Markov Models of Use-Dependence and Reverse Use-Dependence during the Mouse Cardiac Action Potential

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.