title: AZD1305 exerts atrial predominant electrophysiological actions and is effective in suppressing atrial fibrillation and preventing its reinduction in the dog.
abstract: Recent development of drugs for the treatment of atrial fibrillation (AF) has focused on atrial selective agents. We examined the atrioventricular differences in sodium channel block of the antiarrhythmic agent AZD1305 in atria and ventricles of anesthetized dogs in vivo, canine isolated arterially perfused preparations in vitro, and isolated myocytes using whole-cell patch-clamp techniques. AZD1305 did not change heart rate or blood pressure in vivo but prolonged action potential duration and increased effective refractory period, diastolic threshold of excitation, and conduction time preferentially in atria both in vitro and in vivo. AZD1305 reduced the maximum rate of rise of the action potential upstroke (V(max)) predominantly in atria (-51% +/- 10% in atria vs. -31% +/- 23% in ventricles; 3 microM; cycle length = 500 milliseconds). Fast sodium current (I(Na)) was blocked by AZD1305 to a greater degree in atrial versus ventricular myocytes (particularly tonic inhibition). In coronary-perfused right atria, AZD1305 very effectively prevented induction of persistent acetylcholine-mediated AF and, in a different set of atria, terminated persistent AF (in 5 of 5 and 7 of 8 atria, respectively). In conclusion, AZD1305 exerts atrial predominant sodium channel-blocking effects in vitro and in vivo and effectively suppresses AF.
authors.affiliation: Masonic Medical Research Laboratory, Utica, NY 13501, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Burashnikov
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Zygmunt
authors.forename: Jose M
authors.initials: JM
authors.lastname: Di Diego
authors.forename: Gunilla
authors.initials: G
authors.lastname: Linhardt
authors.forename: Leif
authors.initials: L
authors.lastname: Carlsson
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
mesh_terms: D000109:Acetylcholine; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000503:physiopathology; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D055724:Electrophysiological Phenomena / Q000187:drug effects; D005260:Female; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D026941:Sodium Channel Blockers / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D053961:Azabicyclo Compounds; D002219:Carbamates; D026941:Sodium Channel Blockers; C550721:tert-butyl (2-(7-(2-(4-cyano-2-fluorophenoxy)ethyl)-9-oxa-3,7-diazabicyclo(3.3.1)non3-yl)ethyl)carbamate; D000109:Acetylcholine
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