Brainstem Premotor Cardiac Vagal Neurons

  • David Mendelowitz


This chapter focuses on the neurobiology of premotor cardiac vagal neurons that are located in the brainstem. These parasympathetic cardiac neurons play an essential role in the regulation of heart rate, and are responsible for, together with sympathetic activity, cardiovascular homeostasis. Since cardiac vagal neurons are intrinsically silent their activity is determined by the activity and transmitters released by the neurons that synapse upon these neurons. This chapter focuses on the synaptic activation of cardiac vagal neurons, their postsynaptic receptors and electrophysiological responses, and, in particular, how the cellular activity of these neurons is altered during different physiological and pathological conditions.

Key words

Ambiguus parasympathetic heart rate heart sudden infant death syndrome bradycardia 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Andresen, M.C., Kunze, D.L., 1994. Nucleus tractus solitarius-gateway to neural circulatory control. Annu. Rev. Physiol. 5693–116.PubMedCrossRefGoogle Scholar
  2. Andresen, M.C., Mendelowitz, D., 1996. Sensory afferent neurotransmission in caudal nucleus tractus solitarius-common denominators. Chem. Senses 21387–395.PubMedCrossRefGoogle Scholar
  3. Ang, K.K., McRitchie, R.J., Minson, J.B., Llewellyn-Smith, I.J., Pilowsky, P.M., Chalmers, J.P., Arnoida, L.F., 1999. Activation of spinal opioid receptors contributes to hypotension after hemorrhage in conscious rats. Am. J. Physiol. 276H1552–H1558.PubMedGoogle Scholar
  4. Anrep, G.V., Pascual, F.W., Rossler, R., 1935. Respiratory variations of the heart rate. II The central mechanism of the respiratory arrhythmia and the interrelationships between the central and reflex mechanisms. Proc. Roy. Soc. 119218–231.Google Scholar
  5. Barringer, D.L., Bunag, R.D., 1990. Differential anesthetic depression of chronotropic baroreflexes in rats. J. Cardiovasc. Pharmacol. 1510–15.PubMedCrossRefGoogle Scholar
  6. Bedran-de-Castro, M.T., Farah, V.M., Krieger, E.M., 1990. Influence of general anesthetics on baroreflex control of circulation. Braz. J. Med. Biol. Res. 231185–1193.PubMedGoogle Scholar
  7. Blake, D.W., Korner, P.I., 1982. Effects of ketamine and Althesin Anesthesia on baroreceptor-heart rate reflex and hemodynamics of intact and pontine rabbits. J. Auton. Nerv. Syst. 5145–154.PubMedCrossRefGoogle Scholar
  8. Browning, K.N., Mendelowitz, D., 2003. Musings on the wanderer: what’s new in our understanding of vago-vagal reflexes?: II. Integration of afferent signaling from the viscera by the nodose ganglia. Am. J. Physiol. Gastrointest. Liver Physiol. 284G8–G14.PubMedGoogle Scholar
  9. Cole, C.R., Blackstone, E.H., Pashkow, F.J., Snader, CE., Lauer, M.S., 1999. Heart-rate recovery immediately after exercise as a predictor of mortality. N. Engl. J. Med. 3411351–1357.PubMedCrossRefGoogle Scholar
  10. Coleman, T.G., 1980. Arterial baroreflex control of heart rate in the conscious rat. Am. J. Physiol. 238H515–H520.PubMedGoogle Scholar
