Advertisement

Sympathetic and vagal interaction in the control of cardiac pacemaker rhythm in the guinea-pig heart: Importance of expressing heart rhythm using an appropriate metric

  • Sherif Elawa
    Affiliations
    Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, SE-58185 Linköping, Sweden
    Search for articles by this author
  • Robert M. Persson
    Affiliations
    Department of Heart Disease, Haukeland University Hospital, 5021 Bergen, Norway
    Search for articles by this author
  • Su Young Han
    Affiliations
    Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK
    Search for articles by this author
  • Author Footnotes
    1 The study was performed at the Department of Physiology, School of Medical Sciences, University of Otago, PO Box 913, Dunedin, 9054, New Zealand.
    Chris P. Bolter
    Correspondence
    Corresponding author.
    Footnotes
    1 The study was performed at the Department of Physiology, School of Medical Sciences, University of Otago, PO Box 913, Dunedin, 9054, New Zealand.
    Affiliations
    Department of Physiology, School of Medical Sciences, University of Otago, 913, Dunedin 9054, New Zealand
    Search for articles by this author
  • Author Footnotes
    1 The study was performed at the Department of Physiology, School of Medical Sciences, University of Otago, PO Box 913, Dunedin, 9054, New Zealand.
Published:September 10, 2022DOI:https://doi.org/10.1016/j.autneu.2022.103025

      Highlights

      • Illustrated importance of expressing changes in heart rate and heart period as fractions or ratios
      • No evidence for accentuated antagonism in autonomic control of guinea-pig heart rhythm
      • Influence of brief/small vagal input on heart rhythm is reduced by sympathetic stimulation.

      Abstract

      There are many reports that, through pre- and post-junctional mechanisms, sympathetic and parasympathetic (vagal) nerves can interact in the control of heart rate. The predominant interaction is accentuated antagonism (AA), where the bradycardia produced by vagal stimulation (VNS) is amplified when heart rate has been increased by sympathetic stimulation (SNS) or beta-adrenergic agonists. The acetylcholine-activated potassium current (IK,Ach), is the primary driver of vagal bradycardia. To examine the participation of IK,Ach in AA, a series of experiments was performed on isolated, double innervated, guinea-pig atrial preparations. Vagal bradycardia was elicited by 10-s trains (1, 2, 5 and 7.5 Hz) or single bursts of VNS (3 stimuli at 50 Hz) before and during acceleration of HR by either SNS (1–3 Hz) or isoprenaline (ISO), in both absence and presence of tertiapin-Q (TQ–IK,Ach blocker). When expressed as an absolute change in HR (beats/min), bradycardia produced by VNS trains was amplified (AA) at all frequencies of VNS in ISO, and at 5 and 7.5 Hz during SNS. Bradycardia in response to 1 and 2 Hz VNS was reduced during SNS. In TQ, only the bradycardia produced by 5 and 7.5 Hz VNS in ISO was amplified. The bradycardia produced by a single burst of VNS was amplified in both ISO and SNS. After TQ the bradycardia in response to a VNS burst was unchanged in ISO, while it was reduced during SNS. When these data were adjusted to account for the increase in baseline HR brought about by SNS and ISO, there was no longer evidence of AA. Diminished responses to low frequencies of VNS (1 and 2 Hz) persisted, and were also seen during IK,Ach block by TQ. We applied the same adjustment to data from 20 published studies. In 8 studies all data indicated AA; 3 studies provided no evidence for AA, and in 9 studies evidence was mixed. There is no doubt that AA can occur in the control of heart rhythm during simultaneous SNS and VNS, but conditions which determine its occurrence, and the mechanisms involved in this interaction remain unclear.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Autonomic Neuroscience: Basic and Clinical
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Akiyama T.
        • Yamazaki T.
        Adrenergic inhibition of endogenous acetylcholine release on postganglionic cardiac vagal nerve terminals.
        Cardiovasc. Res. 2000; 46: 531-538https://doi.org/10.1016/S0008-6363(00)00027-4
        • Ardell J.L.
        • Butler C.K.
        • Smith F.M.
        • Hopkins D.A.
        • Armour J.A.
        Activity of in vivo atria1 and ventricular neurons in chronically decentralized canine hearts.
