Gögelein Heinz, Brendel J, Steinmeyer K, Strübing C, Picard N, Rampe D, Kopp K, Busch A E, Bleich M
Aventis Pharma Deutschland GmbH, Industriepark Hoechst, H821, 65926 Frankfurt/Main, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 2004 Sep;370(3):183-92. doi: 10.1007/s00210-004-0957-y. Epub 2004 Aug 31.
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.
先前在猪和山羊身上进行的研究表明，AVE0118可延长心房不应期，而对QT间期无任何影响。本研究的目的是调查该化合物对各种心脏离子通道的作用。AVE0分别以5.4±0.7微摩尔和6.2±0.4微摩尔的半数抑制浓度（IC50）阻断猪Kv1.5以及非洲爪蟾卵母细胞中表达的人Kv1.5。在中国仓鼠卵巢（CHO）细胞中，AVE0118以1.1±0.2微摩尔的IC(50)降低稳态hKv1.5电流。AVE0118通过加速失活的表观时间常数（tau(inact)）阻断CHO细胞中的hKv4.3/KChIP2.2电流，并且积分电流以3.4±0.5微摩尔的IC(50)受到抑制。在10微摩尔AVE0118作用下，tau(inact)从9.3±0.6毫秒（n = 8，对照组）降至3.0±0.3毫秒（n = 8）。通过施加10微摩尔卡巴胆碱在离体猪心房肌细胞中研究K(ACh)电流。在钳制电位为-100毫伏时，I(KACh)被4.5±1.6微摩尔AVE0118半数阻断。在无卡巴胆碱的情况下，AVE0118对在-100毫伏记录的内向电流无影响。在CHO细胞中表达的HERG通道上研究对I(Kr)电流的作用。AVE0118约在10微摩尔时半数阻断该电流。在离体豚鼠心室肌细胞中获得了类似结果，其中在相似浓度的AVE0118作用下I(Kr)尾电流出现半数抑制。其他离子电流，如I(Ks)、I(KATP)（在豚鼠心室肌细胞中记录）和L型Ca(2+)（在猪心房肌细胞中记录）分别被10微摩尔AVE0118阻断10±3%（n = 6）、28±7%（n = 4）和22±13%（n = 5）。总之，AVE0118优先抑制心房钾通道I(Kur)、I(to)和I(KACH)。这种特性可能解释了先前在猪和山羊身上描述的心房不应期的选择性延长。
