title: Role of Mg(2+) block of the inward rectifier K(+) current in cardiac repolarization reserve: A quantitative simulation.
abstract: 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.
authors.affiliation: Department of Physiology, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan. keiko@med.saga-u.ac.jp
authors.forename: Keiko
authors.initials: K
authors.lastname: Ishihara
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Sarai
authors.forename: Keiichi
authors.initials: K
authors.lastname: Asakura
authors.forename: Akinori
authors.initials: A
authors.lastname: Noma
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsuoka
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002478:Cells, Cultured; D003198:Computer Simulation; D006168:Guinea Pigs; D008274:Magnesium / Q000494:pharmacology*; D008962:Models, Theoretical; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects*; D013096:Spermine / Q000494:pharmacology
chemical_list: D024661:Potassium Channels, Inwardly Rectifying; D013096:Spermine; D008274:Magnesium