title: Potassium and calcium current blocking properties of the novel antiarrhythmic agent H 345/52: implications for proarrhythmic potential.
abstract: OBJECTIVE
  To study the blocking effects of H 345/52 on ionic currents of rabbit ventricular myocytes and how these features translate into a proarrhythmic potential.
  
  
  METHODS
  The single electrode voltage clamp technique was used to study the effects of H 345/52 on the rapid component of the delayed rectifying potassium current, I(Kr), and the L-type calcium current (I(Ca)). Differential effects of H 345/52 and almokalant on APD prolongation were studied in a rabbit Purkinje fibre/ventricular muscle preparation. The temporal variability of the action potential duration (APD) and its relation to proarrhythmias was examined in Langendorff-perfused rabbit hearts administered H 345/52 or almokalant. Anaesthetised, methoxamine-sensitised rabbits were used to assess the propensity of intravenous H 345/52 and ibutilide to induce torsades de pointes (TdP).
  
  
  RESULTS
  H 345/52 potently blocked I(Kr) (IC(50)=40 nM) without consequential use-dependency. The I(Ca) was also blocked, but at higher concentrations (IC(50)=1.3 microM). Block of I(Ca) was markedly frequency-dependent (positive) and influenced by membrane potential, such that H 345/52 was more effective following clamp steps from plateau potentials than from -80 mV. In the Purkinje fibre-ventricular muscle preparation, almokalant prolonged the Purkinje fibre APD preferentially, whereas H 345/52 homogeneously prolonged APD in both tissue types. In the perfused rabbit heart, H 345/52 (1 microM) and almokalant (0.3 microM) prolonged APD to a similar degree but increased the temporal variability of APD differently, from 3+/-0.4 ms in control hearts to 8+/-1.2 ms and to 38+/-7.5 ms (P<0.001 vs. H 345/52), respectively. Unequivocal early after-depolarisations were seen in 5/6 almokalant-perfused hearts but in no heart administered H 345/52 (P<0.05). In anaesthetised rabbits, H 345/52 (17.4 micromol/kg) or ibutilide (2.6 micromol/kg maximum), maximally lengthened the QT interval from 133+/-4.5 to 177+/-8.0 ms and from 125+/-5.1 to 166+/-9.3 ms (P<0.001, n=8). However, whereas ibutilide induced TdP in all animals at 0.06+/-0.009 micromol/kg, H 345/52 did not induce TdP (P=0.0002) at up to 17.4 micromol/kg.
  
  
  CONCLUSIONS
  H 345/52 blocks I(Kr) with high potency and I(Ca) with somewhat lower potency and was found to delay ventricular repolarisation without substantially increasing temporal or spatial dispersion and without inducing early after-depolarisations or TdP.
authors.affiliation: AstraZeneca Research & Development Mölndal, Integrative Pharmacology, S-43183, Mölndal, Sweden.
authors.forename: G J
authors.initials: GJ
authors.lastname: Amos
authors.forename: C
authors.initials: C
authors.lastname: Abrahamsson
authors.forename: G
authors.initials: G
authors.lastname: Duker
authors.forename: L
authors.initials: L
authors.lastname: Hondeghem
authors.forename: M
authors.initials: M
authors.lastname: Palmer
authors.forename: L
authors.initials: L
authors.lastname: Carlsson
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000473:Alkanes / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008297:Male; D023421:Models, Animal; D018408:Patch-Clamp Techniques; D010477:Perfusion; D015221:Potassium Channels / Q000187:drug effects*; D011412:Propanolamines / Q000494:pharmacology; D011690:Purkinje Fibers / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology; D016171:Torsades de Pointes / Q000139:chemically induced / Q000378:metabolism*
chemical_list: C423187:3,7-diazabicyclo(3.3.1)nonane-3-carboxylic acid, 7-((2S)3-(4-cyanophenoxy)-2-hydroxypropyl)-1,1-dimethylethyl ester; D000473:Alkanes; D000889:Anti-Arrhythmia Agents; D001643:Bridged Bicyclo Compounds; D020746:Calcium Channels, L-Type; D015221:Potassium Channels; D011412:Propanolamines; D013449:Sulfonamides; C067192:ibutilide; C074334:almokalant