Role of Mg 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 (I_K1) has been implicated in the pathogenesis of cardiac arrhythmias. The characteristics of I_K1 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 I_K1 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 I_K1 block to examine the effects of the intracellular spermine and Mg²⁺ concentrations, through modifying I_K1, on the action potential repolarization. Our simulation indicated that an I_K1 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 I_K1 transient. Moreover, reducing both the rapidly activating delayed rectifier current (I_Kr) and the I_K1 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 I_K1 transient caused by relief of Mg²⁺ block is an important repolarizing current, especially when I_Kr is reduced, and that abnormal intracellular free spermine/Mg²⁺ concentrations may be a missing risk factor for malignant arrhythmias in I_Kr-related acquired (drug-induced) and congenital long QT syndromes.