Electrophysiologic and antiarrhythmic effects of AZD1305 in canine pulmonary vein sleeves

J Pharmacol Exp Ther. 2010 Jul;334(1):255-9. doi: 10.1124/jpet.110.166702. Epub 2010 Apr 1.

Abstract

The objective of this study was to examine the electrophysiologic and antiarrhythmic effects of the new antiarrhythmic agent tert-butyl (2-[7-[2-(4-cyano-2-fluorophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non3-yl]ethyl)carbamate (AZD1305) in canine pulmonary vein (PV) sleeve preparations isolated from untreated and long-term amiodarone-treated animals. Ectopic activity arising from PV sleeves plays a prominent role in the development of atrial fibrillation (AF). Delayed afterdepolarizations (DADs) and late phase 3 early afterdepolarizations (EADs), originating from the PV have been proposed as potential triggers in initiation of AF. Action potentials were recorded from canine superfused PV sleeves using standard microelectrode techniques. Acetylcholine (1 microM), isoproterenol (1 microM), or their combination was used to induce EADs, DADs, and triggered activity (TA). The effects of AZD1305 (0.1-10 microM) were evaluated in PV sleeve preparations isolated from untreated and amiodarone-treated (40 mg/kg daily for 6 weeks) dogs. AZD1305 (0.1-10 microM, 30 min) significantly prolonged action potential duration and reduced excitability. Abbreviating basic cycle length from 1000 to 300 ms resulted in a decrease of V(max) from 314 +/- 79 to 251 +/- 55 V/s (Delta = -20%) in control and from 177 +/- 53 to 76.5 +/- 33 V/s (Delta = -57%) after AZD1305 (n = 6, p < 0.05). AZD1305 markedly attenuated or suppressed DADs and DAD-induced TA, but not late phase 3 EADs. AZD1305-induced attenuation of excitability, leading to activation failure at much longer cycle lengths, was much more pronounced in PV from amiodarone-treated dogs. Potent effects of AZD1305 to depress excitability, prolong action potential duration, and suppress DAD-induced triggered activity in canine PV sleeve preparations may be effective in suppressing triggers responsible for the genesis of AF and other atrial arrhythmias.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects*
  • Amiodarone / administration & dosage
  • Amiodarone / pharmacology
  • Amiodarone / therapeutic use
  • Animals
  • Anti-Arrhythmia Agents / administration & dosage
  • Anti-Arrhythmia Agents / pharmacology*
  • Anti-Arrhythmia Agents / therapeutic use
  • Atrial Fibrillation / drug therapy*
  • Atrial Fibrillation / physiopathology
  • Azabicyclo Compounds / administration & dosage
  • Azabicyclo Compounds / pharmacology*
  • Azabicyclo Compounds / therapeutic use
  • Carbamates / administration & dosage
  • Carbamates / pharmacology*
  • Carbamates / therapeutic use
  • Dogs
  • Dose-Response Relationship, Drug
  • In Vitro Techniques
  • Molecular Structure
  • Pulmonary Veins / drug effects*
  • Pulmonary Veins / physiopathology
  • Time Factors

Substances

  • Anti-Arrhythmia Agents
  • Azabicyclo Compounds
  • Carbamates
  • tert-butyl (2-(7-(2-(4-cyano-2-fluorophenoxy)ethyl)-9-oxa-3,7-diazabicyclo(3.3.1)non3-yl)ethyl)carbamate
  • Amiodarone