In vitro and in vivo effects of the atrial selective antiarrhythmic compound AVE1231.
The novel compound AVE1231 was investigated in order to elucidate its potential against atrial fibrillation. In CHO cells, the current generated by hKv1.5 or hKv4.3 + KChIP2.2b channels was blocked with IC50 values of 3.6 microM and 5.9 microM, respectively. In pig left atrial myocytes, a voltage-dependent outward current was blocked with an IC50 of 1.1 microM, mainly by accelerating the time constant of decay. Carbachol-activated IKACh was blocked by AVE1231 with an IC50 of 8.4 microM. Other ionic currents, like the IKr, IKs, IKATP, ICa, and INa were only mildly affected by 10 microM AVE1231. In guinea pig papillary muscle the APD90 and the upstroke velocity were not significantly altered by 30 microM AVE1231. In anesthetized pigs, oral doses of 0.3, 1, and 3 mg/kg AVE1231 caused a dose-dependent increase in left atrial refractoriness (LAERP), associated by inhibition of left atrial vulnerability to arrhythmia. There were no effects on the ECG intervals, ventricular monophasic action potentials, or ventricular refractory periods at 3 mg/kg AVE1231 applied intravenously. In conscious goats, both AVE1231 (3 mg/kg/h iv) and dofetilide (10 microg/kg/h iv) significantly prolonged LAERP. After 72 hours of tachypacing, when LAERP was shortened significantly (electrical remodelling), the prolongation of LAERP induced by AVE1231 was even more pronounced than in sinus rhythm. In contrast, the effect of dofetilide was strongly decreased. The present data demonstrate that AVE1231 blocks early atrial K channels and prolongs atrial refractoriness with no effects on ECG intervals and ventricular repolarisation, suggesting that it is suited for the prevention of atrial fibrillation in patients.
Wirth
Klaus J
KJ
Sanofi-Aventis Deutschland GmbH, D-65926 Frankfurt/M, Germany.
Brendel
Joachim
J
Steinmeyer
Klaus
K
Linz
Dominik K
DK
Rütten
Hartmut
H
Gögelein
Heinz
H
D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000503:physiopathology; D016275:Atrial Function / Q000187:drug effects; D001783:Blood Flow Velocity / Q000187:drug effects; D016466:CHO Cells; D002217:Carbachol / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D006041:Goats; D006168:Guinea Pigs; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D020128:Inhibitory Concentration 50; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D013552:Swine; D013997:Time Factors
D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D007473:Ion Channels; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; D002217:Carbachol; C063533:dofetilide