Two Components of the Delayed Rectifier K + Current in Ventricular Myocytes of the Guinea Pig Type

Abstract

Abstract Two distinct delayed rectifier K + currents, I Kr and I Ks , were found recently in ventricular cells. We formulated these currents theoretically and investigated their roles in action potential repolarization and the restitution of action potential duration (APD). The Luo-Rudy (L-R) model of the ventricular action potential was used in the simulations. The single delayed rectifier K + current in the model was replaced by I Kr and I Ks . Our results show that I Ks is the major outward current during the plateau repolarization. A specific block of either I Kr or I Ks can effectively prolong APD to the same degree. Therefore, either channel provides a target for class III antiarrhythmic drugs. In the simulated guinea pig ventricular cell, complete block of I Kr does not result in early afterdepolarizations (EADs). In contrast, >80% block of I Ks results in abnormal repolarization and EADs. This behavior reflects the high I Ks -to-I Kr density ratio (≈8:1) in this cell and can be reversed (ie, I Kr block can cause EADs) by reducing the ratio of I ks to I Kr . The computed APD restitution curve is consistent with the experimental behavior, displaying fast APD variation at short diastolic intervals (DIs) and downward shift at longer DIs with the decrease of basic drive cycle length (BCL). Examining the ionic currents and their underlying kinetic processes, we found that activation of both I Kr and I Ks is the primary determinant of the APD restitution at shorter DIs, with Ca 2+ current through L-type channels (I Ca ) playing a minor role. The rate of APD change depends on the relative densities of I Kr and I Ks ; it increases when the I Kr -to-I Ks density ratio is large. The BCL-dependent shift of restitution at longer DIs is primarily attributed to long-lasting changes in [Ca 2+ ] i . This in turn causes different degrees of Ca 2+ -dependent inactivation of I Ca and different degrees of Ca 2+ -dependent conductance of I Ks at very long DIs (>5 s) for different BCLs. This BCL dependence of I Ca and I Ks that is secondary to long-lasting changes in [Ca 2+ ] i is responsible for APD changes at long DIs and can be viewed as a “memory property” of cardiac cells.