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(Circulation Research. 1999;85:168-173.)
© 1999 American Heart Association, Inc.

Original Contribution

Glucocorticoid Regulation of Cardiac K⁺ Currents and L-Type Ca²⁺ Current in Neonatal Mice

Li Wang, Zhong-Ping Feng, Henry J. Duff

From the Cardiovascular Research Group, Department of Medicine, University of Calgary, Alberta, Canada.

Correspondence to H.J. Duff, MD, FRCPC, Department of Medicine, University of Calgary, 3330 Hospital Dr NW, Calgary, Alberta, Canada T2N 4N1. E-mail hduff{at}ucalgary.ca

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.

Key Words: dexamethasone • K⁺ current • L-type Ca²⁺ current • action potential duration • mice

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