        Am. J. Physiol. Heart Circ. Physiol. 1991; 260: H713-H721https://doi.org/10.1152/ajpheart.1991.260.3.h713
        • Armour J.A.
        Cardiac neuronal hierarchy in health and disease.
        Am. J. Physiol. Regul. Integr. Comp. Physiol. 2004; 287: R262-R271https://doi.org/10.1152/ajpregu.00183.2004
        • Arnold R.W.
        The human heart rate response profiles to five vagal maneuvers.
        Yale J. Biol. Med. 1999; 72: 237-244
        • Ashton J.L.
        • Thew M.L.
        • LeGrice A.J.
        • Paterson D.J.
        • Paton J.F.R.
        • Gillis A.M.
        • Smaill B.H.
        Shift of leading pacemaker site during reflex vagal stimulation and altered electrical source-to-sink balance.
        J. Physiol. 2019; 597: 3297-3313https://doi.org/10.1113/JP276876
        • Balligand J.-L.
        • Kobzikll L.
        • Hant X.
        • Kaye D.M.
        • Belhassenz L.
        • O'Hara D.S.
        • Kelly R.A.
        • Smith T.W.
        • Michel T.
        Nitric oxide-dependent parasympathetic signaling is due to activation of constitutive endothelial (Type III) nitric oxide synthase in cardiac myocytes.
        J. Biol. Chem. 1995; 270: 14582-14586https://doi.org/10.1074/jbc.270.24.14582
        • Beau S.L.
        • Hand D.E.
        • Schuessler R.B.
        • Bromberg B.I.
        • Kwon B.
        • Boineau J.P.
        Relative densities of muscarinic cholinergic and β-adrenergic receptors in the canine sinoatrial node and their relation to sites of pacemaker activity.
        Circ. Res. 1995; 77: 957-963https://doi.org/10.1161/01.res.77.5.957
        • Boineau J.P.
        • Schuessler R.B.
        • Hackel D.B.
        • Miller C.B.
        • Brockus C.W.
        • Wylds A.C.
        Widespread distribution and rate differentiation of the atrial pacemaker complex.
        Am. J. Physiol. Heart Circ. Physiol. 1980; 239: H406-H415https://doi.org/10.1152/ajpheart.1980.239.3.H406
        • Bolter C.P.
        • Atkinson K.J.
        Maximum heart rate responses to exercise and isoproterenol in the trained rat.
        Am. J. Physiol. Regul. Integr. Comp. Physiol. 1988; 254: R834-R839https://doi.org/10.1152/ajpregu.1988.254.5.R834
        • Bolter C.P.
        • Critz J.B.
        Changes in plasma enzyme activity elicited by running exercise in the dog.
        Exp. Biol. Med. 1974; 145: 1359-1362https://doi.org/10.3181/00379727-145-38013
        • Bolter C.P.
        • English D.J.
        The effects of tertiapin-Q on responses of the sinoatrial pacemaker of the Guinea-pig heart to vagal nerve stimulation and muscarinic agonists.
        Exp. Physiol. 2008; 93: 53-63https://doi.org/10.1113/expphysiol.2007.038901
        • Bolter C.P.
        • Turner M.J.
        Tertiapin-Q removes a large and rapidly acting component of vagal slowing of the Guinea-pig cardiac pacemaker.
        Auton. Neurosci. 2009; 150: 76-81https://doi.org/10.1016/j.autneu.2009.05.244
        • Bolter C.P.
        • Wallace D.J.
        • Hirst G.D.S.
        Failure of Ba2+ and C+ to block the effects of vagal nerve stimulation in sinoatrial node cells of the Guinea-pig heart.
        Auton. Neurosci. 2001; 94: 93-101https://doi.org/10.1016/s1566-0702(01)00355-1
        • Bouman L.N.
        • Gerlings E.D.
        • Biersteker P.A.
        • Bonke F.I.M.
        Pacemaker shift in the sino-atrial node during vagal stimulation.
        Pflugers Arch. 1968; 302: 255-267https://doi.org/10.1007/BF00586730
        • Boyett M.R.
        • Honjo H.
        • Kodama I.
        The sinoatrial node, a heterogeneous pacemaker structure.
        Cardiovasc. Res. 2000; 47: 658-687https://doi.org/10.1016/s0008-6363(00)00135-8
        • Brack K.E.
        • Coote J.H.
