Effect of autonomic influences to induce triggered activity in muscular sleeves extending into the coronary sinus of the canine heart and its suppression by ranolazine

J Cardiovasc Electrophysiol. 2019 Feb;30(2):230-238. doi: 10.1111/jce.13770. Epub 2018 Nov 2.


Introduction: Extrasystoles arising from the muscular sleeves associated with the pulmonary veins (PV), superior vena cava (SVC), and coronary sinus (CS) are known to precipitate atrial fibrillation (AF). The late sodium channel current (INa ) inhibitor ranolazine has been reported to exert antiarrhythmic effects in canine PV and SVC sleeves by suppressing late phase 3 early and delayed after depolarization (EAD and DAD)-induced triggered activity induced by parasympathetic and/or sympathetic stimulation. The current study was designed to extend our existing knowledge of the electrophysiological and pharmacologic properties of canine CS preparations and assess their response to inhibition of late INa following autonomic stimulation.

Methods: Transmembrane action potentials were recorded from canine superfused CS using standard microelectrode techniques. Acetylcholine (ACh, 1 µM), isoproterenol (Iso, 1 µM), high calcium ([Ca2+ ]o = 5.4 mM), or a combination were used to induce EADs, DADs, and triggered activity.

Results: Action potentials (AP) recorded from the CS displayed short and long AP durations (APD), with and without phase 4 depolarization (n = 19). Iso induced DAD-mediated triggered activity. The combination of sympathetic and parasympathetic agonists resulted in late phase 3 EAD-induced triggered activity in all CS preparations. Ranolazine (5-10 µM) suppressed late phase 3 EAD- and DAD-induced triggered activity in 8 of 8 preparations. Subthreshold stimulation induced a prominent hyperpolarization that could be suppressed by atropine.

Conclusions: Our results suggest the important role of parasympathetic innervation in the activity of the CS. Autonomic influences promote DAD- and late phase-3-EAD-mediated triggered activity in canine CS, thus generating extrasystolic activity capable of initiating atrial arrhythmias. Ranolazine effectively suppresses these triggers.

Keywords: atrial fibrillation; coronary sinus; parasympathetic nervous system; ranolazine; sympathetic nervous system.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Anti-Arrhythmia Agents / pharmacology*
  • Arrhythmias, Cardiac / physiopathology
  • Arrhythmias, Cardiac / prevention & control*
  • Coronary Sinus / innervation*
  • Disease Models, Animal
  • Dogs
  • Heart Rate / drug effects*
  • Parasympathetic Nervous System / drug effects*
  • Parasympathetic Nervous System / physiopathology
  • Ranolazine / pharmacology*
  • Sodium Channel Blockers / pharmacology*
  • Time Factors


  • Anti-Arrhythmia Agents
  • Sodium Channel Blockers
  • Ranolazine