Skip to main content
SpringerLink
Log in

Neural Regulation of Cardiac Rhythm

  • Chapter
  • First Online:
Cardiovascular Signaling in Health and Disease

  • 484 Accesses

Abstract

The autonomic nervous system (ANS) regulates cardiac function, including chronotropy, inotropy, lusitropy, and dromotropy. The cardiac nervous system includes afferent, efferent, and interconnecting neurons, which span the intrinsic cardiac nervous system (ICNS: within the pericardium), extracardiac ganglia, and central nervous system (CNS: spinal cord and brain). This chapter focuses primarily on efferent sympathetic and parasympathetic neurotransmission and resulting end-organ (i.e., heart) electrophysiological responses. The signaling mechanisms of primary neurotransmitters are discussed, as well as the contribution of co-transmitters. Finally, several in vitro experimental models for the study of neural control of cardiac rhythm are highlighted, including key physiological findings revealed by these experimental models.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Fukuda K, Kanazawa H, Aizawa Y, Ardell JL, Shivkumar K. Cardiac innervation and sudden cardiac death. Circ Res. 2015;116(12):2005–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wang L, Morotti S, Tapa S, Francis Stuart SD, Jiang Y, Wang Z, et al. Different paths, same destination: divergent action potential responses produce conserved cardiac fight-or-flight response in mouse and rabbit hearts. J Physiol. 2019;597(15):3867–83.

    Article  CAS  PubMed  Google Scholar 

  3. Ripplinger CM, Noujaim SF, Linz D. The nervous heart. Prog Biophys Mol Biol. 2016;120(1-3):199–209.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Butler CK, Smith FM, Cardinal R, Murphy DA, Hopkins DA, Armour JA. Cardiac responses to electrical stimulation of discrete loci in canine atrial and ventricular ganglionated plexi. Am J Phys. 1990;259(5 Pt 2):H1365–73.

    CAS  Google Scholar 

  5. Armour JA, Murphy DA, Yuan BX, Macdonald S, Hopkins DA. Gross and microscopic anatomy of the human intrinsic cardiac nervous system. Anat Rec. 1997;247(2):289–98.

    Article  CAS  PubMed  Google Scholar 

  6. Singh S, Johnson PI, Lee RE, Orfei E, Lonchyna VA, Sullivan HJ, et al. Topography of cardiac ganglia in the adult human heart. J Thorac Cardiovasc Surg. 1996;112(4):943–53.

    Article  CAS  PubMed  Google Scholar 

  7. Rysevaite K, Saburkina I, Pauziene N, Noujaim SF, Jalife J, Pauza DH. Morphologic pattern of the intrinsic ganglionated nerve plexus in mouse heart. Heart Rhythm. 2011;8(3):448–54.

    Article  PubMed  Google Scholar 

  8. Saburkina I, Gukauskiene L, Rysevaite K, Brack KE, Pauza AG, Pauziene N, et al. Morphological pattern of intrinsic nerve plexus distributed on the rabbit heart and interatrial septum. J Anat. 2014;224(5):583–93.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Batulevicius D, Pauziene N, Pauza DH. Topographic morphology and age-related analysis of the neuronal number of the rat intracardiac nerve plexus. Ann Anat. 2003;185(5):449–59.

    Article  PubMed  Google Scholar 

  10. Gagliardi M, Randall WC, Bieger D, Wurster RD, Hopkins DA, Armour JA. Activity of in vivo canine cardiac plexus neurons. Am J Phys. 1988;255(4 Pt 2):H789–800.

    CAS  Google Scholar 

  11. Pauza DH, Skripka V, Pauziene N, Stropus R. Morphology, distribution, and variability of the epicardiac neural ganglionated subplexuses in the human heart. Anat Rec. 2000;259(4):353–82.

    Article  CAS  PubMed  Google Scholar 

  12. Saburkina I, Rysevaite K, Pauziene N, Mischke K, Schauerte P, Jalife J, et al. Epicardial neural ganglionated plexus of ovine heart: anatomic basis for experimental cardiac electrophysiology and nerve protective cardiac surgery. Heart Rhythm. 2010;7(7):942–50.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Kawano H, Okada R, Yano K. Histological study on the distribution of autonomic nerves in the human heart. Heart Vessel. 2003;18(1):32–9.