        • Ng G.A.
        Interaction between direct sympathetic and vagus nerve stimulation on heart rate in the isolated rabbit heart.
        Exp. Physiol. 2004; 89: 128-139https://doi.org/10.1113/expphysiol.2003.002654
        • Brennan J.A.
        • Chen Q.
        • Gams A.
        • Dyavanapalli J.
        • Mendelowitz D.
        • Peng W.
        • Efimov I.R.
        Evidence of superior and inferior sinoatrial nodes in the mammalian heart.
        JACC Clin. Electrophysiol. 2020; 6: 1827-1840https://doi.org/10.1016/j.jacep.2020.09.012
        • Carrier G.O.
        • Bishop V.S.
        The interaction of acetycholine and norepinephrine on heart rate.
        J. Pharmacol. Exp. Therap. 1972; 180: 31-37
        • Cheng Z.
        • Powley T.L.
        • Schwaber J.S.
        • Doyle F.J.I.I.I.
        Vagal afferent innervation of the atria of the rat heart reconstructed with confocal microscopy.
        J. Comp. Neurol. 1997; 381: 1-17https://doi.org/10.1093/cvr/27.5.760
        • Chin S.H.
        • Allen E.
        • Brack K.E.
        • Ng G.A.
        Effects of sympatho-vagal interaction on ventricular electrophysiology and their modulation during beta-blockade.
        J. Mol. Cell. Cardiol. 2020; 139: 201-212https://doi.org/10.1016/j.yjmcc.2020.01.011
        • Franciosi S.
        • Perry F.K.G.
        • Roston T.M.
        • Armstrong K.R.
        • Claydon V.E.
        • Sanatani S.
        The role of the autonomic nervous system in arrhythmias and sudden cardiac death.
        Auton. Neurosci. 2017; 205: 1-11https://doi.org/10.1016/j.autneu.2017.03.005
        • Furukawa Y.
        • Hoyano Y.
        • Chiba S.
        Parasympathetic inhibition of sympathetic effects on sinus rate in anesthetized dogs.
        Am. J. Physiol. Heart Circ. Physiol. 1996; 271: H44-H50https://doi.org/10.1152/ajpheart.1996.271.1.H44
        • Glukhov A.V.
        • Fedorov V.V.
        • Anderson M.E.
        • Mohler P.J.
        • Efimov I.R.
        Functional anatomy of the murine sinus node: high-resolution optical mapping of ankyrin-B heterozygous mice.
        Am. J. Physiol. Heart Circ. Physiol. 2010; 299: H482-H491https://doi.org/10.1152/ajpheart.00756.2009
        • Grodner A.S.
        • Lahrtz H.S.
        • Pool P.E.
        • Braunwald E.
        Neurotransmitter control of sinoatrial pacemaker frequency in isolated rat atria and in intact rabbits.
        Circ. Res. 1970; 27: 867-873https://doi.org/10.1161/01.res.27.6.867
        • Han A.
        • Shimoni Y.
        • Giles W.R.
        An obligatory role for nitric oxide in autonomic control of mammalian heart rate.
        J. Physiol. 1994; 476: 309-314https://doi.org/10.1113/jphysiol.1994.sp020132
        • Han S.Y.
        • Bolter C.P.
        Effects of tertiapin-Q and ZD7288 on changes in sinoatrial pacemaker rhythm during vagal stimulation.
        Auton. Neurosci. 2015; 193: 117-126https://doi.org/10.1016/j.autneu.2015.10.002
        • Henning R.J.
        • Khalil I.R.
        • Levy M.N.
        Vagal stimulation attenuates sympathetic enhancement of left ventricular function.
        Am. J. Physiol. Heart Circ. Physiol. 1990; 258: H1470-H1475https://doi.org/10.1152/ajpheart.1990.258.5.H1470
        • Herring N.
        • Paterson D.J.
        Nitric oxide-cGMP pathway facilitates acetylcholine release and bradycardia during vagal nerve stimulation in the Guinea-pig in vitro.
        J. Physiol. 2001; 535: 507-518https://doi.org/10.1111/j.1469-7793.2001.00507.x
        • Herring N.
        • Golding S.
        • Paterson D.J.
        Pre-synaptic NO-cGMP pathway modulates vagal control of heart rate in isolated adult Guinea pig atria.
