Effects of the atrial antiarrhythmic drug AVE0118 on cardiac ion channels.
Previous studies in pigs and goats have demonstrated that AVE0118 prolongs atrial refractoriness without any effect on the QT-interval. The purpose of the present study was to investigate the effect of the compound on various cardiac ion channels. AVE0118 blocked the pig Kv1.5 and the human Kv1.5 expressed in Xenopus oocytes with IC(50) values of 5.4+/-0.7 microM and 6.2+/-0.4 microM respectively. In Chinese hamster ovary (CHO) cells, AVE0118 decreased the steady-state hKv1.5 current with an IC(50) of 1.1+/-0.2 microM. The hKv4.3/KChIP2.2 current in CHO cells was blocked by AVE0118 by accelerating the apparent time-constant of inactivation ( tau(inact)), and the integral current was inhibited with an IC(50) of 3.4+/-0.5 microM. At 10 microM AVE0118 tau(inact) decreased from 9.3+/-0.6 ms ( n=8, control) to 3.0+/-0.3 ms ( n=8). The K(ACh) current was investigated in isolated pig atrial myocytes by application of 10 microM carbachol. At a clamp potential of -100 mV the I(KACh) was half-maximally blocked by 4.5+/-1.6 microM AVE0118. In the absence of carbachol, AVE0118 had no effect on the inward current recorded at -100 mV. Effects on the I(Kr) current were investigated on HERG channels expressed in CHO cells. AVE0118 blocked this current half-maximally at approximately 10 microM. Comparable results were obtained in isolated guinea pig ventricular myocytes, where half-maximal inhibition of the I(Kr) tail current occurred at a similar concentration of AVE0118. Other ionic currents, like the I(Ks), I(KATP) (recorded in guinea pig ventricular myocytes), and L-type Ca(2+) (recorded in pig atrial myocytes) were blocked by 10 microM AVE0118 by 10+/-3% ( n=6), 28+/-7% ( n=4), and 22+/-13% ( n=5) respectively. In summary, AVE0118 preferentially inhibits the atrial K(+) channels I(Kur), I(to) and I(KACH). This profile may explain the selective prolongation of atrial refractoriness described previously in pigs and goats.
Gögelein
Heinz
H
Aventis Pharma Deutschland GmbH, Industriepark Hoechst, H821, 65926 Frankfurt/Main, Germany. heinz.goegelein@aventis.com
Brendel
J
J
Steinmeyer
K
K
Strübing
C
C
Picard
N
N
Rampe
D
D
Kopp
K
K
Busch
A E
AE
Bleich
M
M
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D016466:CHO Cells; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors; D002217:Carbachol / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004594:Electrophysiology; D006801:Humans; D007473:Ion Channels / Q000187:drug effects*; D051605:Kv Channel-Interacting Proteins; D051666:Kv1.5 Potassium Channel; D008967:Molecular Biology; D032383:Myocytes, Cardiac / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors; D051672:Shal Potassium Channels; D013552:Swine; D014981:Xenopus
D000889:Anti-Arrhythmia Agents; D002135:Calcium-Binding Proteins; D002316:Cardiotonic Agents; D007473:Ion Channels; C496981:KCNA5 protein, human; C497021:KCND3 protein, human; C496752:KCNIP2 protein, human; D051605:Kv Channel-Interacting Proteins; D051666:Kv1.5 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D051672:Shal Potassium Channels; D002217:Carbachol