Effects of L-type Ca2+ channel antagonism on ventricular arrhythmogenesis in murine hearts containing a modification in the Scn5a gene modelling human long QT syndrome 3

J Physiol. 2007 Jan 1;578(Pt 1):85-97. doi: 10.1113/jphysiol.2006.121921. Epub 2006 Nov 16.

Abstract

Ventricular arrhythmogenesis in long QT 3 syndrome (LQT3) involves both triggered activity and re-entrant excitation arising from delayed ventricular repolarization. Effects of specific L-type Ca2+ channel antagonism were explored in a gain-of-function murine LQT3 model produced by a DeltaKPQ 1505-1507 deletion in the SCN5A gene. Monophasic action potentials (MAPs) were recorded from epicardial and endocardial surfaces of intact, Langendorff-perfused Scn5a+/Delta hearts. In untreated Scn5a+/Delta hearts, epicardial action potential duration at 90% repolarization (APD90) was 60.0 +/- 0.9 ms compared with 46.9 +/- 1.6 ms in untreated wild-type (WT) hearts (P < 0.05; n = 5). The corresponding endocardial APD(90) values were 52.0 +/- 0.7 ms and 53.7 +/- 1.6 ms in Scn5a+/Delta and WT hearts, respectively (P > 0.05; n = 5). Epicardial early afterdepolarizations (EADs), often accompanied by spontaneous ventricular tachycardia (VT), occurred in 100% of MAPs from Scn5a+/Delta but not in any WT hearts (n = 10). However, EAD occurrence was reduced to 62 +/- 7.1%, 44 +/- 9.7%, 10 +/- 10% and 0% of MAPs following perfusion with 10 nm, 100 nm, 300 nm and 1 mum nifedipine, respectively (P < 0.05; n = 5), giving an effective IC50 concentration of 79.3 nm. Programmed electrical stimulation (PES) induced VT in all five Scn5a+/Delta hearts (n = 5) but not in any WT hearts (n = 5). However, repeat PES induced VT in 3, 2, 2 and 0 out of 5 Scn5a+/Delta hearts following perfusion with 10 nm, 100 nm, 300 nm and 1 mum nifedipine, respectively. Patch clamp studies in isolated ventricular myocytes from Scn5a+/Delta and WT hearts confirmed that nifedipine (300 nm) completely suppressed the inward Ca2+ current but had no effect on inward Na+ currents. No significant effects were seen on epicardial APD90, endocardial APD90 or ventricular effective refractory period in Scn5a+/Delta and WT hearts following perfusion with nifedipine at 1 nm, 10 nm, 100 nm, 300 nm and 1 microm nifedipine concentrations. We conclude that L-type Ca2+ channel antagonism thus exerts specific anti-arrhythmic effects in Scn5a+/Delta hearts through suppression of EADs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Aniline Compounds
  • Animals
  • Arrhythmias, Cardiac / drug therapy*
  • Arrhythmias, Cardiac / genetics*
  • Arrhythmias, Cardiac / physiopathology
  • Calcium Channel Blockers / pharmacology*
  • Calcium Channels, L-Type / drug effects*
  • Calcium Signaling / drug effects
  • Electric Stimulation
  • Fluorescent Dyes
  • Heart Ventricles / drug effects
  • Heart Ventricles / physiopathology
  • Humans
  • In Vitro Techniques
  • Long QT Syndrome / genetics*
  • Long QT Syndrome / physiopathology*
  • Male
  • Mice
  • Mice, Transgenic
  • Myocytes, Cardiac / drug effects
  • NAV1.5 Voltage-Gated Sodium Channel
  • Nifedipine / pharmacology
  • Patch-Clamp Techniques
  • Potassium Channels, Voltage-Gated / genetics
  • Refractory Period, Electrophysiological / drug effects
  • Sodium Channels / genetics*
  • Xanthenes

Substances

  • Aniline Compounds
  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • Fluorescent Dyes
  • Kcne1 protein, mouse
  • NAV1.5 Voltage-Gated Sodium Channel
  • Potassium Channels, Voltage-Gated
  • SCN5A protein, human
  • Scn5a protein, mouse
  • Sodium Channels
  • Xanthenes
  • Fluo-3
  • Nifedipine