Mechanism of shortened action potential duration in Na + -Ca 2+ exchanger knockout mice

In cardiac-specific Na + -Ca 2+ exchanger (NCX) knockout (KO) mice, the ventricular action potential (AP) is shortened. The shortening of the AP, as well as a decrease of the L-type Ca 2+ current ( I Ca ), provides a critical mechanism for the maintenance of Ca 2+ homeostasis and contractility in the absence of NCX (Pott C, Philipson KD, Goldhaber JI. Excitation-contraction coupling in Na + -Ca 2+ exchanger knockout mice: reduced transsarcolemmal Ca 2+ flux. Circ Res 97: 1288–1295, 2005). To investigate the mechanism that underlies the accelerated AP repolarization, we recorded the transient outward current ( I to ) in patch-clamped myocytes isolated from wild-type (WT) and NCX KO mice. Peak I to was increased by 78% and decay kinetics were slowed in KO vs. WT. Consistent with increased I to , ECGs from KO mice exhibited shortened QT intervals. Expression of the I to -generating K + channel subunit Kv4.2 and the K + channel interacting protein was increased in KO. We used a computer model of the murine AP (Bondarenko VE, Szigeti GP, Bett GC, Kim SJ, and Rasmusson RL. Computer model of action potential of mouse ventricular myocytes. Am J Physiol Heart Circ Physiol 287: 1378–1403, 2004) to determine the relative contributions of increased I to , reduced I Ca , and reduced NCX current ( I NCX ) on the shape and kinetics of the AP. Reduction of I Ca and elimination of I NCX had relatively small effects on the duration of the AP in the computer model. In contrast, AP repolarization was substantially accelerated when I to was increased in the computer model. Thus, the increase in I to , and not the reduction of I Ca or I NCX , is likely to be the major mechanism of AP shortening in KO myocytes. The upregulation of I to may comprise an important regulatory mechanism to limit Ca 2+ influx via a reduction of AP duration, thus preventing Ca 2+ overload in situations of reduced myocyte Ca 2+ extrusion capacity.