Markov models of use-dependence and reverse use-dependence during the mouse cardiac action potential

• Published in: PloS one 2012-08, Vol.7 (8), p.e42295-e42295
• Main Authors: Zhou, Qinlian, Bett, Glenna C L, Rasmusson, Randall L
• Format: Article
• Language: English
• Subjects: Action potential; Action Potentials - drug effects; Action Potentials - physiology; Animal models; Animals; Binding; Biology; Biomedical engineering; Biophysics; Cardiac arrhythmia; Cardiac muscle; Comparative analysis; Drugs; Endocardium - cytology; Endocardium - drug effects; Endocardium - physiology; Formulations; Heart; Heart - drug effects; Heart - physiology; Heart diseases; Heart rate; Ion Channel Gating - drug effects; Markov Chains; Markov processes; Medical screening; Medicine; Mice; Models, Cardiovascular; Myocytes; Pericardium - cytology; Pericardium - drug effects; Pericardium - physiology; Physiology; Potassium; Potassium Channel Blockers - pharmacology; Potassium channels (voltage-gated); Potassium Channels - metabolism; Restitution; Rodents; Ventricle
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0042295

The fast component of the cardiac transient outward current, I(Ktof), is blocked by a number of drugs. The major molecular bases of I(Ktof) 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 I(Ktof)-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 I(Ktof), I(Ktos), I(Kur), I(Ks). We compared effects of theoretical I(Ktof)-specific channel blockers: (1) a closed state, and (2) an open channel blocker. At concentrations lower or close to IC(50), 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 IC(50), 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 IC(50), but also on the drug binding state.