        J. Mol. Cell. Cardiol. 2000; 32: 1795-1804https://doi.org/10.1006/jmcc.2000.1214
        • Herring N.
        • Cranley J.
        • Lokale M.N.
        • Li D.
        • Shanks J.
        • Alston
        • Girard B.M.
        • Carter E.
        • Parsons R.L.
        • Habecker B.A.
        • Paterson D.J.
        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: 667-676https://doi.org/10.1016/j.yjmcc.2011.11.016
        • Herring N.
        • Kalla M.
        • Paterson D.J.
        The autonomic nervous system and cardiac arrhythmias: current concepts and emerging therapies.
        Nat. Rev. Cardiol. 2019; 16: 707-726https://doi.org/10.1038/s41569-019-0221-2
        • Herring N.
        • Tapoulal N.
        • Kalla M.
        • Ye X.
        • Borysova L.
        • Lee R.
        • Dall’Armellina E.
        • Stanley C.
        • Ascione R.
        • Lu C.-J.
        • Banning A.P.
        • Choudhury R.P.
        • Neubauer S.
        • Dora K.
        • Kharbanda R.K.
        • Channon K.M.
        Neuropeptide-Y causes coronary microvascular constriction and is associated with reduced ejection fraction following ST-elevation myocardial infarction.
        Eur. Heart J. 2019; 40: 1920-1929https://doi.org/10.1093/eurheartj/ehz115
        • Jose A.D.
        • Collison D.
        The normal range and determinants of the intrinsic heart rate in man.
        Cardiovasc. Res. 1970; 4: 160-167https://doi.org/10.1093/cvr/4.2.160
        • Kawada T.
        • Sugimachi M.
        • Shishido T.
        • Miyano H.
        • Sato T.
        • Yoshimura R.
        • Miyashita H.
        • Nakahara T.
        • Alexander Jr., J.
        • Sunagawa K.
        Simultaneous identification of static and dynamic vagosympathetic interactions in regulating heart rate.
        Am. J. Physiol. Regul. Integr. Comp. Physiol. 1999; 276: R782-R789https://doi.org/10.1152/ajpregu.1999.276.3.R782
        • Kawada T.
        • Sonobe T.
        • Hayama Y.
        • Nishikawa T.
        • Miyamoto T.
        • Akiyama T.
        • Pearson J.T.
        • Sugimachi M.
        Accentuated antagonism of vagal heart rate control and less potent prejunctional inhibition of vagal acetylcholine release during sympathetic nerve stimulation in the rat.
        Auton. Neurosci. 2019; 218: 25-30https://doi.org/10.1016/j.autneu.2019.02.005
        • Kim D.
        Beta-adrenergic regulation of the muscarinic-gated K+ channel via cyclic AMP-dependent protein kinase in atrial cells.
        Circ. Res. 1990; 67: 1292-1298https://doi.org/10.1161/01.res.67.5.1292
        • Kurogouchi F.
        • Nakane T.
        • Furukawa Y.
        • Hirose M.
        • Inada Y.
        • Chiba S.
        Heterogeneous distribution of beta-adrenoceptors and muscarinic receptors in the sinoatrial node and right atrium of the dog.
        Clin Exptl. Pharmacol. Physiol. 2002; 29: 666-672https://doi.org/10.1046/j.1440-1681.2002.03714.x
        • Lang D.
        • Petrov V.
        • Lou Q.
        • Osipov G.
        • Efimov I.R.
        Spatio-temporal control of the heart rate in the rabbit heart.
        J. Electrocardiol. 2011; 44: 626-634https://doi.org/10.1016/j.exger.2012.03.006
        • Lee S.W.
        • Anderson A.
        • Guzman P.A.
        • Nakano A.
        • Tolkacheva E.G.
        • Wickman K.
        Atrial GIRK channels mediate the effects of vagus nerve stimulation on heart rate dynamics and arrhythmogenesis.
        Front. Physiol. 2018; 9: 943https://doi.org/10.3389/fphys.2018.00943
        • Levy M.N.
        Brief reviews: sympathetic-parasympathetic interactions in the heart.
        Circ. Res. 1971; 29: 437-445https://doi.org/10.1161/01.res.29.5.437
        • Levy M.N.
        Autonomic interactions in cardiac control.