  11. Daly, M.D., 1991. Some reflex cardioinhibitory responses in the cat and their modulation by central inspiratory neuronal activity. J. Physiol. 439559–577.PubMedGoogle Scholar
  12. Davidson, N.S., Goldner, S., McCloskey, D.I., 1976. Respiratory modulation of barareceptor and chemoreceptor reflexes affecting heart rate and cardiac vagal efferent nerve activity. J. Physiol. 259523–530.PubMedGoogle Scholar
  13. Davies, P.A., Kirkness, E.F., Hales, T.G., 2001. Evidence for the formation of functionally distinct α,ß,γ, and ε GABAA receptors. J. Physiol. 537101–113.PubMedCrossRefGoogle Scholar
  14. Davies, P.A., Hanna, M.C., Hales, T.G., Kirkness, E.F., 1997. Insensitivity to anaesthetic agents conferred by a class of GABA(A) receptor subunit. Nature 385820–823.PubMedCrossRefGoogle Scholar
  15. Duffin, J., Aweida, D., 1990. The propriobulbar respiratory neurons in the cat. Exp. Brain Res. 81213–220.PubMedCrossRefGoogle Scholar
  16. Eckberg, D.L., Orshan, C.R., 1977. Respiratory and baroreceptor reflex interactions in man. J. Clin. Invest. 59780–785.PubMedCrossRefGoogle Scholar
  17. Eckberg, D.L., Drabinsky, M., Braunwald, E., 1971. Defective cardiac parasympathetic control in patients with heart disease. New Engl. J. Med. 285877–883.PubMedCrossRefGoogle Scholar
  18. Elghozi, J.L., Laude, D., Girard, A., 1991. Effects of respiration on blood pressure and heart rate variability in humans. Clin. Exp. Pharmacol. Physiol. 18735–742.PubMedCrossRefGoogle Scholar
  19. Evans, C., Baxi, S., Neff, R.A., Venkatesan, P., Mendelowitz, D., 2003. Synaptic activation of cardiac vagal neurons by capsaicin sensitive and insensitive sensory neurons. Brain Res. in press.Google Scholar
  20. Evans, R.G., Ludbrook, J., Potocnik, S.J., 1989. Intracisternal naloxone and cardiac nerve blockade prevent vasodilatation during simulated haemorrhage in awake rabbits. J. Physiol. 4091–14.PubMedGoogle Scholar
  21. Gauthier, P., Barillot, J.C., Dussardier, M., 1980. [Central interactions between laryngeal motoneurones. J. Physiol. (Paris) 76647–661.Google Scholar
  22. Gilbey, M.P., Jordan, D., Richter, D.W., Spyer, K.M., 1984. Synaptic mechanisms involved in the inspiratory modulation of vagal cardio-inhibitory neurones in the cat. J. Physiol. 35665–78.PubMedGoogle Scholar
  23. Gilman, A.G., Goodman L.S., Rail, T.W., Murad, F., (1985) The Pharmacological Basis of TherapeuticsSeventh Edition. New York, NY: Macmillan Publishing Company.Google Scholar
  24. Henderson, G., McKnight, A.T., 1997. The orphan opioid receptor and its endogenous ligand—nociceptin/orphanin FQ. Trends Pharmacol. Sci. 18293–300.PubMedCrossRefGoogle Scholar
  25. Heymans, C., Neil, E., 1958. Reflexogenic Areas of the Cardiovascular System. London: Churchill.Google Scholar
  26. Hrushesky, W.J., 1991. Quantitative respiratory sinus arrhythmia analysis. A simple noninvasive, reimbursable measure of cardiac wellness and dysfunction. Ann. NY Acad. Sci. 61867–101.PubMedCrossRefGoogle Scholar
  27. Inoue, K., Miyake, S., Kumashiro, M., Ogata, H., Yoshimura, O., 1990. Power spectral analysis of heart rate variability in traumatic quadriplegic humans. Am. J. Physiol. 258H1722–H1726.PubMedGoogle Scholar