    Article  Google Scholar 

  14. Ito M, Zipes DP. Efferent sympathetic and vagal innervation of the canine right ventricle. Circulation. 1994;90(3):1459–68.

    Article  CAS  PubMed  Google Scholar 

  15. Crick SJ, Anderson RH, Ho SY, Sheppard MN. Localisation and quantitation of autonomic innervation in the porcine heart II: endocardium, myocardium and epicardium. J Anat. 1999;195(Pt 3):359–73.

    Google Scholar 

  16. Francis Stuart SD, Wang L, Woodard WR, Ng GA, Habecker BA, Ripplinger CM. Age-related changes in cardiac electrophysiology and calcium handling in response to sympathetic nerve stimulation. J Physiol. 2018;596(17):3977–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Coote JH. Myths and realities of the cardiac vagus. J Physiol. 2013;591(17):4073–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ulphani JS, Cain JH, Inderyas F, Gordon D, Gikas PV, Shade G, et al. Quantitative analysis of parasympathetic innervation of the porcine heart. Heart Rhythm. 2010;7(8):1113–9.

    Article  PubMed  Google Scholar 

  19. O'Connell TD, Jensen BC, Baker AJ, Simpson PC. Cardiac alpha1-adrenergic receptors: novel aspects of expression, signaling mechanisms, physiologic function, and clinical importance. Pharmacol Rev. 2014;66(1):308–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Bristow MR, Ginsburg R, Umans V, Fowler M, Minobe W, Rasmussen R, et al. Beta 1- and beta 2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor down-regulation in heart failure. Circ Res. 1986;59(3):297–309.

    Article  CAS  PubMed  Google Scholar 

  21. Nikolaev VO, Moshkov A, Lyon AR, Miragoli M, Novak P, Paur H, et al. Beta2-adrenergic receptor redistribution in heart failure changes cAMP compartmentation. Science. 2010;327(5973):1653–7.

    Article  CAS  PubMed  Google Scholar 

  22. Bucchi A, Baruscotti M, Robinson RB, DiFrancesco D. Modulation of rate by autonomic agonists in SAN cells involves changes in diastolic depolarization and the pacemaker current. J Mol Cell Cardiol. 2007;43(1):39–48.

    Article  CAS  PubMed  Google Scholar 

  23. Bers DM. Cardiac excitation-contraction coupling. Nature. 2002;415(6868):198–205.

    Article  CAS  PubMed  Google Scholar 

  24. Reuter H. Localization of beta adrenergic receptors, and effects of noradrenaline and cyclic nucleotides on action potentials, ionic currents and tension in mammalian cardiac muscle. J Physiol. 1974;242(2):429–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kirchberber MA, Tada M, Katz AM. Phospholamban: a regulatory protein of the cardiac sarcoplasmic reticulum. Recent Adv Stud Cardiac Struct Metab. 1975;5:103–15.

    CAS  PubMed  Google Scholar 

  26. Shannon TR, Ginsburg KS, Bers DM. Potentiation of fractional sarcoplasmic reticulum calcium release by total and free intra-sarcoplasmic reticulum calcium concentration. Biophys J. 2000;78(1):334–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Viatchenko-Karpinski S, Györke S. Modulation of the Ca(2+)-induced Ca(2+) release cascade by beta-adrenergic stimulation in rat ventricular myocytes. J Physiol. 2001;533(Pt 3):837–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, et al. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell. 2000;101(4):365–76.

    Article  CAS  PubMed  Google Scholar 

  29. Valdivia HH, Kaplan JH, Ellis-Davies GC, Lederer WJ. Rapid adaptation of cardiac ryanodine receptors: modulation by Mg2+ and phosphorylation. Science. 1995;267(5206):1997–2000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Vinogradova TM, Lyashkov AE, Zhu W, Ruknudin AM, Sirenko S, Yang D, et al. High basal protein kinase A-dependent phosphorylation drives rhythmic internal Ca2+ store oscillations and spontaneous beating of cardiac pacemaker cells. Circ Res. 2006;98(4):505–14.

    Article  CAS  PubMed  Google Scholar 

  31. Bogdanov KY, Maltsev VA, Vinogradova TM, Lyashkov AE, Spurgeon HA, Stern MD, et al. Membrane potential fluctuations resulting from submembrane Ca2+ releases in rabbit sinoatrial nodal cells impart an exponential phase to the late diastolic depolarization that controls their chronotropic state. Circ Res. 2006;99(9):979–87.

