Role of Mg2+ block of the inward rectifier K+ current in cardiac repolarization reserve: A quantitative simulation

Different K+ currents serve as “repolarization reserve” or a redundant repolarizing mechanism that protects against excessive prolongation of the cardiac action potential and therefore arrhythmia. Impairment of the inward rectifier K+ current (IK1) has been implicated in the pathogenesis of cardiac arrhythmias. The characteristics of IK1 reflect the kinetics of channel block by intracellular cations, primarily spermine (a polyamine) and Mg2+, whose cellular levels may vary under various pathological conditions. However, the relevance of endogenous IK1 blockers to the repolarization reserve is still not fully understood in detail. Here we used a mathematical model of a cardiac ventricular myocyte which quantitatively reproduces the dynamics of IK1 block to examine the effects of the intracellular spermine and Mg2+ concentrations, through modifying IK1, on the action potential repolarization. Our simulation indicated that an IK1 transient caused by relief of Mg2+ block flows during early phase 3. Increases in the intracellular spermine/Mg2+ concentration, or decreases in the intracellular Mg2+ concentration, to levels outside their normal ranges prolonged action potential duration by decreasing the IK1 transient. Moreover, reducing both the rapidly activating delayed rectifier current (IKr) and the IK1 transient caused a marked retardation of repolarization and early afterdepolarization because they overlap in the voltage range at which they flow. Our results indicate that the IK1 transient caused by relief of Mg2+ block is an important repolarizing current, especially when IKr is reduced, and that abnormal intracellular free spermine/Mg2+ concentrations may be a missing risk factor for malignant arrhythmias in IKr-related acquired (drug-induced) and congenital long QT syndromes.