title: Comparison of the rate-dependent properties of the class III antiarrhythmic agents azimilide (NE-10064) and E-4031: considerations on the mechanism of reverse rate-dependent action potential prolongation.
abstract: BACKGROUND
  Reverse rate-dependence, a lessening in Class III antiarrhythmic agent action potential duration (APD) prolongation as heart rate is increased, has been proposed to be related to an incomplete deactivation of the slow component (IKs) of the delayed rectifier K+ current (IK). The rate-dependent properties of block of IK by azimilide were compared to E-4031, which selectively blocks the rapid component (IKr) of IK, in guinea pig ventricular muscle.
  
  
  RESULTS
  Azimilide prolonged APD in isolated papillary muscles in a concentration-dependent manner and to a greater degree than E-4031. Both agents prolonged APD less at fast than slow rates, consistent with a similar reverse rate-dependent effect. Isolation of azimilide block of IKs by subtraction of APD during E-4031 plus azimilide from E-4031 alone revealed rate-independent prolongation of APD. In voltage clamp experiments on single ventricular myocytes, activation of IKs was similar following 30 seconds of conditioning pulses of physiological duration (125 to 200 msec) with either a fast (cycle length 250 msec) or slow (cycle length 2000 msec) rate. The block of IKs by azimilide 3 microM was greater after a fast conditioning pulse train.
  
  
  CONCLUSIONS
  Selective block of IKs prolongs APD in a rate-independent manner. In voltage clamped myocytes, no evidence of a rate-dependent accumulation of IKs was observed. These findings support a mechanism of reverse rate-dependent APD prolongation by Class III antiarrhythmic agents that block IKr independent of IKs.
authors.affiliation: Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Groh
authors.forename: K J
authors.initials: KJ
authors.lastname: Gibson
authors.forename: J G
authors.initials: JG
authors.lastname: Maylie
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004558:Electric Stimulation; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006827:Hydantoins; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000166:cytology; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000889:Anti-Arrhythmia Agents; D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; D010879:Piperazines; D010880:Piperidines; D015221:Potassium Channels; D011725:Pyridines; C063968:E 4031; C086123:azimilide