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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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APD-BCL relationships.A: endocardium and B: epicardium. (i) APD 30; (ii) APD75; (iii) APD90. Control in the absence of drug (▪), 0.1 mM drug C (•), 1 mM drug C (▴), 0.1 mM drug O (○), 1 mM drug O (Δ).
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pone-0042295-g003: APD-BCL relationships.A: endocardium and B: epicardium. (i) APD 30; (ii) APD75; (iii) APD90. Control in the absence of drug (▪), 0.1 mM drug C (•), 1 mM drug C (▴), 0.1 mM drug O (○), 1 mM drug O (Δ).

Mentions: Based on these results, we chose 0.1 (drug O) and 1 mM (drug C) as the test doses to characterize the steady-state rate dependence and the restitution kinetics of the mouse ventricular myocytes. First, we calculated the steady state APD-cycle length relationships of the endocardial and epicardial cell models. Simulations were conducted at the following basic cycle lengths: 80, 100. 200, 300, 400, 500, 800, 1000, 2000, and 3000 ms. The stimulus for all simulations was an 0.5 ms pulse of 60 pA/pF. For each BCL, we paced for 1000 beats and used the last beat to calculate the APD30, APD75, and APD90 values (the interval between (dV/dt)max on the upstroke and 30%, 75% and 90% repolarization respectively). Simulations were conducted in control and with 0.1 and 1 mM of drugs O and C. The resulting APD-BCL relationships are shown in Fig 3.


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

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

APD-BCL relationships.A: endocardium and B: epicardium. (i) APD 30; (ii) APD75; (iii) APD90. Control in the absence of drug (▪), 0.1 mM drug C (•), 1 mM drug C (▴), 0.1 mM drug O (○), 1 mM drug O (Δ).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0042295-g003: APD-BCL relationships.A: endocardium and B: epicardium. (i) APD 30; (ii) APD75; (iii) APD90. Control in the absence of drug (▪), 0.1 mM drug C (•), 1 mM drug C (▴), 0.1 mM drug O (○), 1 mM drug O (Δ).
Mentions: Based on these results, we chose 0.1 (drug O) and 1 mM (drug C) as the test doses to characterize the steady-state rate dependence and the restitution kinetics of the mouse ventricular myocytes. First, we calculated the steady state APD-cycle length relationships of the endocardial and epicardial cell models. Simulations were conducted at the following basic cycle lengths: 80, 100. 200, 300, 400, 500, 800, 1000, 2000, and 3000 ms. The stimulus for all simulations was an 0.5 ms pulse of 60 pA/pF. For each BCL, we paced for 1000 beats and used the last beat to calculate the APD30, APD75, and APD90 values (the interval between (dV/dt)max on the upstroke and 30%, 75% and 90% repolarization respectively). Simulations were conducted in control and with 0.1 and 1 mM of drugs O and C. The resulting APD-BCL relationships are shown in Fig 3.

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