REGULATION OF EXPRESSION OF THE [H-3] DOFETILIDE BINDING-SITE ASSOCIATED WITH THE DELAYED RECTIFIER K+ CHANNEL BY DEXAMETHASONE IN NEONATALMOUSE VENTRICLE

Developmental shortening of cardiac action potential duration in mouse appears to result, at least in part, from replacement of the rapid co mponent of the delayed rectifying potassium current (I-Kr) with the tr ansient outward current (I-tOl) This developmental decrease in the I-K r current density was paralleled by a loss of the high affinity [H-3]- dofetilide binding site and loss of prolongation of action potential d uration by dofetilide. Since glucocorticoid treatment prevented the de velopmental shortening of action potential duration in rats in the per inatal period, we hypothesized that chronic dexamethasone treatment wo uld alter the developmental loss of I-Kr channel expression in mice. A ccordingly 10-day-old mice were randomly allocated to chronic in vivo dexamethasone treatment (1 mg/kg) or placebo treatment for 3-5 days. A t 15 days of life, transmembrane action potentials were recorded in ri ght ventricular endocardium and [H-3]-dofetilide equilibrium binding s tudies were performed. The baseline action potential duration in the d examethasone-treated animals was significantly greater than that in th e control group (66 +/- 3 upsilon 54 +/- 10 ms, respectively; P<0.01). Moreover, dofetilide significantly prolonged action potential duratio n in the dexamethasone-treated animals, but had no effect on the place bo-treated group (P<0.01). In addition, a high affinity [H-3]-dofetili de binding site (Kd 96 +/- 21 nM and Bmax 69 +/- 13 fmoles/mg protein) was observed in the dexamethasone-treated group (n=5), whereas no spe cific [H-3]-dofetilide binding was observed in the placebo-treated gro up. In conclusion, dexamethasone modulates developmental regulation of I-Kr channel expression in mouse ventricle. (C) 1997 Academic Press L imited.