Abstract
The fast component of the cardiac transient outward current, IKtof, is blocked by a number of drugs. The major molecular bases of IKtof are Kv4.2/Kv4.3 voltage-gated potassium channels. Drugs with similar potencies but different blocking mechanisms have differing effects on action potential duration (APD). We used in silico analysis to determine the effect of IKtof-blocking drugs with different blocking mechanisms on mouse ventricular myocytes. We used our existing mouse model of the action potential, and developed 4 new Markov formulations for IKtof, IKtos, IKur, IKs. We compared effects of theoretical IKtof-specific channel blockers: (1) a closed state, and (2) an open channel blocker. At concentrations lower or close to IC50, the drug which bound to the open state always had a much greater effect on APD than the drug which bound to the closed state. At concentrations much higher than IC50, both mechanisms had similar effects at very low pacing rates. However, an open state binding drug had a greater effect on APD at faster pacing rates, particularly around 10 Hz. In summary, our data indicate that drug effects on APD are strongly dependent not only on IC50, but also on the drug binding state.
Highlights
Delayed cardiac repolarization and the associated prolongation of the QT interval on the EKG is an undesired side effect of many drugs [1,2,3]
1) The Rapidly Inactivating Transient Outward K+ Current IKtof; IKtof is a rapidly activating current which plays a role in early repolarization of the action potential
In order to compare the results of the Markov model to experimental data and the previous Hodgkin-Huxley type model [7], we used the conductance of 0.4067 ms/uF in model apical cell in this simulation
Summary
Delayed cardiac repolarization and the associated prolongation of the QT interval on the EKG is an undesired side effect of many drugs [1,2,3]. It is of great importance to develop new tools and methods that can identify, as early as possible, the risk of novel agents in arrhythmogenesis. This requires in depth understanding of the mechanisms by which drug-induced modifications of normal ion channel behavior lead to cardiac arrhythmias. One of the critical factors in drug binding is the consequences of conformation-dependent binding of the blocker to the channel, i.e., the kinetics of drug-channel interaction Markov models are useful when simulating drug-channel interactions, as alteration of the kinetic properties of a single ion channel caused by drug binding can be related to changes in specific rate constants in the Markov model
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