    Article  CAS  PubMed  Google Scholar 

  32. Lakatta EG, Maltsev VA, Vinogradova TM. A coupled SYSTEM of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart's pacemaker. Circ Res. 2010;106(4):659–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Pogwizd SM, Schlotthauer K, Li L, Yuan W, Bers DM. Arrhythmogenesis and contractile dysfunction in heart failure: roles of sodium-calcium exchange, inward rectifier potassium current, and residual beta-adrenergic responsiveness. Circ Res. 2001;88(11):1159–67.

    Article  CAS  PubMed  Google Scholar 

  34. Pogwizd SM, Bers DM. Cellular basis of triggered arrhythmias in heart failure. Trends Cardiovasc Med. 2004;14(2):61–6.

    Article  CAS  PubMed  Google Scholar 

  35. Li L, Desantiago J, Chu G, Kranias EG, Bers DM. Phosphorylation of phospholamban and troponin I in beta-adrenergic-induced acceleration of cardiac relaxation. Am J Physiol Heart Circ Physiol. 2000;278(3):H769–79.

    Article  CAS  PubMed  Google Scholar 

  36. Kentish JC, McCloskey DT, Layland J, Palmer S, Leiden JM, Martin AF, et al. Phosphorylation of troponin I by protein kinase A accelerates relaxation and crossbridge cycle kinetics in mouse ventricular muscle. Circ Res. 2001;88(10):1059–65.

    Article  CAS  PubMed  Google Scholar 

  37. Bartos DC, Grandi E, Ripplinger CM. Ion channels in the heart. Compr Physiol. 2015;5(3):1423–64.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Campbell AS, Johnstone SR, Baillie GS, Smith G. beta-Adrenergic modulation of myocardial conduction velocity: Connexins vs. sodium current. J Mol Cell Cardiol. 2014;77:147–54.

    Article  CAS  PubMed  Google Scholar 

  39. Herren AW, Bers DM, Grandi E. Post-translational modifications of the cardiac Na channel: contribution of CaMKII-dependent phosphorylation to acquired arrhythmias. Am J Physiol Heart Circ Physiol. 2013;305(4):H431–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Somekawa S, Fukuhara S, Nakaoka Y, Fujita H, Saito Y, Mochizuki N. Enhanced functional gap junction neoformation by protein kinase A-dependent and Epac-dependent signals downstream of cAMP in cardiac myocytes. Circ Res. 2005;97(7):655–62.

    Article  CAS  PubMed  Google Scholar 

  41. TenBroek EM, Lampe PD, Solan JL, Reynhout JK, Johnson RG. Ser364 of connexin43 and the upregulation of gap junction assembly by cAMP. J Cell Biol. 2001;155(7):1307–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Salameh A, Frenzel C, Boldt A, Rassler B, Glawe I, Schulte J, et al. Subchronic alpha- and beta-adrenergic regulation of cardiac gap junction protein expression. FASEB J. 2006;20(2):365–7.

    Article  CAS  PubMed  Google Scholar 

  43. Kagan A, Melman YF, Krumerman A, McDonald TV. 14-3-3 amplifies and prolongs adrenergic stimulation of HERG K+ channel activity. EMBO J. 2002;21(8):1889–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Marx SO, Kurokawa J, Reiken S, Motoike H, D'Armiento J, Marks AR, et al. Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel. Science. 2002;295(5554):496–9.

    Article  CAS  PubMed  Google Scholar 

  45. Chiamvimonvat N, Chen-Izu Y, Clancy CE, Deschenes I, Dobrev D, Heijman J, et al. Potassium currents in the heart: functional roles in repolarization, arrhythmia and therapeutics. J Physiol. 2017;595(7):2229–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Xiao RP. Beta-adrenergic signaling in the heart: dual coupling of the beta2-adrenergic receptor to G(s) and G(i) proteins. Sci STKE. 2001;2001(104):re15.

    Google Scholar 

  47. Davare MA, Avdonin V, Hall DD, Peden EM, Burette A, Weinberg RJ, et al. A beta2 adrenergic receptor signaling complex assembled with the Ca2+ channel Cav1.2. Science. 2001;293(5527):98–101.

    Article  CAS  PubMed  Google Scholar 

  48. Gallego M, Casis O. Regulation of cardiac transient outward potassium current by norepinephrine in normal and diabetic rats. Diabetes Metab Res Rev. 2001;17(4):304–9.