  28. Irnaten, M., Wang, J., Chang, K.S., Andresen, M.C., Mendelowitz, D., 2002a. Ketamine inhibits sodium currents in identified cardiac parasympathetic neurons in nucleus ambiguus. Anesthesiology 96659–666.PubMedCrossRefGoogle Scholar
  29. Irnaten, M., Neff, R.A., Wang, J., Loewy, A.D., Mettenleiter, T.C., Mendelowitz, D., 2001. Activity of cardiorespiratory networks revealed by transsynaptic virus expressing GFP. J Neurophysiol. 85435–438.PubMedGoogle Scholar
  30. Irnaten, M., Wang, J., Venkatesan, P., Evans, C., K Chang, K.S., Andresen, M.C., Mendelowitz, D., 2002b. Ketamine inhibits presynaptic and postsynaptic nicotinic excitation of identified cardiac parasympathetic neurons in nucleus ambiguus. Anesthesiology 96667–674.CrossRefGoogle Scholar
  31. Irnaten, M., Aicher, S.A., Wang, J., Venkatesan, P., Evans, C., Baxi, S., Mendelowitz, D., 2003. Mu-opioid receptors are located postsynaptically and endomorphin-1 inhibits voltage-gated calcium currents in premotor cardiac parasympathetic neurons in the rat nucleus ambiguus. Neurosci. 116573–582.CrossRefGoogle Scholar
  32. Irnaten, M., Walwyn, W.M., Wang, J., Venkatesan, P., Evans, C., Chang, K.S., Andresen, M.C., Hales, T.G., Mendelowitz, D., 2002c. Pentobarbital enhances GABAergic neurotransmission to cardiac parasympathetic neurons, which is prevented by expression of GABAA epsilon subunit. Anesthesiology 97717–724.CrossRefGoogle Scholar
  33. Jones, M.V., Harrison, N.L., Pritchett, D.B., Hales, T.G., 1995. Modulation of the GABAA receptor by propofol is independent of the gamma subunit. J. Pharmacol. Exp. Ther. 274962–968.PubMedGoogle Scholar
  34. Jordan, D., Khalid, M.E., Schneiderman, N., Spyer, K.M., 1982. The location and properties of preganglionic vagal cardiomotor neurones in the rabbit. Pflugers Arch. 395244–250.PubMedCrossRefGoogle Scholar
  35. Kalia, M., 1981. Brain stem localization of vagal preganglionic neurons. J. Auton. Nerv. Syst. 3451–481.PubMedCrossRefGoogle Scholar
  36. Kunze, D.L., 1972. Reflex discharge patterns of cardiac vagal efferent fibres. J. Physiol. 2221–15.PubMedGoogle Scholar
  37. Kwok, E.H., Dun, N.J., 1998. Endomorphins decrease heart rate and blood pressure possibly by activating vagal afferents in anesthetized rats. Brain Res. 803204–207.PubMedCrossRefGoogle Scholar
  38. La Rovere, M.T., Specchia, G., Mortara, A., Schwartz, P.J., 1988. Baroreflex sensitivity, clinical correlates, and cardiovascular mortality among patients with a first myocardial infarction. A prospective study. Circ. 78816–824.Google Scholar
  39. Levy, M.N., Zieske, H., 1969. Autonomie control of cardiac pacemaker activity and atrioventricular transmission. J. Appl. Physiol. 27465–470.PubMedGoogle Scholar
  40. Lipski, J., Zhang, X., Kruszewska, B., Kanjhan, R., 1994. Morphological study of long axonal projections of ventral medullary inspiratory neurons in the rat. Brain Res. 640171–184.PubMedCrossRefGoogle Scholar
  41. Loewy, A.D., Spyer, K.M. (1990) Central Regulation of Autonomic Functions: Oxford University Press.Google Scholar
  42. McAllen, R.M., Spyer, K.M., 1978. The baroreceptor input to cardiac vagal motoneurones. J. Physiol. 282365–374.PubMedGoogle Scholar
