Regional differences in ion channel activity in the heart control the sequence of repolarization and may contribute to differences in contraction. Corticosteroids such as aldosterone or corticosterone increase the L-type Ca 2+ current (I CaL ) in the heart via the mineralocorticoid receptor (MR). Here, we investigate the differential impact of corticosteroid-mediated increase in I CaL on action potentials (AP), ion currents, intracellular Ca 2+ handling and contractility in endo- and epicardial myocytes of the rat left ventricle. Dexamethasone led to a similar increase in I CaL in endocardial and epicardial myocytes, while the K + currents I to and I K were unaffected. However, AP duration (APD) and AP-induced Ca 2+ influx (Q Ca ) significantly increased exclusively in epicardial myocytes, thus abrogating the normal differences between the groups. Dexamethasone increased Ca 2+ transients, contractility and SERCA activity in both regions, the latter possibly due to a decrease in total phospholamban (PLB) and an increase PLBpThr17. These results suggest that corticosteroids are powerful modulators of I CaL , Ca 2+ transients and contractility in both endo- and epicardial myocytes, while APD and Q Ca are increased in epicardial myocytes only. This indicates that increased I CaL and SERCA activity rather than Q Ca are the primary drivers of contractility by adrenocorticoids.