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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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Comparison of action potentials at with S1S2 interval at 40 ms.Endocardium was stimulated at A: 1 Hz B: 10 Hz. Epicardium was stimulated at C: 1 Hz D: 10 Hz. Control, in the absence of drug is indicated by solid black line. Drug C is shown in blue, and drug O in red.
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pone-0042295-g009: Comparison of action potentials at with S1S2 interval at 40 ms.Endocardium was stimulated at A: 1 Hz B: 10 Hz. Epicardium was stimulated at C: 1 Hz D: 10 Hz. Control, in the absence of drug is indicated by solid black line. Drug C is shown in blue, and drug O in red.

Mentions: The AP traces for the final S1 and S2 beat are shown in Figure 9 for the S1–S2 interval of 40 ms at 1 and 10 Hz pacing. The shape of the S2 AP varies greatly. For endocardial cell at 1s pacing rate, the drugs suppress the peak AP depolarization but have no effect on repolarization or APD. For endocardial cell at 10 Hz pacing, the peak depolarization is suppressed and also delayed, followed by delayed repolarization. For epicardial cell at 1 Hz pacing, the AP peaks depolarization is reduced and delayed. At 10 Hz pacing, drug C delayed and reduced the AP peak, whereas drug O abolished the second action potential.


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

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

Comparison of action potentials at with S1S2 interval at 40 ms.Endocardium was stimulated at A: 1 Hz B: 10 Hz. Epicardium was stimulated at C: 1 Hz D: 10 Hz. Control, in the absence of drug is indicated by solid black line. Drug C is shown in blue, and drug O in red.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0042295-g009: Comparison of action potentials at with S1S2 interval at 40 ms.Endocardium was stimulated at A: 1 Hz B: 10 Hz. Epicardium was stimulated at C: 1 Hz D: 10 Hz. Control, in the absence of drug is indicated by solid black line. Drug C is shown in blue, and drug O in red.
Mentions: The AP traces for the final S1 and S2 beat are shown in Figure 9 for the S1–S2 interval of 40 ms at 1 and 10 Hz pacing. The shape of the S2 AP varies greatly. For endocardial cell at 1s pacing rate, the drugs suppress the peak AP depolarization but have no effect on repolarization or APD. For endocardial cell at 10 Hz pacing, the peak depolarization is suppressed and also delayed, followed by delayed repolarization. For epicardial cell at 1 Hz pacing, the AP peaks depolarization is reduced and delayed. At 10 Hz pacing, drug C delayed and reduced the AP peak, whereas drug O abolished the second action potential.

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