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

Zhou Q, Bett GC, Rasmusson RL - PLoS ONE (2012)

Bottom Line: We compared effects of theoretical I(Ktof)-specific channel blockers: (1) a closed state, and (2) an open channel blocker.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Cellular and Systems Electrophysiology, State University of New York, University at Buffalo, Buffalo, New York, United States of America.

ABSTRACT
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.

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Relative APD-BCL relationships.A: endocardium and B: epicardium. (i) APD 30; (ii) APD75; (iii) APD90. Simulations are with 0.1 mM drug C (•), 1 mM drug C (▴), 0.1 mM drug O (○), 1 mM drug O (Δ). All APDs are normalized for control in the absence of drug.
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pone-0042295-g005: Relative APD-BCL relationships.A: endocardium and B: epicardium. (i) APD 30; (ii) APD75; (iii) APD90. Simulations are with 0.1 mM drug C (•), 1 mM drug C (▴), 0.1 mM drug O (○), 1 mM drug O (Δ). All APDs are normalized for control in the absence of drug.

Mentions: To further compare the different effects of drug C and O on the APD-BCL relationships, we normalized the APDs at each BCL in the presence of drugs to their corresponding APD at control, as shown in Figure 5.


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

Zhou Q, Bett GC, Rasmusson RL - PLoS ONE (2012)

Relative APD-BCL relationships.A: endocardium and B: epicardium. (i) APD 30; (ii) APD75; (iii) APD90. Simulations are with 0.1 mM drug C (•), 1 mM drug C (▴), 0.1 mM drug O (○), 1 mM drug O (Δ). All APDs are normalized for control in the absence of drug.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3412869&req=5

pone-0042295-g005: Relative APD-BCL relationships.A: endocardium and B: epicardium. (i) APD 30; (ii) APD75; (iii) APD90. Simulations are with 0.1 mM drug C (•), 1 mM drug C (▴), 0.1 mM drug O (○), 1 mM drug O (Δ). All APDs are normalized for control in the absence of drug.
Mentions: To further compare the different effects of drug C and O on the APD-BCL relationships, we normalized the APDs at each BCL in the presence of drugs to their corresponding APD at control, as shown in Figure 5.

Bottom Line: We compared effects of theoretical I(Ktof)-specific channel blockers: (1) a closed state, and (2) an open channel blocker.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Cellular and Systems Electrophysiology, State University of New York, University at Buffalo, Buffalo, New York, United States of America.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus