Barann M, Bönisch H, Urban B W, Göthert M
Institut für Pharmakologie und Toxikologie, Universität Bonn, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 1998 Aug;358(2):145-52. doi: 10.1007/pl00005236.
The patch-clamp technique was applied in out-side-out patches of N1E-115 mouse neuroblastoma cells to investigate the effects of ifenprodil [(+/-) erythreo-ifenprodil tartratel, a drug with neuroprotective properties in cerebral ischemia, on the inward currents through 5-HT3 receptor channels. A high time resolution was achieved by using a rapid solution exchange system (exchange rate <1 ms). Ifenprodil inhibited the peak currents evoked by 30 microM 5-HT in a concentration-dependent but voltage-independent manner. The effect was most potent when ifenprodil was continuously applied to the patches 45 s before and during the 2-s administration of 5-HT (IC50=16 microM) and it was only slightly less potent when it was applied during the 45 s prior to 5-HT only (IC50=29 microM). When applied in this manner, ifenprodil also produced a concentration-dependent increase of the onset time constant (tauON) of the 5-HT (30 microM)-induced currents. When the drug was exclusively co-applied with 5-HT, ifenprodil was least potent in inhibiting the peak currents (IC50=98 microM), and it had no effect on the current onset kinetics. All protocols of ifenprodil application accelerated current inactivation as reflected by a decrease of the current inactivation time constant (tauOFF). All effects of ifenprodil were reversible after washout periods of 2-5 min. In conclusion, the potency of ifenprodil in inhibiting the inward current through 5-HT3 receptor channels is strongly dependent on the application protocol: presence of the drug before the agonist-induced activation of the 5-HT3 receptor channels is necessary for a relatively potent inhibition of the 5-HT-induced peak current and is a prerequisite for the prolongation of tauON; in addition, a weak but fast inhibitory effect on the current amplitude and decay constant of the 5-HT-induced current was revealed by the experiments in which ifenprodil was exclusively present during exposure to 5-HT. Three alternatives compatible with the components of the ifenprodil effect have been discussed: (1) different effects of the two enantiomers, (2) action via two different mechanisms, and (3) operation via a single mechanism only.
采用膜片钳技术，在N1E-115小鼠神经母细胞瘤细胞的外侧膜片上，研究具有脑缺血神经保护特性的药物艾芬地尔[（±）赤藓醇-艾芬地尔酒石酸盐]对5-HT3受体通道内向电流的影响。使用快速溶液交换系统（交换速率<1毫秒）实现了高时间分辨率。艾芬地尔以浓度依赖性但电压非依赖性的方式抑制30微摩尔5-HT诱发的峰值电流。当在5-HT给药前45秒及给药期间的2秒内持续将艾芬地尔应用于膜片时，其效果最为显著（IC50 = 16微摩尔），而仅在5-HT给药前45秒应用时，效果略弱（IC50 = 29微摩尔）。以这种方式应用时，艾芬地尔还使5-HT（30微摩尔）诱发电流的起始时间常数（tauON）呈浓度依赖性增加。当该药物仅与5-HT共同应用时，艾芬地尔抑制峰值电流的效力最低（IC50 = 98微摩尔），且对电流起始动力学无影响。所有艾芬地尔应用方案均加速了电流失活，这表现为电流失活时间常数（tauOFF）降低。在2 - 5分钟的洗脱期后，艾芬地尔的所有效应均可逆。总之，艾芬地尔抑制5-HT3受体通道内向电流的效力强烈依赖于应用方案：在激动剂诱导激活5-HT3受体通道之前存在该药物，对于相对有效地抑制5-HT诱发的峰值电流是必要的，并且是延长tauON的先决条件；此外，在仅在暴露于5-HT期间存在艾芬地尔的实验中，揭示了其对5-HT诱发电流的幅度和衰减常数具有微弱但快速的抑制作用。已经讨论了与艾芬地尔效应成分兼容的三种可能性：（1）两种对映体的不同效应，（2）通过两种不同机制起作用，以及（3）仅通过单一机制起作用。
