Abstract
BackgroundIt 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 ResultsIn 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.ConclusionIn 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 RegistrationClinicalTrials.gov, NCT01837108
Highlights
Despite state-of-the-art reperfusion strategies, mortality and morbidity in patients with an acute myocardial infarction remain significant
It is unlikely that an increased extracellular adenosine formation contributes to the cardioprotective effect of mineralocorticoid receptor antagonists
A recent series of experiments, using genetic and pharmacological approaches in mouse and rat models of myocardial infarction, convincingly demonstrated that the cardioprotective effects of the mineralocorticoid receptor (MR) antagonists eplerenone and canrenoate were crucially dependent on extracellular adenosine formation by CD73 and adenosine receptor stimulation [6]
Summary
Despite state-of-the-art reperfusion strategies, mortality and morbidity in patients with an acute myocardial infarction remain significant. It has been suggested that the mineralocorticoid receptor (MR) antagonists spironolactone and eplerenone could potentially serve this goal, because these drugs reduce mortality in patients with heart failure [2,3,4]. The underlying mechanisms of the infarct size-limiting effect are not yet fully understood, but it has been suggested that the endogenous purine nucleoside adenosine is crucially involved. A recent series of experiments, using genetic and pharmacological approaches in mouse and rat models of myocardial infarction, convincingly demonstrated that the cardioprotective effects of the MR antagonists eplerenone and canrenoate were crucially dependent on extracellular adenosine formation by CD73 and adenosine receptor stimulation [6]. It has been suggested that mineralocorticoid receptor antagonists have direct cardioprotective properties, because these drugs reduce mortality in patients with heart failure. We 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
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