AUTHOR=Zhang Henggui , Butters Timothy , Adeniran Ismail , Higham Jonathan , Holden Arun , Boyett Mark R., Hancox Jules C.

TITLE=Modeling the Chronotropic Effect of Isoprenaline on Rabbit Sinoatrial Node

JOURNAL=Frontiers in Physiology

VOLUME=3

YEAR=2012

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2012.00241

DOI=10.3389/fphys.2012.00241

ISSN=1664-042X

ABSTRACT=<p><bold>Introduction:</bold> 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 <italic>I</italic><sub>f</sub> activation to more positive potentials resulting in an increase of <italic>I</italic><sub>f</sub>, 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 <italic>I</italic><sub>f</sub> is blocked. ISO also increases <italic>I</italic><sub>CaL</sub>, <italic>I</italic><sub>st</sub>, <italic>I</italic><sub>Kr</sub>, and <italic>I</italic><sub>Ks</sub>; and shifts the activation of <italic>I</italic><sub>Kr</sub> to more negative potentials and increases the rate of its deactivation. ISO has also been reported to increase the intracellular Ca<sup>2+</sup> transient, which can contribute to chronotropy by modulating the “Ca<sup>2+</sup> 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. <bold>Methods and results:</bold> We modified the Boyett et al. (<xref ref-type="bibr" rid="B8">2001</xref>) and Kurata et al. (<xref ref-type="bibr" rid="B35">2008</xref>) 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 (<italic>I</italic><sub>CaL</sub>, <italic>I</italic><sub>st</sub>, <italic>I</italic><sub>Kr</sub>, and <italic>I</italic><sub>Ks</sub>), kinetics of <italic>I</italic><sub>Kr</sub> and <italic>I</italic><sub>f</sub>, and the intracellular Ca<sup>2+</sup> 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. <bold>Conclusion:</bold> 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 <italic>I</italic><sub>CaL</sub>, <italic>I</italic><sub>f</sub>, <italic>I</italic><sub>st</sub>, <italic>I</italic><sub>Kr</sub>, and <italic>I</italic><sub>Ks</sub>, among which an increase in the rate of deactivation of <italic>I</italic><sub>Kr</sub> plays a prominent role, though the effect of ISO on <italic>I</italic><sub>f</sub> and [Ca<sup>2+</sup>]<sub>i</sub> also plays a role.</p>