Abstract
Ionic mechanisms of spontaneous action potential (AP) in sinoatrial (SA) node pacemaker cells have been discussed for decades. Although several theoretical studies have proposed different mathematical models, no scientific consensus has been achieved yet, because of the complexity and variations in experimental findings used for developing models. Here, we introduce a theoretical method in simulation study, the lead potential (VL) analysis, which enabled us to isolate the contribution of individual currents from the secondary effect of modified channel activities. We compared three models suggesting different ionic mechanisms (Himeno et al. model, Kurata et al. model, and Maltsev and Lakatta model), and contributions of Ca2+ through activation of INaCa are estimated. Finally, the primary mechanisms of the SA node pacemaker activity were examined by the VL analysis and confirmed by the bifurcation analysis using a simple minimal cardiac action potential model.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Wilders R. Computer modelling of the sinoatrial node. Med Biol Eng Comput. 2007;45:189–207.
Wilders R, Jongsma HJ, van Ginneken AC. Pacemaker activity of the rabbit sinoatrial node. A comparison of mathematical models. Biophys J. 1991;60:1202–16.
Demir SS, Clark JW, Murphey CR, Giles WR. A mathematical model of a rabbit sinoatrial node cell. Am J Phys. 1994;266:C832–52.
Kurata Y, Hisatome I, Imanishi S, Shibamoto T. Dynamical description of sinoatrial node pacemaking: improved mathematical model for primary pacemaker cell. Am J Physiol Heart Circ Physiol. 2002;283:H2074–101.
Sarai N, Matsuoka S, Kuratomi S, Ono K, Noma A. Role of individual ionic current systems in the SA node hypothesized by a model study. Jpn J Physiol. 2003;53:125–34.
Himeno Y, Sarai N, Matsuoka S, Noma A. Ionic mechanisms underlying the positive chronotropy induced by beta1-adrenergic stimulation in Guinea pig sinoatrial node cells: a simulation study. J Physiol Sci. 2008;58:53–65.
Maltsev VA, Lakatta EG. Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model. Am J Physiol Heart Circ Physiol. 2009;296:H594–615.
Cha CY, Himeno Y, Shimayoshi T, Amano A, Noma A. A novel method to quantify contribution of channels and transporters to membrane potential dynamics. Biophys J. 2009;97:3086–94.
Takeuchi A, Tatsumi S, Sarai N, Terashima K, Matsuoka S, Noma A. Ionic mechanisms of cardiac cell swelling induced by blocking Na+/K+ pump as revealed by experiments and simulation. J Gen Physiol. 2006;128:495–507.
Sarai N, Kobayashi T, Matsuoka S, Noma A. A simulation study to rescue the Na+/Ca2+ exchanger knockout mice. J Physiol Sci. 2006;56:211–7.
Hagiwara N, Irisawa H, Kameyama M. Contribution of two types of calcium currents to the pacemaker potentials of rabbit sino-atrial node cells. J Physiol. 1988;395:233–53.
Fermini B, Nathan RD. Removal of sialic acid alters both T- and L-type calcium currents in cardiac myocytes. Am J Phys. 1991;260:H735–43.
Guo J, Ono K, Noma A. A sustained inward current activated at the diastolic potential range in rabbit sino-atrial node cells. J Physiol. 1995;483:1–13.
Guo J, Mitsuiye T, Noma A. The sustained inward current in sino-atrial node cells of Guinea-pig heart. Pflugers Arch. 1997;433:390–6.
Mitsuiye T, Guo J, Noma A. Nicardipine-sensitive Na+−mediated single channel currents in Guinea-pig sinoatrial node pacemaker cells. J Physiol. 1999;521:69–79.
Cho HS, Takano M, Noma A. The electrophysiological properties of spontaneously beating pacemaker cells isolated from mouse sinoatrial node. J Physiol. 2003;550:169–80.
Shinagawa Y, Satoh H, Noma A. The sustained inward current and inward rectifier K+ current in pacemaker cells dissociated from rat sinoatrial node. J Physiol. 2000;523:593–605.
Toyoda F, Ding WG, Matsuura H. Responses of the sustained inward current to autonomic agonists in Guinea-pig sino-atrial node pacemaker cells. Br J Pharmacol. 2005;144:660–8.
Toyoda F, Mesirca P, Dubel S, et al. CaV1.3 L-type Ca2+ channel contributes to the heartbeat by generating a dihydropyridine-sensitive persistent Na+ current. Sci Rep. 2017;7:7869.
Ishihara K, Yan DH, Yamamoto S, Ehara T. Inward rectifier K(+) current under physiological cytoplasmic conditions in Guinea-pig cardiac ventricular cells. J Physiol. 2002;540:831–41.
Matsuoka S, Sarai N, Kuratomi S, Ono K, Noma A. Role of individual ionic current systems in ventricular cells hypothesized by a model study. Jpn J Physiol. 2003;53:105–23.
