Introduction: β-adrenergic stimulation increases the heart rate by accelerating the electrical activity of the pacemaker of the heart, the sinoatrial node (SAN). Ionic mechanisms underlying the actions of β-adrenergic stimulation are not yet fully understood. Isoprenaline (ISO), a β-adrenoceptor agonist, shifts voltage-dependent I f activation to more positive potentials resulting in an increase of I f, which has been suggested to be the main mechanism underlying the effect of β-adrenergic stimulation. However, ISO has been found to increase the firing rate of rabbit SAN cells when I f is blocked. ISO also increases I CaL, I st, I Kr, and I Ks; and shifts the activation of I Kr to more negative potentials and increases the rate of its deactivation. ISO has also been reported to increase the intracellular Ca 2+transient, which can contribute to chronotropy by modulating the "Ca 2+ clock." The aim of this study was to analyze the ionic mechanisms underlying the positive chronotropy of β-adrenergic stimulation using two distinct and well established computational models of the electrical activity of rabbit SAN cells. Methods and results: We modified the Boyett et al. (2001) and Kurata et al. (2008) models of electrical activity for the central and peripheral rabbit SAN cells by incorporating equations for the known dose-dependent actions of ISO on various ionic channel currents (I CaL, I st, I Kr, and I Ks), kinetics of I Kr and I f, and the intracellular Ca 2+ transient. These equations were constructed from experimental data. To investigate the ionic basis of the effects of ISO, we simulated the chronotropic effect of a range of ISO concentrations when ISO exerted all its actions or just a subset of them. Conclusion: In both the Boyett et al. and Kurata et al. SAN models, the chronotropic effect of ISO was found to result from an integrated action of ISO on I CaL, I f, I st, I Kr, and I Ks, among which an increase in the rate of deactivation of I Kr plays a prominent role, though the effect of ISO on I f and [Ca 2+] i also plays a role. © 2012 Zhang, Butters, Adeni-ran, Higham, Holden, Boyett and Hancox.
CITATION STYLE
Zhang, H., Butters, T., Adeniran, I., Higham, J., Holden, A. V., Boyett, M. R., & Hancox, J. C. (2012). Modeling the chronotropic effect of isoprenaline on rabbit sinoatrial node. Frontiers in Physiology, 3 JUL. https://doi.org/10.3389/fphys.2012.00241
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