Developmental Changes in the Delayed Rectifier K + Channels in Mouse Heart

Abstract

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 [ 3 H]dofetilide binding sites. The extent of prolongation of action potential duration at 95% repolarization (APD 95 ) by a selective I Kr blocker, dofetilide (1 μmol/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 [ 3 H]dofetilide was present in fetal mouse ventricles but was absent in adult ventricles. The complementary data from microelectrode, voltage-clamp, and [ 3 H]dofetilide binding studies demonstrate that expression of the I K channel is developmentally regulated in the mouse heart.