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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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Effect of drugs O and C on APD prolongation.A: simulated action potentials of the mouse ventricular model for the epicardial and endocardial cells. Pacing rate was 1 Hz. Relative APD prolongation normalized to the maximum prolongation with IKtof completely blocked was determined at various drug concentrations for drug O (○) and drug C (▪) on B: endocardium and C: Epicardium. Pacing rate was 1 Hz.
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pone-0042295-g002: Effect of drugs O and C on APD prolongation.A: simulated action potentials of the mouse ventricular model for the epicardial and endocardial cells. Pacing rate was 1 Hz. Relative APD prolongation normalized to the maximum prolongation with IKtof completely blocked was determined at various drug concentrations for drug O (○) and drug C (▪) on B: endocardium and C: Epicardium. Pacing rate was 1 Hz.

Mentions: Figure 2A shows drug free traces from epicardial and endocardial cells. Next, we determined the effect of drugs O and C binding to IKtof on prolonging the ventricular APD. Action potential duration was measured as the interval between (dV/dt)max on the upstroke and 50% of repolarization (APD50), The myocyte was paced at 1 Hz with various concentrations of drug, or drug free. The prolongation in APD50 was normalized to the maximum prolongation achieved with IKtof completely blocked. This test was conducted for both the endocardial and epicardial cell models.


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

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

Effect of drugs O and C on APD prolongation.A: simulated action potentials of the mouse ventricular model for the epicardial and endocardial cells. Pacing rate was 1 Hz. Relative APD prolongation normalized to the maximum prolongation with IKtof completely blocked was determined at various drug concentrations for drug O (○) and drug C (▪) on B: endocardium and C: Epicardium. Pacing rate was 1 Hz.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0042295-g002: Effect of drugs O and C on APD prolongation.A: simulated action potentials of the mouse ventricular model for the epicardial and endocardial cells. Pacing rate was 1 Hz. Relative APD prolongation normalized to the maximum prolongation with IKtof completely blocked was determined at various drug concentrations for drug O (○) and drug C (▪) on B: endocardium and C: Epicardium. Pacing rate was 1 Hz.
Mentions: Figure 2A shows drug free traces from epicardial and endocardial cells. Next, we determined the effect of drugs O and C binding to IKtof on prolonging the ventricular APD. Action potential duration was measured as the interval between (dV/dt)max on the upstroke and 50% of repolarization (APD50), The myocyte was paced at 1 Hz with various concentrations of drug, or drug free. The prolongation in APD50 was normalized to the maximum prolongation achieved with IKtof completely blocked. This test was conducted for both the endocardial and epicardial cell models.

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