In this issue of Hypertension , Mihailidou et al1 provide important new information regarding the role of corticosteroids in myocardial infarction (MI). These findings are timely and of particular relevance because mineralocorticoid receptor (MR) antagonists are now thought to be among the first drugs used for treatment after MI along with angiotensin-converting enzyme inhibitors, β-blockers, and aspirin. The authors found in an ex vivo model of regional myocardial ischemia (30 minutes) followed by reperfusion with Krebs-Henseleit buffer (2.5 hours) that aldosterone or cortisol infusion could increase infarct size. These effects were blocked by spironolactone, suggesting that both of these corticosteroids act to promote damage through MR stimulation. Dexamethasone and mifepristone (RU486), a glucocorticoid receptor (GR)/progesterone receptor antagonist, also increased infarct size, and, surprisingly, both of these effects were reversed by spironolactone as well. However, spironolactone alone had a protective effect against reperfusion injury in the absence of aldosterone or cortisol infusion suggestive of a direct, inverse agonist action. The ability of spironolactone to decrease baseline infarct size was maintained in hearts from animals that were adrenalectomized 2 to 5 days earlier and provides strong evidence that the mechanism of the protective effect of spironolactone is not dependent on the presence of endogenous corticosteroids. These studies expand our view on the role of corticosteroids in end-organ damage and how MR antagonists may work to provide cardiac protection. The present study is consistent with the observations of Dorrance et al,2 who found that spironolactone treatment reduced the size of cerebral infarcts in stroke-prone spontaneously hypertensive rats subjected to permanent middle cerebral artery occlusion. Triphenyl-tetrazolium chloride staining was used to assess viable tissue in both of these studies. Several studies have described the ability of chronic in vivo treatment with spironolactone …