Hagiwara N, Irisawa H, Kasanuki H, Hosoda S. Background current in sino-atrial node cells of the rabbit heart. J Physiol. 1992;448:53–72.
Tellez JO, Dobrzynski H, Greener ID, et al. Differential expression of ion channel transcripts in atrial muscle and sinoatrial node in rabbit. Circ Res. 2006;99:1384–93.
Irisawa A, editor. Fine structure of the small sinoatrial node specimen used for voltage clamp experiment, vol. 26. The Hague: Martinus Nijihoff Medical Division; 1978. p. 311–9.
Glukhovsky A, Adam DR, Amitzur G, Sideman S. Mechanism of Ca++ release from the sarcoplasmic reticulum: a computer model. Ann Biomed Eng. 1998;26:213–29.
Snyder SM, Palmer BM, Moore RL. A mathematical model of cardiocyte Ca(2+) dynamics with a novel representation of sarcoplasmic reticular Ca(2+) control. Biophys J. 2000;79:94–115.
Doerr T, Denger R, Trautwein W. Calcium currents in single SA nodal cells of the rabbit heart studied with action potential clamp. Pflugers Arch. 1989;413:599–603.
Vinogradova TM, Zhou YY, Maltsev V, Lyashkov A, Stern M, Lakatta EG. Rhythmic ryanodine receptor Ca2+ releases during diastolic depolarization of sinoatrial pacemaker cells do not require membrane depolarization. Circ Res. 2004;94:802–9.
Lyashkov AE, Juhaszova M, Dobrzynski H, et al. Calcium cycling protein density and functional importance to automaticity of isolated sinoatrial nodal cells are independent of cell size. Circ Res. 2007;100:1723–31.
Maltsev VA, Lakatta EG. Dynamic interactions of an intracellular Ca2+ clock and membrane ion channel clock underlie robust initiation and regulation of cardiac pacemaker function. Cardiovasc Res. 2008;77:274–84.
Ferrier GR. The effects of tension on acetylstrophanthidin-induced transient depolarizations and aftercontractions in canine myocardial and Purkinje tissues. Circ Res. 1976;38:156–62.
Matsuda H, Noma A, Kurachi Y, Irisawa H. Transient depolarization and spontaneous voltage fluctuations in isolated single cells from Guinea pig ventricles. Calcium-mediated membrane potential fluctuations. Circ Res. 1982;51:142–51.
Stern MD, Maltseva LA, Juhaszova M, et al. Hierarchical clustering of ryanodine receptors enables emergence of a calcium clock in sinoatrial node cells. J Gen Physiol. 2014;143:577–604.
Himeno Y, Asakura K, Cha CY, Memida H, Powell T, Amano A, Noma A. A human ventricular myocyte model with a refined representation of excitation-contraction coupling. Biophys J. 2015;109:415–27.
Asakura K, Cha CY, Yamaoka H, Horikawa Y, Memida H, Powell T, Amano A, Noma A, et al. EAD and DAD mechanisms analyzed by developing a new human ventricular cell model. Prog Biophys Mol Biol. 2014;116:11–24.
Okamoto Y, Takano M, Ohba T, Ono K. Arrhythmogenic coupling between the Na+ -Ca2+ exchanger and inositol 1,4,5-triphosphate receptor in rat pulmonary vein cardiomyocytes. J Mol Cell Cardiol. 2012;52:988–97.
Umehara S, Tan X, Okamoto Y, Ono K, Noma A, Amano A, Himeno Y. Mechanisms underlying spontaneous action potential generation induced by catecholamine in pulmonary vein cardiomyocytes: a simulation study. Int J Mol Sci. 2019;20:2913.
Himeno Y, Toyoda F, Satoh H, Amano A, Cha CY, Matsuura H, Noma A. Minor contribution of cytosolic Ca2+ transients to the pacemaker rhythm in Guinea pig sinoatrial node cells. Am J Physiol Heart Circ Physiol. 2011;300:H251–61.
Acknowledgments
This work was supported by JSPS Grant-in-Aid for Young Scientists (B) (JP16K18996), the Research Promotion Program for Acquiring Grants in-Aid for Scientific Research (KAKENHI) and Individual Research Allowance at Ritsumeikan University to Y. H.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2023 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Himeno, Y., Amano, A., Noma, A. (2023). Ionic Basis of the Pacemaker Activity of SA Node Cell Revealed by the Lead Potential Analysis. In: Tripathi, O.N., Quinn, T.A., Ravens, U. (eds) Heart Rate and Rhythm. Springer, Cham. https://doi.org/10.1007/978-3-031-33588-4_3
Download citation
DOI: https://doi.org/10.1007/978-3-031-33588-4_3
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-33587-7
Online ISBN: 978-3-031-33588-4
eBook Packages: MedicineMedicine (R0)