Regulation of expression of the [3H]-dofetilide binding site associated with the delayed rectifier K+ channel by dexamethasone in neonatal mouse ventricle.

Developmental shortening of cardiac action potential duration in mouse appears to result, at least in part, from replacement of the rapid component of the delayed rectifying potassium current (IKr) with the transient outward current (ItO1). This developmental decrease in the IKr current density was paralleled by a loss of the high affinity [3H]-dofetilide binding site and loss of prolongation of action potential duration by dofetilide. Since glucocorticoid treatment prevented the developmental shortening of action potential duration in rats in the perinatal period, we hypothesized that chronic dexamethasone treatment would alter the developmental loss of IKr channel expression in mice. Accordingly, 10-day-old mice were randomly allocated to chronic in vivo dexamethasone treatment (1 mg/kg) or placebo treatment for 3-5 days. At 15 days of life, transmembrane action potentials were recorded in right ventricular endocardium and [3H]-dofetilide equilibrium binding studies were performed. The baseline action potential duration in the dexamethasone-treated animals was significantly greater than that in the control group (66+/-3 v 54+/-10 ms, respectively; P<0.01). Moreover, dofetilide significantly prolonged action potential duration in the dexamethasone-treated animals, but had no effect on the placebo-treated group (P<0.01). In addition, a high affinity [3H]-dofetilide binding site (Kd 96+/-21 nM and Bmax 69+/-13 fmoles/mg protein) was observed in the dexamethasone-treated group (n=5), whereas no specific [3H]-dofetilide binding was observed in the placebo-treated group. In conclusion, dexamethasone modulates developmental regulation of IKr channel expression in mouse ventricle.