Tag: NVP-AEW541 cost

Introduction: -adrenergic stimulation increases the heart rate by accelerating the electrical

Introduction: -adrenergic stimulation increases the heart rate by accelerating the electrical activity of the pacemaker of the heart, the sinoatrial node (SAN). central and peripheral rabbit SAN cells by incorporating equations for the known dose-dependent actions of ISO on various ionic channel currents ( em I /em CaL, em I /em st, em I /em Kr, and em I /em Ks), kinetics of em I /em Kr and em I /em f, and the intracellular Ca2+ transient. These equations were constructed from experimental data. To investigate the ionic basis NVP-AEW541 cost 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 em I /em CaL, em I /em f, em I /em st, em I /em Kr, and em I /em Ks, among which an increase in the rate of deactivation of em I /em Kr plays a prominent role, though the effect of ISO on em I /em f and [Ca2+]i also plays a role. strong class=”kwd-title” Keywords: sinoatrial node, isoprenaline, action potential Introduction -Adrenergic stimulation increases the heart rate through accelerating the spontaneous activity of the pacemaker of the heart, the sinoatrial node (SAN; Abramochkin et al., 2009). It is believed that this occurs through -adrenoceptor mediated modulation of ionic currents that contribute to pacemaker activity; however the precise ionic mechanisms underlying the effect of -adrenergic stimulation are not Mouse monoclonal to ABL2 yet fully elucidated. Experiments have shown that isoprenaline (ISO), a -adrenergic agonist, increases the L-type calcium current ( em I /em CaL; Noma et al., 1980; Walsh et al., 1988; Zaza et al., 1996; Vinogradova et al., 2002; Ke et al., 2007; Alig et al., 2009), delayed rectifier potassium current (both em I /em Kr and em I /em Ks; Walsh et al., 1988; Duchatelle-Gourdon et al., 1989; Giles et al., 1989; Yazawa and Kameyama, 1990; Freeman and Kass, 1993;Lei et al., 2000, 2002; Ke et al., 2007; Vinogradova et al., 2008), and shifts voltage-dependent activation of the hyperpolarization activated current ( em I /em f) toward positive potentials resulting in an increase of em I /em f (Brown et al., 1979; Cai et al., 1995; DiFrancesco, 1995; Zaza et al., 1996; Accili et al., 1997a,b; Bucchi et al., 2003; Barbuti et al., 2007; Alig et al., 2009; Baruscotti et al., 2010; Liao et al., 2010). As em I /em f has been regarded to be a major pacemaker current in mammalian pacemaker cells, an increase in em I /em f has been suggested to be the main mechanism underlying the positive chronotropic effect of -adrenergic stimulation (DiFrancesco, 1995, 2010; Zaza et al., 1996; DiFrancesco and Borer, 2007; Liao et al., 2010). However, ISO has been found to increase the firing rate of the rabbit SAN when em I /em f was blocked by Cs+ (Cai et al., 1995), suggesting that em I /em f enhancement may not be predominantly responsible for the positive chronotropic action of ISO. Previous studies have shown that ISO increases the amplitude of the systolic rise of intracellular Ca2+ concentration ([Ca2+]i) in cardiac cells (Ju and Allen, 1999; Huser et al., 2000; Shannon et al., 2004; Maltsev and Lakatta, 2009; Wu et al., 2009). This raises the possibility NVP-AEW541 cost that changes to [Ca2+]i with ISO might contribute to the increase in firing rate via the Ca2+ clock mechanism (Vinogradova et al., 2002, 2008; Maltsev and Lakatta, 2009). A number of studies have shown that interventions altering [Ca2+]i change the firing rate of pacemaker cells (Hagiwara, 1989; Ju and Allen, 1999; Huser et al., 2000; Shannon et al., 2004; Vinogradova et al., 2008; Maltsev and Lakatta, 2009; Wu et al., 2009). In both mammalian cardiac cells (Hagiwara, 1989; Huser et al., 2000; Vinogradova et al., 2002, 2008; Maltsev and Lakatta, 2009; Wu et al., 2009) and amphibian pacemaker cells in which em I /em f is absent (Ju and Allen, 1999), it has been found that the firing rate was dependent on the amplitude NVP-AEW541 cost of the [Ca2+]i transient: agents modifying SR Ca2+ release consequently affect the firing rate. -Adrenergic stimulation increases the amplitude of the [Ca2+]i transient. It has been argued that much of the increase in firing rate caused by -stimulation seems to occur through the Ca2+ clock mechanism (Vinogradova et al., 2002, 2008; Maltsev.