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Inhibitory effects of N-methyl-D-aspartate (NMDA) and α1-adrenergic receptor antagonist ifenprodil on human Kv1.5 channel

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Abstract

Ifenprodil has been known to reduce cardiac contractility and cerebral vasodilation by antagonizing α1-adrenergic and N-methyl D-aspartate receptor-mediated intracellular signals. This study aimed to investigate the direct effect of ifenprodil on the human voltage-gated Kv1.5 channel (hKv1.5) by using a Xenopus oocyte expression system and a two-microelectrode voltage clamp technique. The amplitudes of hKv1.5 currents, including peak and steady state, were suppressed in a concentration-dependent manner (IC50; 43.1 and 35.5 μM, respectively) after 6 min of ifenprodil treatment. However, these effects were  ~ 80% reversed by washout, suggesting that ifenprodil directly inhibited the hKv1.5 independent of membrane receptors or intracellular signals. The inhibition rate of steady state showed voltage dependence, wherein the rates increased according to test voltage depolarization. Ifenprodil reduced the time constants of hKv1.5 inactivation but has higher effects on activation. hKv1.5 inhibition by ifenprodil showed use dependency because the drug more rapidly reduced the current at the higher activation frequencies, and subsequent reduction in frequency after high activation frequency caused a partial channel block relief. Therefore, ifenprodil directly blocked the hKv1.5 in an open state and accelerated the time course of the channel inactivation, which provided a biophysical mechanism for the hKv1.5 blocking effects of ifenprodil.

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Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (no. 2020R1A2C1013958).

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  1. Department of Physiology, Institute of Bioscience and Biotechnology, BK21 plus Graduate Program, Kangwon National University College of Medicine, Hyoja-Dong, Chuncheon, 200-701, Korea

    Soobeen Hwang, Byeongjun Yoon & Su-Hyun Jo

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Soobeen Hwang: data collection, designing the figure, and manuscript wiring. Byeongjun Yoon: manuscript wiring. Su-Hyun Jo: writing, reviewing, and editing. The authors declare that all data were generated in-house and that no paper mill was used.

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Hwang, S., Yoon, B. & Jo, SH. Inhibitory effects of N-methyl-D-aspartate (NMDA) and α1-adrenergic receptor antagonist ifenprodil on human Kv1.5 channel. Naunyn-Schmiedeberg's Arch Pharmacol 396, 3149–3161 (2023). https://doi.org/10.1007/s00210-023-02521-6

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