title: Combined potassium and calcium channel antagonistic activities as a basis for neutral frequency dependent increase in action potential duration: comparison between BRL-32872 and azimilide.
abstract: OBJECTIVE
  The effects of BRL-32872, azimilide and a selective blocker of the delayed rectifier potassium current, E-4031, were measured at two different basic cycle lengths (BCL), 300 and 1000 ms. Calcium channel antagonists of sarcolemmal (verapamil and nitrendipine) and sarcoplasmic reticulum (ryanodine) membranes were used to investigate whether the inhibition of the calcium current or the calcium release from the sarcoplasmic reticulum could alter the reverse-rate dependence of E-4031 on action potential duration (APD).
  
  
  METHODS
  Guinea pig isolated papillary muscles were superfused with a Tyrode solution maintained at 37 degrees C and stimulated at a BCL of 300 or 1000 ms. The standard microelectrode technique was used to record action potential parameters and to study the effects of azimilide, BRL-32872 and E-4031. E-4031 was superfused at increasing concentrations (0.01, 0.03, 0.1 and 0.3 microM) in the absence or in the presence of verapamil (0.3 microM), nitrendipine (0.03 microM) or ryanodine (0.1 microM).
  
  
  RESULTS
  BRL-32872 and azimilide induced a self-limited concentration-dependent increase in APD. The effect of BRL-32872 was not dependent on the stimulation frequency whereas the effect of azimilide was significantly reduced at the shorter BCL. E-4031 induced a concentration-dependent increase in APD at both stimulation BCL. The increase in APD was significantly more pronounced in fibres stimulated at a BCL of 1000 ms than in fibres stimulated at a BCL of 300 ms, characterising the reverse-frequency dependent effect of class III antiarrhythmic agents. The reverse-frequency dependence in action potential prolongation induced by E-4031 was significantly reduced in the presence of a low concentration of verapamil (0.3 microM), nitrendipine (0.03 microM), or ryanodine (0.1 microM.
  
  
  CONCLUSIONS
  The results show that BRL-32872, in contrast to azimilide, does not induce the reverse-rate dependency of action potential prolongation typically produced by class III antiarrhythmic agents such as E-4031. Our results also show that reverse-rate dependency induced by E-4031 can be reduced by the simultaneous administration of a low concentration of a calcium channel antagonist or an inhibitor of the release of calcium from the sarcoplasmic reticulum. It is thus suggested that compounds with a suitable balance of potassium and calcium antagonistic activities may have less adverse effects than purely selective potassium channel blockers.
authors.affiliation: SmithKline Beecham Laboratoires Pharmaceutiques, Saint-Grégoire, France. antoine_bril@sbphrd.com
authors.forename: A
authors.initials: A
authors.lastname: Bril
authors.forename: M C
authors.initials: MC
authors.lastname: Forest
authors.forename: B
authors.initials: B
authors.lastname: Cheval
authors.forename: J F
authors.initials: JF
authors.lastname: Faivre
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004558:Electric Stimulation; D006168:Guinea Pigs; D006827:Hydantoins; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009568:Nitrendipine / Q000494:pharmacology; D010210:Papillary Muscles; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D026902:Potassium Channel Blockers; D011725:Pyridines / Q000494:pharmacology; D011897:Random Allocation; D012433:Ryanodine / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D001549:Benzamides; D002121:Calcium Channel Blockers; D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; D010879:Piperazines; D010880:Piperidines; D026902:Potassium Channel Blockers; D011725:Pyridines; C094198:BRL 32872; C063968:E 4031; D012433:Ryanodine; C086123:azimilide; D009568:Nitrendipine; D014700:Verapamil