Positive Rate-Dependent Action Potential Prolongation by Modulating Potassium Ion Channels

Authors

Candido Cabo, CUNY New York City College of TechnologyFollow

Document Type

Article

Publication Date

6-24-2022

Abstract

Pharmacological agents that prolong action potential duration (APD) to a larger extent at slow rates than at the fast excitation rates typical of ventricular tachycardia exhibit reverse rate dependence. Reverse rate dependence has been linked to the lack of efficacy of class III agents at preventing arrhythmias because the doses required to have an anti-arrhythmic effect at fast rates may have pro-arrhythmic effects at slow rates due to an excessive APD prolongation. In this report we show that, in computer models of the ventricular action potential, APD prolongation by accelerating phase 2 repolarization (by increasing I_Ks) and decelerating phase 3 repolarization (by blocking I_Kr and I_K1) results in a robust positive rate dependence (i.e., larger APD prolongation at fast rates than at slow rates). In contrast, APD prolongation by blocking a specific potassium channel type results in reverse rate dependence or a moderate positive rate dependence. Interventions that result in a strong positive rate dependence tend to decrease the repolarization reserve because they require substantial I_K1 block. However, limiting I_K1 block to ~50% results in a strong positive rate dependence with moderate decrease in repolarization reserve. In conclusion, the use of a combination of I_Ks activators and I_Kr and I_K1 blockers could result in APD prolongation that potentially maximizes anti-arrhythmic effects (by maximizing APD prolongation at fast excitation rates) and minimizes pro-arrhythmic effects (by minimizing APD prolongation at slow excitation rates).

Comments

Cabo, Candido. “Positive Rate‐dependent Action Potential Prolongation by Modulating Potassium Ion Channels.” Physiological Reports, vol. 10, no. 12, 2022, p. e15356–n/a, https://doi.org/10.14814/phy2.15356

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