        Ann. N. Y. Acad. Sci. 1990; 601: 209-221https://doi.org/10.1111/j.1749-6632.1990.tb37302.x
        • Levy M.N.
        • Blattberg B.
        Effect of vagal stimulation on the overflow of norepinephrine into the coronary sinus during cardiac sympathetic nerve stimulation in the dog.
        Circ. Res. 1976; 38: 81-84https://doi.org/10.1161/01.res.38.2.81
        • Levy M.N.
        • Zieske H.
        Autonomic control of cardiac pacemaker activity and atrioventricular transmission.
        J. Appl. Physiol. 1969; 27: 465-470https://doi.org/10.1152/jappl.1969.27.4.465
        • Levy M.N.
        • Martin P.J.
        • Lano T.
        • Zieske H.
        Paradoxical effect of vagus nerve stimulation on heart rate in dogs.
        Circ. Res. 1969; 25: 303-314https://doi.org/10.1161/01.res.25.3.303
        • Levy M.N.
        • Lano T.
        • Zieske H.
        Effects of repetitive bursts of vagal activity on heart rate.
        Circ. Res. 1972; 30: 185-186https://doi.org/10.1161/01.res.30.2.186
        • Li D.
        • Paterson D.J.
        Cyclic nucleotide regulation of cardiac sympatho-vagal responsiveness.
        J. Physiol. 2016; 594: 3993-4008https://doi.org/10.1113/JP271827
        • Löffelholz K.
        • Muscholl E.
        Inhibition by parasympathetic nerve stimulation of the release of the adrenergic transmitter.
        Naunyn Schmiedeberg's Arch. Pharmacol. 1970; 267: 181-184https://doi.org/10.1007/BF00999400
        • Mackaay A.J.C.
        • Op’t Hof T.
        • Bleeker W.K.
        • Jongsma H.J.
        • Bouman L.N.
        Interaction of adrenaline and acetylcholine on cardiac pacemaker function. Functional inhomogeneity of the rabbit sinus node.
        J. Pharmacol. Exp. Ther. 1980; 214: 417-422
        • Manabe N.
        • Foldes F.F.
        • Töröcsik A.
        • Nagashima H.
        • Goldiner P.L.
        • Vizi E.S.
        Presynaptic interaction between vagal and sympathetic innervation in the heart: modulation of acetylcholine and noradrenaline release.
        J. Auton. Nerv. Syst. 1991; 32: 233-242https://doi.org/10.1016/0165-1838(91)90117-l
        • Manolis A.A.
        • Manolis T.A.
        • Apostolopoulos E.J.
        • Apostolaki N.E.
        • Melita H.
        • Manolis A.S.
        The role of the autonomic nervous system in cardiac arrhythmias: the neuro-cardiac axis, more foe than friend?.
        Trends Cardiovasc.Med. 2021; 31: 290-302https://doi.org/10.1016/j.tcm.2020.04.011
        • Mantravadi R.
        • Gabris B.
        • Liu T.
        • Choi B.-R.
        • de Groat W.C.
        • Ng G.A.
        • Salama S.
        Autonomic nerve stimulation reverses ventricular repolarization sequence in rabbit hearts.
        Circ. Res. 2007; 100: e2-e80https://doi.org/10.1161/01.RES.0000264101.06417.33
        • McGuirt A.S.
        • Schmacht D.C.
        • Ardell J.L.
        Autonomic interactions for control of atrial rate are maintained after SA nodal parasympathectomy.
        Am. J. Physiol. Heart Circ. Physiol. 1997; 272: H2525-H2533https://doi.org/10.1152/ajpheart.1997.272.6.H2525
        • Miyamoto T.
        • Kawada T.
        • Takaki H.
        • Inagaki M.
        • Yanagiya Y.
        • Jin Y.
        • Sugimachi M.
        • Sunagawa K.
        High plasma norepinephrine attenuates the dynamic heart rate response to vagal stimulation.
        Am. J. Physiol. Heart Circ. Physiol. 2003; 284: H2412-H2418https://doi.org/10.1152/ajpheart.00660.2002
        • Miyamoto T.
        • Kawada T.
        • Yanagiya Y.
        • Inagaki M.
        • Takaki H.
        • Sugimachi M.
        • Sunagawa K.
