title: Direct effects of arsenic trioxide on action potentials in isolated cardiac tissues: importance of the choice of species, type of cardiac tissue and perfusion time.
abstract: BACKGROUND
  The aim of the present study was to evaluate direct/acute effects of arsenic trioxide on action potentials (APs) in isolated cardiac tissues, and to investigate if the choice of species and tissue and the duration of the perfusion play a role in arsenic-induced acute/direct prolongation of AP/QT.
  
  
  RESULTS
  Direct electrophysiological effects of arsenic trioxide were measured in cardiac tissues isolated from four different species using micro-electrode recording. Arsenic (after 30 to 95 min perfusion at 10 μM) significantly prolonged APD(90), increased triangulation of the AP and elicited early afterdepolarizations (EADs) only in isolated guinea-pig and dog Purkinje fibers but not in rabbit and porcine (minipig) Purkinje fibers. Arsenic induced a prolongation of the APD(90) and increases in triangulation and the occurrence of EADs was not observed in papillary muscles of guinea-pigs and rabbits. Arsenic at 4 increasing concentrations from 0.1 μM to 10 μM at the standard perfusion-time of 15 min per concentration, and after a continuous 90-min perfusion at 1 μM and 1 Hz did not induce these direct effects on APD(90), triangulation and EADs in isolated guinea-pig Purkinje fibers, but it at 1 µM elicited EADs in 2 out of 7 preparations after 90 min at 0.2 Hz.
  
  
  CONCLUSIONS
  The present study demonstrates that the choice of species and cardiac tissue as well as perfusion-time play important roles in arsenic-induced direct/acute effects on APD(90) and induction of EADs in vitro.
authors.affiliation: Center of Excellence for Cardiovascular Safety Research & Mechanistic Pharmacology, Janssen Research & Development, Division of Janssen Pharmaceutica N.V., Belgium. hlu@its.jnj.com
authors.forename: Hua Rong
authors.initials: HR
authors.lastname: Lu
authors.forename: Eddy
authors.initials: E
authors.lastname: Vlaminckx
authors.forename: Frank
authors.initials: F
authors.lastname: Cools
authors.forename: David J
authors.initials: DJ
authors.lastname: Gallacher
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000830:Animals, Laboratory / Q000502:physiology*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000009:adverse effects*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D015425:Myocardial Reperfusion; D010087:Oxides / Q000009:adverse effects*; D010477:Perfusion; D011690:Purkinje Fibers / Q000187:drug effects / Q000503:physiopathology; D011817:Rabbits; D013045:Species Specificity; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors; D018675:Toxicity Tests / Q000379:methods; D018879:Ventricular Premature Complexes / Q000139:chemically induced / Q000503:physiopathology
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D000077237:Arsenic Trioxide