PMID- 35751378
OWN - NLM
STAT- MEDLINE
DCOM- 20220823
LR  - 20221015
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 179
IP  - 18
DP  - 2022 Sep
TI  - Contribution of haemodynamic side effects and associated autonomic reflexes to 
      ventricular arrhythmias triggering by torsadogenic hERG blocking drugs.
PG  - 4549-4562
LID - 10.1111/bph.15905 [doi]
AB  - BACKGROUND AND PURPOSE: HERG blocking drugs known for their propensity to trigger 
      Torsades de Pointes (TdP) were reported to induce a sympatho-vagal coactivation 
      and to enhance High Frequency heart rate (HFHR) and QT oscillations (HFQT) in 
      telemetric data. The present work aimed to characterize the underlying 
      mechanism(s) leading to these autonomic changes. EXPERIMENTAL APPROACH: Effects 
      of 15 torsadogenic hERG blocking drugs (astemizole, chlorpromazine, cisapride, 
      droperidol, ibutilide, dofetilide, haloperidol, moxifloxacin, pimozide, 
      quinidine, risperidone, sotalol, sertindole, terfenadine, and thioridazine) were 
      assessed by telemetry in beagle dogs. Haemodynamic effects on diastolic and 
      systolic arterial pressure were analysed from the first doses causing QTc 
      prolongation and/or HFQT oscillations enhancement. Autonomic control changes were 
      analysed using the high frequency autonomic modulation (HFAM) model. KEY RESULTS: 
      Except for moxifloxacin and quinidine, all torsadogenic hERG blockers induced 
      parasympathetic activation or sympatho-vagal coactivation combined with 
      enhancement of HFQT oscillations. These autonomic effects result from reflex 
      compensatory mechanisms in response to mild haemodynamic side effects. These 
      haemodynamic mechanisms were characterized by transient HR acceleration during HF 
      oscillations. A phenomenon of concealed QT prolongation was unmasked for several 
      torsadogenic hERG blockers under beta-adrenoceptor blockade with atenolol. Resulting 
      enhancement of HFQT oscillations was shown to contribute directly to triggering 
      dofetilide-induced ventricular arrhythmias. CONCLUSION AND IMPLICATIONS: This 
      work supports for the first time a contribution of haemodynamic side properties 
      to ventricular arrhythmias triggered by torsadogenic hERG blocking drugs. These 
      haemodynamic side effects may constitute a second component of their arrhythmic 
      profile, acting as a trigger alongside their intrinsic arrhythmogenic 
      electrophysiological properties.
CI  - (c) 2022 The Authors. British Journal of Pharmacology published by John Wiley & 
      Sons Ltd on behalf of British Pharmacological Society.
FAU - Champeroux, Pascal
AU  - Champeroux P
AD  - ERBC France, Chemin de Montifault, Baugy, France.
FAU - Fares, Raafat
AU  - Fares R
AD  - ERBC France, Chemin de Montifault, Baugy, France.
FAU - Bastogne, Thierry
AU  - Bastogne T
AD  - CRAN CNRS UMR 7039, Universite de Lorraine, Vandoeuvre-les-Nancy, France.
FAU - Richard, Serge
AU  - Richard S
AD  - ERBC France, Chemin de Montifault, Baugy, France.
FAU - Le Guennec, Jean-Yves
AU  - Le Guennec JY
AD  - Laboratoire PHYMEDEXP, Universite de Montpellier, INSERM 1046, CNRS UMR 9214, 
      Montpellier, France.
FAU - Thireau, Jerome
AU  - Thireau J
AUID- ORCID: 0000-0002-1641-5142
AD  - Laboratoire PHYMEDEXP, Universite de Montpellier, INSERM 1046, CNRS UMR 9214, 
      Montpellier, France.
LA  - eng
SI  - figshare/10.6084/m9.figshare.19322975
PT  - Journal Article
DEP - 20220713
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Ether-A-Go-Go Potassium Channels)
RN  - ITX08688JL (Quinidine)
RN  - U188XYD42P (Moxifloxacin)
SB  - IM
MH  - Animals
MH  - Arrhythmias, Cardiac/chemically induced
MH  - Dogs
MH  - *Drug-Related Side Effects and Adverse Reactions
MH  - Electrocardiography
MH  - Ether-A-Go-Go Potassium Channels/physiology
MH  - Heart Rate
MH  - *Long QT Syndrome/chemically induced
MH  - Moxifloxacin/adverse effects
MH  - Quinidine
MH  - Reflex
MH  - *Torsades de Pointes/chemically induced
PMC - PMC9543494
OTO - NOTNLM
OT  - HF oscillations
OT  - QTc prolongation
OT  - Torsades de Pointes
OT  - hERG channel
OT  - haemodynamic
COIS- None declared.
EDAT- 2022/06/26 06:00
MHDA- 2022/08/24 06:00
PMCR- 2022/07/13
CRDT- 2022/06/25 01:32
PHST- 2022/05/16 00:00 [revised]
PHST- 2021/11/16 00:00 [received]
PHST- 2022/06/01 00:00 [accepted]
PHST- 2022/06/26 06:00 [pubmed]
PHST- 2022/08/24 06:00 [medline]
PHST- 2022/06/25 01:32 [entrez]
PHST- 2022/07/13 00:00 [pmc-release]
AID - BPH15905 [pii]
AID - 10.1111/bph.15905 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2022 Sep;179(18):4549-4562. doi: 10.1111/bph.15905. Epub 2022 Jul 
      13.