title: Hydroxychloroquine reduces heart rate by modulating the hyperpolarization-activated current If: Novel electrophysiological insights and therapeutic potential.
abstract: BACKGROUND
  Bradycardic agents are of interest for the treatment of ischemic heart disease and heart failure, as heart rate is an important determinant of myocardial oxygen consumption.
  
  
  OBJECTIVE
  The purpose of this study was to investigate the propensity of hydroxychloroquine (HCQ) to cause bradycardia.
  
  
  METHODS
  We assessed the effects of HCQ on (1) cardiac beating rate in vitro (mice); (2) the "funny" current (If) in isolated guinea pig sinoatrial node (SAN) myocytes (1, 3, 10 µM); (3) heart rate and blood pressure in vivo by acute bolus injection (rat, dose range 1-30 mg/kg), (4) blood pressure and ventricular function during feeding (mouse, 100 mg/kg/d for 2 wk, tail cuff plethysmography, anesthetized echocardiography).
  
  
  RESULTS
  In mouse atria, spontaneous beating rate was significantly (P < .05) reduced (by 9% ± 3% and 15% ± 2% at 3 and 10 µM HCQ, n = 7). In guinea pig isolated SAN cells, HCQ conferred a significant reduction in spontaneous action potential firing rate (17% ± 6%, 1 μM dose) and a dose-dependent reduction in If (13% ± 3% at 1 µM; 19% ± 2% at 3 µM). Effects were also observed on L-type calcium ion current (ICaL) (12% ± 4% reduction) and rapid delayed rectifier potassium current (IKr) (35% ± 4%) at 3 µM. Intravenous HCQ decreased heart rate in anesthetized rats (14.3% ± 1.1% at 15mg/kg; n = 6) without significantly reducing mean arterial blood pressure. In vivo feeding studies in mice showed no significant change in systolic blood pressure nor left ventricular function.
  
  
  CONCLUSIONS
  We have shown that HCQ acts as a bradycardic agent in SAN cells, in atrial preparations, and in vivo. HCQ slows the rate of spontaneous action potential firing in the SAN through multichannel inhibition, including that of If.
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Capel
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Neil
authors.initials: N
authors.lastname: Herring
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Manish
authors.initials: M
authors.lastname: Kalla
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Arash
authors.initials: A
authors.lastname: Yavari
authors.affiliation: Department of Computer Science, University of Oxford, Oxford, United Kingdom.
authors.forename: Gary R
authors.initials: GR
authors.lastname: Mirams
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Gillian
authors.initials: G
authors.lastname: Douglas
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Gil
authors.initials: G
authors.lastname: Bub
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Keith
authors.initials: K
authors.lastname: Channon
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Paterson
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Terrar
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom. Electronic address: Rebecca.burton@dpag.ox.ac.uk.
authors.forename: Rebecca-Ann B
authors.initials: RA
authors.lastname: Burton
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001919:Bradycardia / Q000139:chemically induced* / Q000150:complications / Q000503:physiopathology; D004195:Disease Models, Animal; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000503:physiopathology; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D006886:Hydroxychloroquine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012849:Sinoatrial Node / Q000187:drug effects / Q000503:physiopathology*
chemical_list: D004791:Enzyme Inhibitors; D006886:Hydroxychloroquine
keywords: Arrhythmia; Electrophysiology; Funny current; Heart failure; Heart rate; Hydroxychloroquine; I(f); Ion channels; Pacemaker