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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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Dose dependent blockade of IKtof.The effect of various concentrations of drug on the action potential for A: open state block, and B: closed state block. The degree of block was determined by holding at −70 mV, the applying a test pulse to +50 mV for 500 ms. C: Open state binding of Drug O. D: Closed state binding of Drug C. Change in peak (▪), change in total current flow (○). Solid lines are Boltzmann fits to the data .
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pone-0042295-g001: Dose dependent blockade of IKtof.The effect of various concentrations of drug on the action potential for A: open state block, and B: closed state block. The degree of block was determined by holding at −70 mV, the applying a test pulse to +50 mV for 500 ms. C: Open state binding of Drug O. D: Closed state binding of Drug C. Change in peak (▪), change in total current flow (○). Solid lines are Boltzmann fits to the data .

Mentions: We first compared the blocking effect of the two hypothetical drugs on IKtof. We determined dose-response relationships for drug C and O at a test pulse of 50 mV for 500 ms from a holding potential of −70 mV. Figure 1 shows dose-response curves for both drugs. The effect was measured on the peak current (Ipeak), and on the total current flow (area under the curve). The peak curve was constructed as the normalized reduction in peak IKtof (1- Ipeak-dose/Ipeak-in- control) as a function of the applied dose of the drug. The area under the curve was constructed as the normalized reduction in the current area (1-Areadose/Areain-control) as a function of the applied dose of the drug.


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

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

Dose dependent blockade of IKtof.The effect of various concentrations of drug on the action potential for A: open state block, and B: closed state block. The degree of block was determined by holding at −70 mV, the applying a test pulse to +50 mV for 500 ms. C: Open state binding of Drug O. D: Closed state binding of Drug C. Change in peak (▪), change in total current flow (○). Solid lines are Boltzmann fits to the data .
© Copyright Policy
Related In: Results  -  Collection

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

pone-0042295-g001: Dose dependent blockade of IKtof.The effect of various concentrations of drug on the action potential for A: open state block, and B: closed state block. The degree of block was determined by holding at −70 mV, the applying a test pulse to +50 mV for 500 ms. C: Open state binding of Drug O. D: Closed state binding of Drug C. Change in peak (▪), change in total current flow (○). Solid lines are Boltzmann fits to the data .
Mentions: We first compared the blocking effect of the two hypothetical drugs on IKtof. We determined dose-response relationships for drug C and O at a test pulse of 50 mV for 500 ms from a holding potential of −70 mV. Figure 1 shows dose-response curves for both drugs. The effect was measured on the peak current (Ipeak), and on the total current flow (area under the curve). The peak curve was constructed as the normalized reduction in peak IKtof (1- Ipeak-dose/Ipeak-in- control) as a function of the applied dose of the drug. The area under the curve was constructed as the normalized reduction in the current area (1-Areadose/Areain-control) as a function of the applied dose of the drug.

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