Functional role of inward rectifier current in heart probed by Kir2.1 overexpression and dominant-negative suppression

The inward rectifier current I-K1 is tightly regulated regionally within the heart, downregulated in heart failure, and genetically suppressed in Andersen syndrome. We used in vivo viral gene transfer to dissect the role of I-K1 in cardiac repolarization and maintenance of the resting membrane potential (RMP) in guinea pig ventricular myocytes. Kir2.1 overexpression boosted Ba2+-sensitive I-K1 by more than 100% (at -50mV), significantly shortened action potential durations (APDs), accelerated phase 3 repolarization, and hyperpolarized RMP compared with control cells (nongreen cells from the same hearts and green cells from GFP-transduced hearts). The dominant-negative Kir2AAAA reduced I-K1 by 50-90%; those cells with less than 80% reduction of I-K1 exhibited prolonged APDs, decelerated phase 3 repolarization, and depolarization of the RMP. Further reduction of I-K1 resulted in a pacemaker phenotype, as previously described. ECGs revealed a 7.7% +/- 0.9% shortening of the heart rate-corrected QT interval (QTc interval) in Kir2.1-transduced animals (n = 4) and a 16.7% +/- 1.8% prolongation of the QTc interval (n = 3) in Kir2.1AAA-transduced animals 72 hours after gene delivery compared with immediate postoperative recordings. Thus, I-K1 is essential for establishing the distinctive electrical phenotype of the ventricular myocyte: rapid terminal repolarization to a stable and polarized resting potential. Additionally, the long-QT phenotype seen in Andersen syndrome is a direct consequence of dominant-negative suppression of Kir2 channel function.