    Article  CAS  PubMed  Google Scholar 

  49. Gallego M, Setien R, Puebla L, Boyano-Adanez Mdel C, Arilla E, Casis O. alpha1-Adrenoceptors stimulate a Galphas protein and reduce the transient outward K+ current via a cAMP/PKA-mediated pathway in the rat heart. Am J Physiol Cell Physiol. 2005;288(3):C577–85.

    Article  CAS  PubMed  Google Scholar 

  50. Gallego M, Alday A, Alonso H, Casis O. Adrenergic regulation of cardiac ionic channels: role of membrane microdomains in the regulation of kv4 channels. Biochim Biophys Acta. 2014;1838(2):692–9.

    Article  CAS  PubMed  Google Scholar 

  51. Krapivinsky G, Krapivinsky L, Wickman K, Clapham DE. G beta gamma binds directly to the G protein-gated K+ channel, IKACh. J Biol Chem. 1995;270(49):29059–62.

    Article  CAS  PubMed  Google Scholar 

  52. Han SY, Bolter CP. Effects of tertiapin-Q and ZD7288 on changes in sinoatrial pacemaker rhythm during vagal stimulation. Auton Neurosci. 2015;193:117–26.

    Article  CAS  PubMed  Google Scholar 

  53. Dhein S, van Koppen CJ, Brodde OE. Muscarinic receptors in the mammalian heart. Pharmacol Res. 2001;44(3):161–82.

    Article  CAS  PubMed  Google Scholar 

  54. Wang Z, Shi H, Wang H. Functional M3 muscarinic acetylcholine receptors in mammalian hearts. Br J Pharmacol. 2004;142(3):395–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ho HT, Belevych AE, Liu B, Bonilla IM, Radwanski PB, Kubasov IV, et al. Muscarinic stimulation facilitates sarcoplasmic reticulum ca release by modulating ryanodine receptor 2 phosphorylation through protein Kinase G and Ca/Calmodulin-dependent protein Kinase II. Hypertension. 2016;68(5):1171–8.

    Article  CAS  PubMed  Google Scholar 

  56. Baine S, Thomas J, Bonilla I, Ivanova M, Belevych A, Li J, et al. Muscarinic-dependent phosphorylation of the cardiac ryanodine receptor by protein kinase G is mediated by PI3K-AKT-nNOS signaling. J Biol Chem. 2020;295(33):11720–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Burnstock G. Autonomic neurotransmission: 60 years since sir Henry Dale. Annu Rev Pharmacol Toxicol. 2009;49:1–30.

    Article  CAS  PubMed  Google Scholar 

  58. Smith-White MA, Herzog H, Potter EK. Role of neuropeptide Y Y(2) receptors in modulation of cardiac parasympathetic neurotransmission. Regul Pept. 2002;103(2-3):105–11.

    Article  CAS  PubMed  Google Scholar 

  59. Herring N, Lokale MN, Danson EJ, Heaton DA, Paterson DJ. Neuropeptide Y reduces acetylcholine release and vagal bradycardia via a Y2 receptor-mediated, protein kinase C-dependent pathway. J Mol Cell Cardiol. 2008;44(3):477–85.

    Article  CAS  PubMed  Google Scholar 

  60. Kalla M, Hao G, Tapoulal N, Tomek J, Liu K, Woodward L, et al. The cardiac sympathetic co-transmitter neuropeptide Y is pro-arrhythmic following ST-elevation myocardial infarction despite beta-blockade. Eur Heart J. 2019;41:2168.

    Article  PubMed Central  CAS  Google Scholar 

  61. Ajijola OA, Chatterjee NA, Gonzales MJ, Gornbein J, Liu K, Li D, et al. Coronary sinus neuropeptide Y levels and adverse outcomes in patients with stable chronic heart failure. JAMA Cardiol. 2019;5:318.

    Article  PubMed Central  Google Scholar 

  62. Herring N, Cranley J, Lokale MN, Li D, Shanks J, Alston EN, et al. The cardiac sympathetic co-transmitter galanin reduces acetylcholine release and vagal bradycardia: implications for neural control of cardiac excitability. J Mol Cell Cardiol. 2012;52(3):667–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Christophe J, Waelbroeck M, Chatelain P, Robberecht P. Heart receptors for VIP, PHI and secretin are able to activate adenylate cyclase and to mediate inotropic and chronotropic effects. Species variations and physiopathology. Peptides. 1984;5(2):341–53.

