Simultaneous activation of the small conductance calcium-activated potassium current by acetylcholine and inhibition of sodium current by ajmaline cause J-wave syndrome in Langendorff-perfused rabbit ventricles

Heart Rhythm. 2021 Jan;18(1):98-108. doi: 10.1016/j.hrthm.2020.07.036. Epub 2020 Aug 4.

Abstract

Background: Concomitant apamin-sensitive small conductance calcium-activated potassium current (IKAS) activation and sodium current inhibition induce J-wave syndrome (JWS) in rabbit hearts. Sudden death in JWS occurs predominantly in men at night when parasympathetic tone is strong.

Objective: The purpose of this study was to test the hypotheses that acetylcholine (ACh), the parasympathetic transmitter, activates IKAS and causes JWS in the presence of ajmaline.

Methods: We performed optical mapping in Langendorff-perfused rabbit hearts and whole-cell voltage clamp to determine IKAS in isolated ventricular cardiomyocytes.

Results: ACh (1 μM) + ajmaline (2 μM) induced J-point elevations in all (6 male and 6 female) hearts from 0.01± 0.01 to 0.31 ± 0.05 mV (P<.001), which were reduced by apamin (specific IKAS inhibitor, 100 nM) to 0.14 ± 0.02 mV (P<.001). More J-point elevation was noted in male than in female hearts (P=.037). Patch clamp studies showed that ACh significantly (P<.001) activated IKAS in isolated male but not in female ventricular myocytes (n=8). Optical mapping studies showed that ACh induced action potential duration (APD) heterogeneity, which was more significant in right than in left ventricles. Apamin in the presence of ACh prolonged both APD at the level of 25% (P<.001) and APD at the level of 80% (P<.001) and attenuated APD heterogeneity. Ajmaline further increased APD heterogeneity induced by ACh. Ventricular arrhythmias were induced in 6 of 6 male and 1 of 6 female hearts (P=.015) in the presence of ACh and ajmaline, which was significantly suppressed by apamin in the former.

Conclusion: ACh activates ventricular IKAS. ACh and ajmaline induce JWS and facilitate the induction of ventricular arrhythmias more in male than in female ventricles.

Keywords: Brugada syndrome; Early repolarization syndrome; J-wave syndrome; Sex difference; Ventricular arrhythmia.

Publication types

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

MeSH terms

  • Acetylcholine / pharmacology*
  • Ajmaline / pharmacology*
  • Animals
  • Arrhythmias, Cardiac / drug therapy*
  • Arrhythmias, Cardiac / metabolism
  • Arrhythmias, Cardiac / pathology
  • Cholinergic Agonists / pharmacology
  • Disease Models, Animal
  • Heart Ventricles / drug effects
  • Heart Ventricles / metabolism*
  • Heart Ventricles / pathology
  • Isolated Heart Preparation / methods
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Optical Imaging
  • Patch-Clamp Techniques
  • Potassium Channels, Calcium-Activated / drug effects*
  • Potassium Channels, Calcium-Activated / metabolism
  • Rabbits
  • Small-Conductance Calcium-Activated Potassium Channels / antagonists & inhibitors
  • Sodium Channels / drug effects
  • Sodium Channels / metabolism*
  • Voltage-Gated Sodium Channel Blockers / pharmacology

Substances

  • Cholinergic Agonists
  • Potassium Channels, Calcium-Activated
  • Small-Conductance Calcium-Activated Potassium Channels
  • Sodium Channels
  • Voltage-Gated Sodium Channel Blockers
  • Ajmaline
  • Acetylcholine