  43. McGrath, J.C., MacKenzie, J.E., Millar, R.A., 1975. Effects of ketamine on central sympathetic discharge and the baroreceptor reflex during mechanical ventilation. Br. J. Anaesth. 471141–1147.PubMedCrossRefGoogle Scholar
  44. Mendelowitz, D., 1996. Firing properties of identified parasympathetic cardiac neurons in nucleus ambiguus. Am. J. Physiol. 271H2609–H2614.PubMedGoogle Scholar
  45. Mendelowitz, D., 1998. Nicotine excites cardiac vagal neurons via three sites of action. Clin. Exp. Pharmacol. Physiol. 25453–456.PubMedCrossRefGoogle Scholar
  46. Mendelowitz, D., 1999. Advances in Parasympathetic Control of Heart Rate and Cardiac Function. News Physiol. Sci. 14155–161.PubMedGoogle Scholar
  47. Mendelowitz, D., Kunze, D.L., 1991. Identification and dissociation of cardiovascular neurons from the medulla for patch clamp analysis. Neurosci. Lett. 132217–221.PubMedCrossRefGoogle Scholar
  48. Meunier, J.C., 1997. Nociceptin/orphanin FQ and the opioid receptor-like ORL1 receptor. Eur. J. Pharmacol. 3401–15.PubMedCrossRefGoogle Scholar
  49. Mihalevich, M., Neff, R.A., Mendelowitz, D., 1996. Voltage-gated currents in identified parasympathetic cardiac neurons in the nucleus ambiguus. Brain Res. 739258–262.PubMedCrossRefGoogle Scholar
  50. Morillo, A.M., Nunez-Abades, P.A., Gaytan, S.P., Pasaro, R., 1995. Brain stem projections by axonal collaterals to the rostral and caudal ventral respiratory group in the rat. Brain Res. Bull. 37205–211.PubMedCrossRefGoogle Scholar
  51. Murthy, V.S., Zagar, M.E., Vollmer, R.R., Schmidt, D.H., 1982. Pentobarbital-induced changes in vagal tone and reflex vagal activity in rabbits. Eur. J. Pharmacol. 8441–50.PubMedCrossRefGoogle Scholar
  52. Neelands, T.R., Fisher, J.L., Bianchi, M., Macdonald, R.L., 1999. Spontaneous and gamma-aminobutyric acid (GABA)-activated GABA(A) receptor channels formed by epsilon subunit-containing isoforms. Mol. Pharmacol. 55168–178.PubMedGoogle Scholar
  53. Neff, R.A., Mihalevich, M., Mendelowitz, D., 1998a. Stimulation of NTS activates NMDA and non-NMDA receptors in rat cardiac vagal neurons in the nucleus ambiguus. Brain Res. 792277–282.PubMedCrossRefGoogle Scholar
  54. Neff, R.A., Humphrey, J., Mihalevich, M., Mendelowitz, D., 1998b. Nicotine enhances presynaptic and postsynaptic glutamatergic neurotransmission to activate cardiac parasympathetic neurons. Circ. Res. 831241–1247.PubMedCrossRefGoogle Scholar
  55. Ohnishi, M., Kirkman, E., Marshall, H.W., Little, R.A., 1997. Morphine blocks the bradycardia associated with severe hemorrhage in the anesthetized rat. Brain Res. 76339–46.PubMedCrossRefGoogle Scholar
  56. Pickering, T.G., Gribbin, B., Petersen, E.S., Cunningham, D.J., Sleight, P., 1972. Effects of autonomic blockade on the baroreflex in man at rest and during exercise. Circ. Res. 30177–185.PubMedCrossRefGoogle Scholar
  57. Pilowsky, P., Llewellyn-Smith, I.J., Lipski, J., Minson, J., Amolda, L., Chalmers, J., 1994. Projections from inspiratory neurons of the ventral respiratory group to the subretrofacial nucleus of the cat. Brain Res. 63363–71.PubMedCrossRefGoogle Scholar