    Article  CAS  PubMed  Google Scholar 

  64. Rigel DF. Effects of neuropeptides on heart rate in dogs: comparison of VIP, PHI, NPY, CGRP, and NT. Am J Phys. 1988;255(2 Pt 2):H311–7.

    CAS  Google Scholar 

  65. De Neef P, Robberecht P, Chatelain P, Waelbroeck M, Christophe J. The in vitro chronotropic and inotropic effects of vasoactive intestinal peptide (VIP) on the atria and ventricular papillary muscle from Cynomolgus monkey heart. Regul Pept. 1984;8(3):237–44.

    Article  PubMed  Google Scholar 

  66. Markos F, Snow HM. An investigation into the physiological relevance of the vagal tachycardia in the anaesthetized dog. Acta Physiol (Oxf). 2006;186(3):179–84.

    Article  CAS  Google Scholar 

  67. Hogan K, Markos F. Vasoactive intestinal polypeptide receptor antagonism enhances the vagally induced increase in cardiac interval of the rat atrium in vitro. Exp Physiol. 2006;91(3):641–6.

    Article  CAS  PubMed  Google Scholar 

  68. Fischmeister R, Castro L, Abi-Gerges A, Rochais F, Vandecasteele G. Species- and tissue-dependent effects of NO and cyclic GMP on cardiac ion channels. Comp Biochem Physiol A Mol Integr Physiol. 2005;142(2):136–43.

    Article  PubMed  CAS  Google Scholar 

  69. Massion PB, Feron O, Dessy C, Balligand JL. Nitric oxide and cardiac function: ten years after, and continuing. Circ Res. 2003;93(5):388–98.

    Article  CAS  PubMed  Google Scholar 

  70. Brack KE, Patel VH, Coote JH, Ng GA. Nitric oxide mediates the vagal protective effect on ventricular fibrillation via effects on action potential duration restitution in the rabbit heart. J Physiol. 2007;583(Pt 2):695–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Chowdhary S, Vaile JC, Fletcher J, Ross HF, Coote JH, Townend JN. Nitric oxide and cardiac autonomic control in humans. Hypertension. 2000;36(2):264–9.

    Article  CAS  PubMed  Google Scholar 

  72. Paterson D. Nitric oxide and the autonomic regulation of cardiac excitability. The G.L. Brown Prize Lecture. Exp Physiol. 2001;86(1):1–12.

    Article  CAS  PubMed  Google Scholar 

  73. Herring N. Autonomic control of the heart: going beyond the classical neurotransmitters. Exp Physiol. 2015;100(4):354–8.

    Article  CAS  PubMed  Google Scholar 

  74. Burnstock G. Purinergic signaling in the cardiovascular system. Circ Res. 2017;120(1):207–28.

    Article  CAS  PubMed  Google Scholar 

  75. Headrick JP, Ashton KJ, Rose'meyer RB, Peart JN. Cardiovascular adenosine receptors: expression, actions and interactions. Pharmacol Ther. 2013;140(1):92–111.

    Article  CAS  PubMed  Google Scholar 

  76. Belardinelli L, Giles WR, West A. Ionic mechanisms of adenosine actions in pacemaker cells from rabbit heart. J Physiol. 1988;405:615–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. West GA, Belardinelli L. Correlation of sinus slowing and hyperpolarization caused by adenosine in sinus node. Pflugers Arch. 1985;403(1):75–81.

    Article  CAS  PubMed  Google Scholar 

  78. Katchanov G, Xu J, Hurt CM, Pelleg A. Electrophysiological-anatomic correlates of ATP-triggered vagal reflex in the dog. III. Role of cardiac afferents. Am J Phys. 1996;270(5 Pt 2):H1785–90.

    CAS  Google Scholar 

  79. Ajijola OA, Vaseghi M, Zhou W, Yamakawa K, Benharash P, Hadaya J, et al. Functional differences between junctional and extrajunctional adrenergic receptor activation in mammalian ventricle. Am J Physiol Heart Circ Physiol. 2013;304(4):H579–88.

