AZD1305 exerts atrial predominant electrophysiological actions and is effective in suppressing atrial fibrillation and preventing its reinduction in the dog.
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.
Burashnikov
Alexander
A
Masonic Medical Research Laboratory, Utica, NY 13501, USA.
Zygmunt
Andrew C
AC
Di Diego
Jose M
JM
Linhardt
Gunilla
G
Carlsson
Leif
L
Antzelevitch
Charles
C
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
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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