Zebrafish Heart as a Model to Study the Integrative Autonomic Control of Pacemaker Function

Am J Physiol Heart Circ Physiol. 2016 Sep 1;311(3):H676-88. doi: 10.1152/ajpheart.00330.2016. Epub 2016 Jun 24.


The cardiac pacemaker sets the heart's primary rate, with pacemaker discharge controlled by the autonomic nervous system through intracardiac ganglia. A fundamental issue in understanding the relationship between neural activity and cardiac chronotropy is the identification of neuronal populations that control pacemaker cells. To date, most studies of neurocardiac control have been done in mammalian species, where neurons are embedded in and distributed throughout the heart, so they are largely inaccessible for whole-organ, integrative studies. Here, we establish the isolated, innervated zebrafish heart as a novel alternative model for studies of autonomic control of heart rate. Stimulation of individual cardiac vagosympathetic nerve trunks evoked bradycardia (parasympathetic activation) and tachycardia (sympathetic activation). Simultaneous stimulation of both vagosympathetic nerve trunks evoked a summative effect. Effects of nerve stimulation were mimicked by direct application of cholinergic and adrenergic agents. Optical mapping of electrical activity confirmed the sinoatrial region as the site of origin of normal pacemaker activity and identified a secondary pacemaker in the atrioventricular region. Strong vagosympathetic nerve stimulation resulted in a shift in the origin of initial excitation from the sinoatrial pacemaker to the atrioventricular pacemaker. Putative pacemaker cells in the sinoatrial and atrioventricular regions expressed adrenergic β2 and cholinergic muscarinic type 2 receptors. Collectively, we have demonstrated that the zebrafish heart contains the accepted hallmarks of vertebrate cardiac control, establishing this preparation as a viable model for studies of integrative physiological control of cardiac function by intracardiac neurons.

Keywords: atrioventricular node; intracardiac nervous system; parasympathetic; sinoatrial node; sympathetic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Antagonists / pharmacology
  • Animals
  • Atrioventricular Node / drug effects
  • Atrioventricular Node / innervation*
  • Atrioventricular Node / physiology
  • Atrioventricular Node / physiopathology
  • Atropine / pharmacology
  • Autonomic Nervous System / drug effects
  • Autonomic Nervous System / physiology
  • Bradycardia / physiopathology
  • Electrocardiography
  • Heart / drug effects
  • Heart / innervation*
  • Heart / physiology
  • Heart / physiopathology
  • Heart Rate
  • Hexamethonium / pharmacology
  • Isolated Heart Preparation
  • Isoproterenol / pharmacology
  • Models, Animal
  • Muscarine / pharmacology
  • Muscarinic Agonists / pharmacology
  • Muscarinic Antagonists / pharmacology
  • Nicotine / pharmacology
  • Nicotinic Agonists / pharmacology
  • Nicotinic Antagonists / pharmacology
  • Parasympathetic Nervous System / drug effects
  • Parasympathetic Nervous System / physiology*
  • Receptor, Muscarinic M2 / metabolism
  • Receptors, Adrenergic, beta-2 / metabolism
  • Sinoatrial Node / drug effects
  • Sinoatrial Node / innervation*
  • Sinoatrial Node / physiology
  • Sinoatrial Node / physiopathology
  • Sympathetic Nervous System / drug effects
  • Sympathetic Nervous System / physiology*
  • Sympathomimetics / pharmacology
  • Tachycardia / physiopathology
  • Timolol / pharmacology
  • Vagus Nerve Stimulation
  • Zebrafish


  • Adrenergic beta-Antagonists
  • Muscarinic Agonists
  • Muscarinic Antagonists
  • Nicotinic Agonists
  • Nicotinic Antagonists
  • Receptor, Muscarinic M2
  • Receptors, Adrenergic, beta-2
  • Sympathomimetics
  • Hexamethonium
  • Nicotine
  • Atropine
  • Muscarine
  • Timolol
  • Isoproterenol