  58. Porter, F.L., Porges, S.W., Marshall, R.E., 1988. Newborn pain cries and vagal tone: parallel changes in response to circumcision. Child Dev. 59495–505.PubMedCrossRefGoogle Scholar
  59. Pritchett, D.B., Sontheimer, H., Shivers, B.D., Ymer, S., Kettenmann, H., Schofield, P.R., Seeburg, P.H., 1989. Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology. Nature 338582–585.PubMedCrossRefGoogle Scholar
  60. Ransom, B.R., Barker, J.L., 1975. Pentobarbital modulates transmitter effects on mouse spinal neurones grown in tissue culture. Nature 254703–705.PubMedCrossRefGoogle Scholar
  61. Rardon, D.P., Bailey, J.C., 1983. Parasympathetic effects on electrophysiologic properties of cardiac ventricular tissue. J. Am. Coll. Cardiol. 21200–1209.PubMedCrossRefGoogle Scholar
  62. Richards, C.D., 1972. On the mechanism of barbiturate anaesthesia. J. Physiol. 227749–767.PubMedGoogle Scholar
  63. Robertson, B., 1989. Actions of anaesthetics and avermectin on GABAA chloride channels in mammalian dorsal root ganglion neurones. Br. J. Pharmacol. 98167–176.PubMedCrossRefGoogle Scholar
  64. Scher, A.M., Young, A.C., 1970. Reflex control of heart rate in the unanesthetized dog. Am. J. Physiol. 218780–789.PubMedGoogle Scholar
  65. Shykoff, B.E., Naqvi, S.S., Menon, A.S., Slutsky, A.S., 1991. Respiratory sinus arrhythmia in dogs. Effects of phasic afferents and chemostimulation. J. Clin. Invest. 871621–1627.PubMedCrossRefGoogle Scholar
  66. Slogoff, S., Allen, G.W., 1974. The role of baroreceptors in the cardiovascular response to ketamine. Anesth. Analg. 53704–707.PubMedGoogle Scholar
  67. Spyer, K.M., 1981. Neural organisation and control of the baroreceptor reflex. Rev. Physiol. Biochem. Pharmacol. 8824–124.PubMedGoogle Scholar
  68. Spyer, K.M., Gilbey, M.P., 1988. Cardiorespiratory interactions in heart-rate control. Ann. NY Acad. Sci. 533350–357.PubMedCrossRefGoogle Scholar
  69. Standish, A., Enquist, L.W., Schwaber, J.S., 1994. Innervation of the heart and its central medullary origin defined by viral tracing. Sci. 263232–234.CrossRefGoogle Scholar
  70. Stornetta, R.L., Guyenet, P.G., McCarty, R.C., 1987. Autonomic nervous system control of heart rate during baroreceptor activation in conscious and anesthetized rats. J. Auton. Nerv. Syst. 20121–127.PubMedCrossRefGoogle Scholar
  71. Taylor, E.W., 1994. The evolution of efferent vagal control of the heart in vertebrates. Cardiosci. 5173–182.Google Scholar
  72. Townend, J.N., Littler, W.A., 1995. Cardiac vagal activity: a target for intervention in heart disease. Lancet 345937–938.PubMedCrossRefGoogle Scholar
  73. van Lieshout, J.J., Wieling, W., Karemaker, J.M., Eckberg, D.L., 1991. The vasovagal response. Clin. Sci. (Lond) 81575–586.Google Scholar
  74. Vanoli, E., De Ferrari, G.M., Stramba-Badiale, M., Hull, S.S., Jr., Foreman, R.D., Schwartz, P.J., 1991. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction. Circ. Res. 681471–1481.PubMedCrossRefGoogle Scholar
  75. Venkatesan, P., Wang, J., Evans, C., Irnaten, M., Mendelowitz, D., 2002a. Endomorphin — 2 inhibits GABAergic inputs to cardiac parasympathetic neurons in the nucleus ambiguus. Neurosci. 111699–705.Google Scholar
