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 IC50 values of 5.4+/-0.7 muM and 6.2 +/-0.4 muM respectively. In Chinese hamster ovary (CHO) cells, AVE0118 decreased the steady-state hKv1.5 current with an IC50 of 1.1+/-0.2 muM. 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 IC50 of 3.4+/-0.5 muM. At 10 muM 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 muM carbachol. At a clamp potential of -100 mV the I-KACh was half-maximally blocked by 4.5 +/-1.6 muM 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 muM. 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 Ca2+ (recorded in pig atrial myocytes) were blocked by 10 muM 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.