DEVELOPMENTAL-CHANGES IN THE DELAYED RECTIFIER K+ CHANNELS IN MOUSE HEART

Expression of cardiac transient outward current and inwardly rectifyin g K+ current is age dependent. However, little is known about age-rela ted changes in cardiac delayed rectifier K+ current (I-K, With rapidly and slowly activating components, I-Kr and I-Ks, respectively). Accor dingly, the purpose of the present study was to assess developmental c hanges in I-K channels in fetal, neonatal, and adult mouse ventricles. Three techniques were used: conventional microelectrode to measure th e 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% repolariz ation (APD(95)) by a selective I-Kr blocker, dofetilide (1 mu mol/L), dramatically decreased from fetal (137%+/-18%) to day-1 (75%+/-29%) an d day-3 (20%+/-15%) neonatal mouse ventricular tissues (P<.01). Dofeti lide did not prolong APD(95) in adult myocardium. I-Kr is the sole com ponent of I-K in day-18 fetal mouse ventricular myocytes. However, bot h 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 i n adult ventricles. The complementary data from microelectrode, voltag e-clamp, and [H-3]dofetilide binding studies demonstrate that expressi on of the I-K channel is developmentally regulated in the mouse heart.