  76. Venkatesan, P., Wang, J., Evans, C., Irnaten, M., Mendelowitz, D., 2002b. Nociceptin inhibits gamma-aminobutyric acidergic inputs to cardiac parasympathetic neurons in the nucleus ambiguus. J. Pharmacol. Exp. Ther. 30078–82.PubMedCrossRefGoogle Scholar
  77. Wang, J., Irnaten, M., Mendelowitz, D., 2001a. Characteristics of spontaneous and evoked GABAergic synaptic currents in cardiac vagal neurons in rats. Brain Res. 88978–83.PubMedCrossRefGoogle Scholar
  78. Wang, J., Irnaten, M., Mendelowitz, D., 2001b. Agatoxin-IVA-sensitive calcium channels mediate the presynaptic and postsynaptic nicotinic activation of cardiac vagal neurons. J. Neurophysiol. 85164–168.PubMedGoogle Scholar
  79. Wang, J., Irnaten, M., Venkatesan, P., Evans, C., Mendelowitz, D., 2002. Arginine vasopressin enhances GABAergic inhibition of cardiac parasympathetic neurons in the nucleus ambiguus. Neurosci. 111(3)699–705.CrossRefGoogle Scholar
  80. Wang, J., Wang, X., Irnaten, M, Venkatesan, P., Evans, C., Baxi, S., Mendelowitz, D., 2003. Endogenous Acetylcholine and Nicotine Activation Enhances GABAergic and Glycinergic Inputs to Cardiac Vagal Neurons. J. Neurophysiol. 89(5)2473–2481.PubMedCrossRefGoogle Scholar
  81. Wang, J., Irnaten, M., Neff, R.A., Venkatesan, P., Evans, C., Loewy, A.D., Mettenleiter, T.C., Mendelowitz, D., 2001c. Synaptic and neurotransmitter activation of cardiac vagal neurons in the nucleus ambiguus. Ann. NY Acad. Sci. 940237–246.CrossRefGoogle Scholar
  82. Warner, M.R., deTarnowsky, J.M., Whitson, C.C., Loeb, J.M., 1986. Beat-by-beat modulation of AV conduction. II. Autonomic neural mechanisms. Am. J. Physiol. 251H1134–H1142.PubMedGoogle Scholar
  83. Watkins, L., Maixner, W., 1991. The effect of pentobarbital anesthesia on the autonomic nervous system control of heart rate during baroreceptor activation. J. Auton. Nerv. Syst. 36107–114.PubMedCrossRefGoogle Scholar
  84. Waxman, M.B., Wald, R.W., 1977. Termination of ventricular tachycardia by an increase in cardiac vagal drive. Circ. 56385–391.CrossRefGoogle Scholar
  85. Whitescarver, S.A., Ott, CE., Kotchen, T.A., 1990. Parasympathetic impairment of baroreflex control of heart rate in Dahl S rats. Am. J. Physiol. 259R76–83.PubMedGoogle Scholar
  86. Whiting, P.J., Bonnert, T.P., McKernan, R.M., Farrar, S., Le Bourdelles, B., Heavens, R.P., Smith, D.W., Hewson, L., Rigby, M.R., Sirinathsinghji, D.J., Thompson, S.A., Wafford, K.A., 1999. Molecular and functional diversity of the expanding GABA-A receptor gene family. Ann. NY Acad. Sci. 868645–653.PubMedCrossRefGoogle Scholar
  87. Yamada, H., Ezure, K., Manabe, M., 1988. Efferent projections of inspiratory neurons of the ventral respiratory group. A dual labeling study in the rat. Brain Res. 455283–294.PubMedCrossRefGoogle Scholar
  88. Zheng, Y., Barillot, J.C., Bianchi, A.L., 1991. Are the post-inspiratory neurons in the decerebrate rat cranial motoneurons or interneurons? Brain Res. 551256–266.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • David Mendelowitz
    • 1
  1. 1.Department of PharmacologyGeorge Washington UniversityWashingtonUSA

Personalised recommendations