2 COMPONENTS OF THE DELAYED RECTIFIER K-PIG TYPE - THEORETICAL FORMATION AND THEIR ROLE IN REPOLARIZATION( CURRENT IN VENTRICULAR MYOCYTES OF THE GUINEA)

Two distinct delayed rectifier K+ currents, I-Kr and I-Ks, were found recently in ventricular cells. We formulated these currents theoretica lly and investigated their roles in action potential repolarization an d the restitution of action potential duration (APD). The Luo-Rudy (L- R) model of the ventricular action potential was used in the simulatio ns. 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 curr ent during the plateau repolarization. A specific block of either I-Kr or I-Ks can effectively prolong APD to the same degree. Therefore, ei ther 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% bl ock of I-Ks results in abnormal repolarization and EADs. This behavior reflects the high I-Ks-to-I-Kr density ratio (similar to 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 consi stent 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 c urrents and their underlying kinetic processes, we found that activati on of both I-Kr and I-Ks is the primary determinant of the APD restitu tion at shorter DIs, with Ca2+ current through L-type channels (I-Ca) playing a minor role. The rate of APD change depends on the relative d ensities 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 i s primarily attributed to long-lasting changes in [Ca2+](i), This in t urn causes different degrees of Ca2+-dependent inactivation of I-Ca an d different degrees of Ca2+-dependent conductance of I-Ks at very long DIs (>5 s) fur different BCLs. This BCL dependence of I-Ca and I-Ks t hat is secondary to long-lasting changes in [Ca2+](i) is responsible f or APD changes at long DIs and can be viewed as a ''memory property'' of cardiac cells.