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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 from endocardium and epicardium at fast and slow pacing rates.Endocardium: A: 200 ms B: 2s. Epicardium: C: 200 ms D: 2 s. Control is solid black line. Drug O is red, drug C blue.
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pone-0042295-g004: Comparison of action potentials from endocardium and epicardium at fast and slow pacing rates.Endocardium: A: 200 ms B: 2s. Epicardium: C: 200 ms D: 2 s. Control is solid black line. Drug O is red, drug C blue.

Mentions: An interesting phenomenon happens at APD30. First, in the presence of 0.1 mM drug O, both the endocardial and epicardial model show increasing APD30 with shortening BCL for all BCLs tested, in contrast to the V-shaped curve obtained in control and other drug conditions. Second, because of the consistently decreasing APD30 with increasing BCL, the curve for 0.1 mM drug O crosses over the curve for 1 mM drug C at a point such that for BCLs longer than that point (∼300 ms for epicardium and 600 ms for endocardium), 1 mM drug C has a stronger effect in prolonging APD30 than 0.1 mM drug O, which does not happen for APD75 and APD90. To illustrate this, Figure 4 shows APs at 200 ms and 2s for endocardial and epicardial cells. At 200 ms, AP repolarization in the presence of 0.1 mM drug O is always more rapid (i.e., shorter APD) than for 1 mM drug C. However, at 2s, initial early AP repolarization with 0.1 mM drug O is more rapid, then subsequently less rapid than for 1 mM drug C later in repolarization. Therefore, 1 mM drug C has a longer APD30 but shorter APD75 and APD90 than 0.1 mM drug O.


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 from endocardium and epicardium at fast and slow pacing rates.Endocardium: A: 200 ms B: 2s. Epicardium: C: 200 ms D: 2 s. Control is solid black line. Drug O is red, drug C blue.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0042295-g004: Comparison of action potentials from endocardium and epicardium at fast and slow pacing rates.Endocardium: A: 200 ms B: 2s. Epicardium: C: 200 ms D: 2 s. Control is solid black line. Drug O is red, drug C blue.
Mentions: An interesting phenomenon happens at APD30. First, in the presence of 0.1 mM drug O, both the endocardial and epicardial model show increasing APD30 with shortening BCL for all BCLs tested, in contrast to the V-shaped curve obtained in control and other drug conditions. Second, because of the consistently decreasing APD30 with increasing BCL, the curve for 0.1 mM drug O crosses over the curve for 1 mM drug C at a point such that for BCLs longer than that point (∼300 ms for epicardium and 600 ms for endocardium), 1 mM drug C has a stronger effect in prolonging APD30 than 0.1 mM drug O, which does not happen for APD75 and APD90. To illustrate this, Figure 4 shows APs at 200 ms and 2s for endocardial and epicardial cells. At 200 ms, AP repolarization in the presence of 0.1 mM drug O is always more rapid (i.e., shorter APD) than for 1 mM drug C. However, at 2s, initial early AP repolarization with 0.1 mM drug O is more rapid, then subsequently less rapid than for 1 mM drug C later in repolarization. Therefore, 1 mM drug C has a longer APD30 but shorter APD75 and APD90 than 0.1 mM drug O.

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