Glucocorticoids Activate Cardiac Mineralocorticoid Receptors During Experimental Myocardial Infarction

Abstract

Abstract-Myocardial ischemia-reperfusion leads to significant changes in redox state, decreased postischemic functional recovery, and cardiomyocyte apoptosis, with development and progression of heart failure. Ischemia-reperfusion in the isolated perfused rat heart has been used as a model of heart failure. Clinically, mineralocorticoid receptor blockade in heart failure decreases morbidity and mortality versus standard care alone. The effects of corticosteroids on infarct area and apoptosis were determined in rat hearts subjected to 30 minutes of ischemia and 2.5 hours of reperfusion. Both aldosterone and cortisol increased infarct area and apoptotic index, an effect half-maximal between 1 and 10 nM and reversed by spironolactone. Dexamethasone and mifepristone aggravated infarct area and apoptotic index, similarly reversed by spironolactone. Spironolactone alone reduced infarct area and apoptotic index below ischemia-reperfusion alone, in hearts from both intact and adrenalectomized rats. The present study shows that cardiac damage is aggravated by activation of mineralocorticoid receptors by aldosterone or cortisol or of glucocorticoid receptors by dexamethasone.Mifepristone unexpectedly acted as a glucocorticoid receptor agonist, for which there are several precedents. Spironolactone protected cardiomyocytes via inverse agonist activity at mineralocorticoid receptors, an effect near maximal at a relatively low dose (10 nM

Preconditioning actions of aldosterone through p38 signaling modulation in isolated rat hearts

“…In agreement with these findings, the present ex vivo study demonstrated the rapid, favorable effects of aldosterone on cardiac functional recovery and injury during ischemia-reperfusion, although aldosterone did not affect the baseline cardiac function (Table 1), congruent with the findings of previous reports by other groups (Fujita et al 2005, Matsui et al 2007). However, our results do not completely agree with the findings of several other studies showing that rapid, MR-independent actions of aldosterone induce positive inotropic effects at baseline (Barbato et al 2002, Chai et al 2005, while the administration of aldosterone results in no significant effects (Chai et al 2005, Schmidt et al 2010, but rather results in detrimental effects (Fujita et al 2005, Mihailidou et al 2009) on cardiac functional recovery and injury after ischemia-reperfusion. This discrepancy may be explained by the differences in the experimental conditions and the time course of aldosterone stimulation: temporal induction of the aldosterone cascade, at a physiological dose (a relatively lower dose than that commonly used in previous studies), during the pre-ischemic period only (not during the entire IRI protocol) is crucial for the ability of aldosterone to exert favorable effects on the heart during IRI.…”

“…This discrepancy may be explained by the differences in the experimental conditions and the time course of aldosterone stimulation: temporal induction of the aldosterone cascade, at a physiological dose (a relatively lower dose than that commonly used in previous studies), during the pre-ischemic period only (not during the entire IRI protocol) is crucial for the ability of aldosterone to exert favorable effects on the heart during IRI. Mihailidou and colleagues previously demonstrated that spironolactone protects the heart from IRI, not merely by excluding aldosterone and/or glucocorticoids from MR but also via its inverse agonist activity against MR (Mihailidou et al 2009). It is also possible that eplerenone acts as a partial agonist under ligand-free conditions, such as ex vivo isolated heart models.…”

Aldosterone, hypertension and heart failure: insights from clinical trials

“…11 In the failing heart, as in RALES, or post-myocardial infarction, as in EPHESUS, 12 cardiomyocytes show high levels of reactive oxygen species, with accompanying changes in intracellular redox state. In ischemia-reperfusion studies, 13 aldosterone increases area at risk and infarct size in Langendorf (isolated, perfused) preparations of rat hearts. In the same preparations, cortisol-at low nanomolar dosesmimics these aldosterone effects; the effects of aldosterone are blocked by spironolactone and those of cortisol similarly by spironolactone but not by the glucocorticoid receptor/progesterone receptor antagonist RU486.…”

“…Spironolactone not only antagonizes the effects of aldosterone and cortisol, on area-at-risk and apoptotic index, but administered alone is protective-that is, it reduces the area at risk and apoptotic index below control (no added steroid) levels. 13 It does this in hearts from both intact and adrenalectomized rats, and at low nanomolar concentrations, by reciprocal actions on key effectors in the apoptotic pathways (AS Mihailidou, unpublished). There is no question that at therapeutic concentrations spironolactone might substantially exclude aldosterone from MR, although given its much higher intracellular levels, excluding cortisol is another question altogether.…”

The case against aldosterone: not proven

“…Normally the physiologic glucocorticoids block the MRmediated effects of aldosterone; in tissue damage, however, they mimic them, as recently shown to be the case in cardiac ischemia-reperfusion studies [5].…”