Region-specific mechanisms of corticosteroid-mediated inotropy in rat cardiomyocytes

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.