        Cardiac sympathetic nerve stimulation does not attenuate dynamic vagal control of heart rate via alpha-adrenergic mechanism.
        Am. J. Physiol. Heart Circ. Physiol. 2004; 287: H860-H865https://doi.org/10.1152/ajpheart.00752.2003
        • Miyashita Y.
        • Furukawa Y.
        • Nakajima K.
        • Hirose M.
        • Kurogouchi F.
        • Chiba S.
        Parasympathetic inhibition of sympathetic effects on pacemaker location and rate in hearts of anesthetized dogs.
        J. Cardiovasc. Electrophysiol. 1999; 10: 1066-1076https://doi.org/10.1111/j.1540-8167.1999.tb00279.x
        • Mizuno M.
        • Kamiya A.
        • Kawada T.
        • Miyamoto T.
        • Shimizu S.
        • Shishido T.
        • Sugimachi M.
        Accentuated antagonism in vagal heart rate control mediated through muscarinic potassium channels.
        J. Physiol. Sci. 2008; 58: 381-388https://doi.org/10.2170/physiolsci.RP011508
        • Mori T.
        • Hashimoto A.
        • Takase H.
        • Kambe T.
        Nitric oxide (NO) is not involved in accentuated antagonism for chronotropy in the isolated mouse atrium.
        Naunyn Schmiedeberg's Arch. Pharmacol. 2004; 369: 363-366https://doi.org/10.1007/s00210-004-0924-7
        • Müllner C.
        • Vorobiov D.
        • Bera A.K.
        • Uezono Y.
        • Yakubovich D.
        • Frohnwieser-Steinecker B.
        • Dascal N.
        • Schreibmayer W.
        Heterologous facilitation of G protein-activated K+ channels by β-adrenergic stimulation via cAMP-dependent protein kinase.
        J. Gen. Physiol. 2000; 115: 547-558https://doi.org/10.1085/jgp.115.5.547
        • Nakahara T.
        • Kawada T.
        • Sugimachi M.
        • Miyano H.
        • Sato T.
        • Shishido T.
        • Yoshimura R.
        • Miyashita H.
        • Inagaki M.
        • Alexander Jr., J.
        • Sunagawa K.
        Accumulation of cAMP augments dynamic vagal control of heart rate.
        Am. J. Physiol. Heart Circ. Physiol. 1998; 275: H562-H567https://doi.org/10.1152/ajpheart.1998.275.2.H562
        • Perneger T.V.
        What's wrong with bonferroni adjustments.
        Br. Med. J. 1998; 316: 1236-1238https://doi.org/10.1136/bmj.316.7139.1236
        • Potter E.K.
        Prolonged non-adrenergic inhibition of cardiac vagal action following sympathetic stimulation: neuromodulation by neuropeptide Y?.
        Neurosci. Lett. 1985; 54: 117-121https://doi.org/10.1016/s0304-3940(85)80065-3
        • Reid J.V.O.
        The cardiac pacemaker: effects of regularly spaced nervous input.
        Am. Heart J. 1969; 78: 58-64https://doi.org/10.1016/0002-8703(69)90259-2
        • Rosenblueth A.
        • Simeone F.A.
        The interrelations of vagal and accelerator effects on the cardiac rate.
        Am. J. Phys. 1934; 110: 42-55
        • Salata J.J.
        • Gill R.M.
        • Gilmour R.F.
        • Zipes D.P.
        Effects of sympathetic tone on vagally induced phasic changes in heart rate and atrioventricular node conduction in the anesthetized dog.
        Circ. Res. 1986; 58: 584-594https://doi.org/10.1161/01.res.58.4.584
        • Samaan A.
        The antagonistic cardiac nerves and heart rate.
        J. Physiol. 1935; 83: 332-340https://doi.org/10.1113/jphysiol.1935.sp003232
        • Sasaki S.
        • Daitoku K.
        • Iwasa A.
        • Motomura S.
        NO is involved in MCh-induced accentuated antagonism via type II PDE in the canine blood-perfused SA node.
        Am. J. Physiol. Heart Circ. Physiol. 2000; 279: H2509-H2518https://doi.org/10.1152/ajpheart.2000.279.5.h2509
        • Schuessler R.B.
        • Boineau J.P.
        • Wylds A.C.
        • Hill D.A.
        • Miller C.B.
        • Roeske W.R.