    Article  CAS  PubMed  Google Scholar 

  80. Ajijola OA, Yagishita D, Patel KJ, Vaseghi M, Zhou W, Yamakawa K, et al. Focal myocardial infarction induces global remodeling of cardiac sympathetic innervation: neural remodeling in a spatial context. Am J Physiol Heart Circ Physiol. 2013;305(7):H1031–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Vaseghi M, Lux RL, Mahajan A, Shivkumar K. Sympathetic stimulation increases dispersion of repolarization in humans with myocardial infarction. Am J Physiol Heart Circ Physiol. 2012;302(9):H1838–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lockhart ST, Turrigiano GG, Birren SJ. Nerve growth factor modulates synaptic transmission between sympathetic neurons and cardiac myocytes. J Neurosci. 1997;17(24):9573–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Shcherbakova OG, Hurt CM, Xiang Y, Dell'Acqua ML, Zhang Q, Tsien RW, et al. Organization of beta-adrenoceptor signaling compartments by sympathetic innervation of cardiac myocytes. J Cell Biol. 2007;176(4):521–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Barnett JV, Taniuchi M, Yang MB, Galper JB. Co-culture of embryonic chick heart cells and ciliary ganglia induces parasympathetic responsiveness in embryonic chick heart cells. Biochem J. 1993;292(Pt 2):395–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Marvin WJ Jr, Atkins DL, Chittick VL, Lund DD, Hermsmeyer K. In vitro adrenergic and cholinergic innervation of the developing rat myocyte. Circ Res. 1984;55(1):49–58.

    Article  PubMed  Google Scholar 

  86. Prando V, Da Broi F, Franzoso M, Plazzo AP, Pianca N, Francolini M, et al. Dynamics of neuroeffector coupling at cardiac sympathetic synapses. J Physiol. 2018;596(11):2055–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Winbo A, Ramanan S, Eugster E, Jovinge S, Skinner JR, Montgomery JM. Functional coculture of sympathetic neurons and cardiomyocytes derived from human-induced pluripotent stem cells. Am J Physiol Heart Circ Physiol. 2020;319(5):H927–H37.

    Article  CAS  PubMed  Google Scholar 

  88. Takayama Y, Kushige H, Akagi Y, Suzuki Y, Kumagai Y, Kida YS. Selective induction of human autonomic neurons enables precise control of Cardiomyocyte beating. Sci Rep. 2020;10(1):9464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Larsen HE, Lefkimmiatis K, Paterson DJ. Sympathetic neurons are a powerful driver of myocyte function in cardiovascular disease. Sci Rep. 2016;6:38898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Flannery RJ, Bruses JL. N-cadherin induces partial differentiation of cholinergic presynaptic terminals in heterologous cultures of brainstem neurons and CHO cells. Front Synaptic Neurosci. 2012;4:6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zarzoso M, Rysevaite K, Milstein ML, Calvo CJ, Kean AC, Atienza F, et al. Nerves projecting from the intrinsic cardiac ganglia of the pulmonary veins modulate sinoatrial node pacemaker function. Cardiovasc Res. 2013;99(3):566–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Allen E, Coote JH, Grubb BD, Batten TFC, Pauza DH, Ng GA, et al. Electrophysiological effects of nicotinic and electrical stimulation of intrinsic cardiac ganglia in the absence of extrinsic autonomic nerves in the rabbit heart. Heart Rhythm. 2018;15(11):1698–707.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Rajendran PS, Challis RC, Fowlkes CC, Hanna P, Tompkins JD, Jordan MC, et al. Identification of peripheral neural circuits that regulate heart rate using optogenetic and viral vector strategies. Nat Commun. 2019;10(1):1944.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Hoover DB, Ganote CE, Ferguson SM, Blakely RD, Parsons RL. Localization of cholinergic innervation in guinea pig heart by immunohistochemistry for high-affinity choline transporters. Cardiovasc Res. 2004;62(1):112–21.

    Article  CAS  PubMed  Google Scholar 

  95. Jungen C, Scherschel K, Eickholt C, Kuklik P, Klatt N, Bork N, et al. Disruption of cardiac cholinergic neurons enhances susceptibility to ventricular arrhythmias. Nat Commun. 2017;8:14155.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Wengrowski AM, Wang X, Tapa S, Posnack NG, Mendelowitz D, Kay MW. Optogenetic release of norepinephrine from cardiac sympathetic neurons alters mechanical and electrical function. Cardiovasc Res. 2015;105(2):143–50.

