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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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Example of APs recorded with different S1–S2 intervals.The first AP (control) represents the last beat of the pacing train at a cycle length of 1s (S1) on endocardial cells. APs are shown for S1–S2 intervals of 60, 100, 200, and 300 ms. Peak amplitudes are shown above the AP. APD30 is 4.89 ms, 8.17 ms, 6.11 ms, 5.58 ms, and 5.56 ms; APD75 is 18.11 ms, 22.07 ms, 18.65 ms, 17.81 ms, and 17.81 ms; and APD90 is 29.82 ms, 32.73 ms, 30.13 ms, 29.54 ms, and 29.47 ms for control, 60, 100, 200, and 300 ms S1–S2 intervals respectively.
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pone-0042295-g006: Example of APs recorded with different S1–S2 intervals.The first AP (control) represents the last beat of the pacing train at a cycle length of 1s (S1) on endocardial cells. APs are shown for S1–S2 intervals of 60, 100, 200, and 300 ms. Peak amplitudes are shown above the AP. APD30 is 4.89 ms, 8.17 ms, 6.11 ms, 5.58 ms, and 5.56 ms; APD75 is 18.11 ms, 22.07 ms, 18.65 ms, 17.81 ms, and 17.81 ms; and APD90 is 29.82 ms, 32.73 ms, 30.13 ms, 29.54 ms, and 29.47 ms for control, 60, 100, 200, and 300 ms S1–S2 intervals respectively.

Mentions: We then tested restitution at various drug concentrations. Each model was paced with a train of 1000 beats (S1) at three rates: 1s, 500 ms and 100 ms, followed by a single S2 beat with a shorter S1–S2 interval. The S1–S2 interval varied from 40 ms (the smallest duration which can generate a reasonable AP) to 300 ms. Figure 6 shows the last beat of the train of pacing (S1 = 1 Hz) with superimposed premature responses at successively longer S1–S2 intervals in control conditions. For an S1–S2 interval of 60 ms, the AP amplitude of the S2 beat is smaller than that of S1. With increasing S1–S2 intervals, the amplitude of the S2 APs becomes larger and gradually recovers to the steady state magnitude. This agrees very well with experimental observations [25]. However, our simulation results do not show a shortened APD90 at short S1–S2 levels. The S1–S2 restitution curves for endocardial and epicardial cell models are shown in Figures 7 and 8 respectively.


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

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

Example of APs recorded with different S1–S2 intervals.The first AP (control) represents the last beat of the pacing train at a cycle length of 1s (S1) on endocardial cells. APs are shown for S1–S2 intervals of 60, 100, 200, and 300 ms. Peak amplitudes are shown above the AP. APD30 is 4.89 ms, 8.17 ms, 6.11 ms, 5.58 ms, and 5.56 ms; APD75 is 18.11 ms, 22.07 ms, 18.65 ms, 17.81 ms, and 17.81 ms; and APD90 is 29.82 ms, 32.73 ms, 30.13 ms, 29.54 ms, and 29.47 ms for control, 60, 100, 200, and 300 ms S1–S2 intervals respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0042295-g006: Example of APs recorded with different S1–S2 intervals.The first AP (control) represents the last beat of the pacing train at a cycle length of 1s (S1) on endocardial cells. APs are shown for S1–S2 intervals of 60, 100, 200, and 300 ms. Peak amplitudes are shown above the AP. APD30 is 4.89 ms, 8.17 ms, 6.11 ms, 5.58 ms, and 5.56 ms; APD75 is 18.11 ms, 22.07 ms, 18.65 ms, 17.81 ms, and 17.81 ms; and APD90 is 29.82 ms, 32.73 ms, 30.13 ms, 29.54 ms, and 29.47 ms for control, 60, 100, 200, and 300 ms S1–S2 intervals respectively.
Mentions: We then tested restitution at various drug concentrations. Each model was paced with a train of 1000 beats (S1) at three rates: 1s, 500 ms and 100 ms, followed by a single S2 beat with a shorter S1–S2 interval. The S1–S2 interval varied from 40 ms (the smallest duration which can generate a reasonable AP) to 300 ms. Figure 6 shows the last beat of the train of pacing (S1 = 1 Hz) with superimposed premature responses at successively longer S1–S2 intervals in control conditions. For an S1–S2 interval of 60 ms, the AP amplitude of the S2 beat is smaller than that of S1. With increasing S1–S2 intervals, the amplitude of the S2 APs becomes larger and gradually recovers to the steady state magnitude. This agrees very well with experimental observations [25]. However, our simulation results do not show a shortened APD90 at short S1–S2 levels. The S1–S2 restitution curves for endocardial and epicardial cell models are shown in Figures 7 and 8 respectively.

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