Developmental changes in the delayed rectifier K+ channels in mouse heart

Expression of cardiac transient outward current and inwardly rectifying K+ current is age dependent. However, little is known about age-related changes in cardiac delayed rectifier K+ current (I-K, With rapidly and slowly activating components, I-Kr and I-Ks, respectively). Accordingly, the purpose of the present study was to assess developmental changes in I-K channels in fetal, neonatal, and adult mouse ventricles. Three techniques were used: conventional microelectrode to measure the action potential, voltage clamp to record macroscopic currents of I-K, and radioligand assay to examine [H-3]dofetilide binding sites. The extent of prolongation of action potential du ration at 95% repolarization (APD(95)) by a selective I-Kr blocker, dofetilide (1 mu mol/L), dramatically decreased from fetal (137%+/-18%) to day-1 (75%+/-29%) and day-3 (20%+/-15%) neonatal mouse ventricular tissues (P<.01). Dofetilide did not prolong APD(95) in adult myocardium. I-Kr is the sole component of I-K in day-18 fetal mouse ventricular myocytes. However, both I-Kr and I-Ks were observed in day-1 neonatal ventricular myocytes. With further development, I-Ks became the dominant component of I-K in day-3 neonates. In adult mouse ventricular myocytes, neither I-Kr nor I-Ks was observed. Correspondingly, a high-affinity binding site for [H-3]dofetilide was present in fetal mouse ventricles but was absent in adult ventricles. The complementary data from microelectrode, voltage-clamp, and [H-3]dofetilide binding studies demonstrate that expression of the I-K channel is developmentally regulated in the mouse heart.