Glucocorticoid regulation of cardiac K+ currents and L-type CA2+ current in neonatal mice

Abstract

Previous studies have reported that dexamethasone (Dex) prolongs cardiac action potential repolarization in mice and rats. However, the cellular mechanisms of this effect have not been addressed. Because action potential duration is influenced by a complex interplay of both inward and outward currents, this study evaluated the role of K+ currents and the L-type Ca2+ current in response to chronic in vivo Dex treatment. Accordingly, neonatal mice were randomly allocated to treatment with Dex (1 mg/kg per day) or placebo (saline) given subcutaneously for 5 days. At 14 to 15 days of age, the L-type Ca2+ current and K+ currents were recorded in ventricular myocytes using whole-cell patch-clamp techniques. The density of peak outward K+ currents was significantly decreased in the chronic Dex-treated group, but the current measured at the end of a 1-second depolarization pulse was similar in both groups. We further measured the magnitudes of the fast- inactivating (I(to)) and the slowly inactivating (I(slow)) currents that contribute to the peak outward K+ currents. I(to) was reduced from 17.5±3.0 pA/pF (control) to 10.6±2.5 pA/pF (Dex) at +50 mV (P<0.05), but I(slow) was not significantly different. These data suggest that downregulation of I(to) is responsible for the reduced peak outward current. Time courses of the onset and offset of in vivo Dex effects were also assessed. A period of 3 days of treatment was required to observe the Dex effect on peak outward K+ currents, whereas a 7-day period after discontinuation of Dex was required to recover the baseline current density. Acute in vitro treatment with Dex (1 μmol/L) had no effect on K+ current densities. In addition, chronic Dex treatment significantly increased the density of the L-type Ca2+ current (I(Ca-L)) from -7.2±0.5 pA/pF of control to -8.9±0.6 pA/pF of Dex at + 10 mV, P<0.05. In conclusion, chronic in vivo Dex treatment decreases I(to) and increases I(Ca-L) in neonatal mouse ventricular myocytes, both of which contribute to the prolongation of cardiac action potential repolarization induced by glucocorticoids.