        Effect of canine cardiac nerves on heart rate, rhythm, and pace- maker location.
        Am. J. Physiol. Heart Circ. Physiol. 1986; 250: H630-H644https://doi.org/10.1152/ajpheart.1986.250.4.H630
        • Sears C.E.
        • Choate J.K.
        • Paterson D.J.
        Effect of nitric oxide synthase inhibition on the sympatho-vagal control of heart rate.
        J. Auton. Nerv. Syst. 1998; 73: 63-73https://doi.org/10.1016/s0165-1838(98)00123-4
        • Sears C.E.
        • Choate J.K.
        • Paterson D.J.
        NO-cGMP pathway accentuates the decrease in heart rate caused by cardiac vagal nerve stimulation.
        J. Appl. Physiol. 1999; 86: 510-516https://doi.org/10.1152/jappl.1999.86.2.510
        • Smith-White M.A.
        • Wallace D.
        • Potter E.K.
        Sympathetic-parasympathetic interactions at the heart in the anaesthetised rat.
        J. Auton. Nerv. Syst. 1999; 75: 171-175https://doi.org/10.1016/s0165-1838(98)00169-6
        • Takahashi N.
        • Zipes D.P.
        Vagal modulation of adrenergic effects on canine sinus and atrioventricular nodes.
        Am. J. Physiol. Heart Circ. Physiol. 1983; 244: H775-H781https://doi.org/10.1152/ajpheart.1983.244.6.H775
        • Thompson G.W.
        • Collier K.
        • Ardell J.L.
        • Kember G.
        • Armour J.A.
        Functional interdependence of neurons in a single canine intrinsic cardiac ganglionated plexus.
        J. Physiol. 2000; 528: 561-571https://doi.org/10.1111/j.1469-7793.2000.00561.x
        • Urthaler F.
        • Neely B.H.
        • Hageman G.R.
        • Smith L.R.
        Differential sympathetic- parasympathetic interactions in sinus node and AV junction.
        Am. J. Physiol. Heart Circ. Physiol. 1986; 250: H43-H51https://doi.org/10.1152/ajpheart.1986.250.1.H43
        • Warner M.R.
        Time-course and frequency dependence of sympathetic stimulation-evoked inhibition of vagal effects at the sinus node.
        J. Auton. Nerv. Syst. 1995; 52: 23-33https://doi.org/10.1016/0165-1838(94)00141-6
        • Warner M.R.
        • Levy M.N.
        Neuropeptide Y as a putative modulator of the vagal effects on heart rate.
        Circ. Res. 1989; 64: 882-889https://doi.org/10.1161/01.res.64.5.882
        • West T.C.
        • Falk G.
        • Cervoni P.
        Drug alteration of transmembrane potentials in atrial pacemaker cells.
        J. Pharmacol. Exp. Ther. 1956; 117: 245-252
        • Wetzel G.T.
        • Goldstein D.
        • Brown J.H.
        Acetylcholine release from rat atria can be regulated through an alpha 1-adrenergic receptor.
        Circ. Res. 1985; 56: 763-766https://doi.org/10.1161/01.res.56.5.763
        • White D.W.
        • Raven P.B.
        Autonomic neural control of heart rate during dynamic exercise: revisited.
        J. Physiol. 2014; 592: 2491-2500https://doi.org/10.1113/jphysiol.2014.271858
        • Yang T.
        • Levy M.N.
        Sequence of excitation as a factor in sympathetic-parasympathetic interactions in the heart.
        Circ. Res. 1992; 71: 898-905https://doi.org/10.1161/01.res.71.4.898
        • Yoo S.
        • Lee S.H.
        • Choi B.H.
        • Yeom J.B.
        • Ho W.-K.
        • Earm Y.E.
        Dual effect of nitric oxide on the hyperpolarization-activated inward current (If) in sino-atrial node cells of the rabbit.
        J. Mol. Cell. Cardiol. 1998; 30: 2729-2738https://doi.org/10.1006/jmcc.1998.0845
        • Yuan B.-X.
        • Ardell J.L.
        • Hopkins D.A.
        • Armour J.A.
        Differential cardiac responses induced by nicotine sensitive canine atrial and ventricular neurones.
        Cardiovasc. Res. 1993; 27: 760-769https://doi.org/10.1093/cvr/27.5.760