration of caffeine (C) in a constant dosage of 90 µg·dL−1·min−1, during placebo (grey) and eplerenone (black) treatment in the experimental (filled squares) and non-experimental (open squares) arm.
Mentions: Baseline FBF before intra-arterial infusion of dipyridamole was 1.34 (0.82) ml·dl−1·min−1 during placebo and 1.47 (1.05) ml·dl−1·min−1 during eplerenone treatment. The incremental dosages of dipyridamole increased FBF in the experimental arm to 1.63 (0.60), 2.13 (1.51) and 2.71 (1.32) ml·dl−1·min−1, and 2.00 (1.45), 2.68 (1.87) and 3.22 (1.94) ml·dl−1·min−1 during placebo and eplerenone treatment, respectively. There was no significant increase in FBF response to dipyridamole during eplerenone treatment compared to the placebo experiment (Figure 3A; p = 0.51). Similarly, the FBF ratio did not differ between placebo and eplerenone treatment (p = 0.79). In none of the experiments changes in FBF in the non-experimental arm were observed.

Bottom Line: Using gene deletion and pharmacological approaches, it has been shown that extracellular formation of the endogenous nucleoside adenosine is crucial for this protective effect.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology-Toxicology, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.

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.

Methods and 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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov, NCT01837108.

Show MeSH
Related in: MedlinePlus