    Article  CAS  PubMed  Google Scholar 

  97. Moreno A, Endicott K, Skancke M, Dwyer MK, Brennan J, Efimov IR, et al. Sudden heart rate reduction upon optogenetic release of acetylcholine from cardiac parasympathetic neurons in perfused hearts. Front Physiol. 2019;10:16.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Choate JK, Edwards FR, Hirst GD, O'Shea JE. Effects of sympathetic nerve stimulation on the sino-atrial node of the guinea-pig. J Physiol. 1993;471:707–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Bramich NJ, Brock JA, Edwards FR, Hirst GD. Responses to sympathetic nerve stimulation of the sinus venosus of the toad. J Physiol. 1993;461:403–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Campbell GD, Edwards FR, Hirst GD, O'Shea JE. Effects of vagal stimulation and applied acetylcholine on pacemaker potentials in the guinea-pig heart. J Physiol. 1989;415:57–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Hutter OF. The vagus and the heart: revisiting an early contribution to a still on-going dispute. J Physiol. 2012;590(10):2535–6. author reply 7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Ng GA, Brack KE, Coote JH. Effects of direct sympathetic and vagus nerve stimulation on the physiology of the whole heart--a novel model of isolated Langendorff perfused rabbit heart with intact dual autonomic innervation. Exp Physiol. 2001;86(3):319–29.

    Article  CAS  PubMed  Google Scholar 

  103. Ng GA, Mantravadi R, Walker WH, Ortin WG, Choi BR, de Groat W, et al. Sympathetic nerve stimulation produces spatial heterogeneities of action potential restitution. Heart Rhythm. 2009;6(5):696–706.

    Article  PubMed  Google Scholar 

  104. Mantravadi R, Gabris B, Liu T, Choi BR, de Groat WC, Ng GA, et al. Autonomic nerve stimulation reverses ventricular repolarization sequence in rabbit hearts. Circ Res. 2007;100(7):e72–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Tapa S, Wang L, Francis Stuart SD, Wang Z, Jiang Y, Habecker BA, et al. Adrenergic supersensitivity and impaired neural control of cardiac electrophysiology following regional cardiac sympathetic nerve loss. Sci Rep. 2020;10(1):18801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Wang L, Olivas A, Francis Stuart SD, Tapa S, Blake MR, Woodward WR, et al. Cardiac sympathetic nerve transdifferentiation reduces action potential heterogeneity after myocardial infarction. Am J Physiol Heart Circ Physiol. 2020;318(3):H558–H65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Paton JF. A working heart-brainstem preparation of the mouse. J Neurosci Methods. 1996;65(1):63–8.

    Article  CAS  PubMed  Google Scholar 

  108. Ashton JL, Paton JF, Trew ML, LeGrice IJ, Smaill BH. A working heart-brainstem preparation of the rat for the study of reflex mediated autonomic influences on atrial arrhythmia development. Annu Int Conf IEEE Eng Med Biol Soc. 2013;2013:3785–8.

    PubMed  Google Scholar 

  109. Ashton JL, Trew ML, LeGrice IJ, Paterson DJ, Paton JF, Gillis AM, et al. Shift of leading pacemaker site during reflex vagal stimulation and altered electrical source-to-sink balance. J Physiol. 2019;597(13):3297–313.

    Article  CAS  PubMed  Google Scholar 

  110. Habecker BA, Anderson ME, Birren SJ, Fukuda K, Herring N, Hoover DB, et al. Molecular and cellular neurocardiology: development, and cellular and molecular adaptations to heart disease. J Physiol. 2016;594(14):3853–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, UC Davis School of Medicine, Davis, CA, USA

    Crystal M. Ripplinger

Authors
  1. Crystal M. Ripplinger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Crystal M. Ripplinger .

Editor information

Editors and Affiliations

  1. Division of Pulmonary, Critical Care, and Sleep Medicine Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    Narasimham L. Parinandi

  2. Departments of Biomedical Engineering and Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA

    Thomas J. Hund

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Ripplinger, C.M. (2022). Neural Regulation of Cardiac Rhythm. In: Parinandi, N.L., Hund, T.J. (eds) Cardiovascular Signaling in Health and Disease. Springer, Cham. https://doi.org/10.1007/978-3-031-08309-9_11

Download citation

Publish with us

Policies and ethics

Search

Navigation