Role of Mg(2+) 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 Mg(2+), 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 Mg(2+) concentrations, through modifying I(K1), on the action potential repolarization. Our simulation indicated that an I(K1) transient caused by relief of Mg(2+) block flows during early phase 3. Increases in the intracellular spermine/Mg(2+) concentration, or decreases in the intracellular Mg(2+) 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 Mg(2+) block is an important repolarizing current, especially when I(Kr) is reduced, and that abnormal intracellular free spermine/Mg(2+) concentrations may be a missing risk factor for malignant arrhythmias in I(Kr)-related acquired (drug-induced) and congenital long QT syndromes.