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.
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