Koya Taro, Watanabe Masaya, Natsui Hiroyuki, Kadosaka Takahide, Koizumi Takuya, Nakao Motoki, Hagiwara Hikaru, Kamada Rui, Temma Taro, Anzai Toshihisa
Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Am J Physiol Heart Circ Physiol. 2022 Nov 1;323(5):H869-H878. doi: 10.1152/ajpheart.00252.2022. Epub 2022 Sep 23.
Atrial fibrillation (AF) is associated with electrical remodeling processes that promote a substrate for the maintenance of AF. Although the small-conductance Ca-activated K (SK) channel is a key factor in atrial electrical remodeling, the mechanism of its activation remains unclear. Regional nitric oxide (NO) production by neuronal nitric oxide synthase (nNOS) is involved in atrial electrical remodeling. In this study, atrial tachyarrhythmia (ATA) induction and optical mapping were performed on perfused rat hearts. nNOS is pharmacologically inhibited by -methylthiocitrulline (SMTC). The influence of the SK channel was examined using a specific channel inhibitor, apamin (APA). Parameters such as action potential duration (APD), conduction velocity, and calcium transient (CaT) were evaluated using voltage and calcium optical mapping. The dominant frequency was examined in the analysis of AF dynamics. SMTC (100 nM) increased the inducibility of ATA and apamin (100 nM) mitigated nNOS inhibition-induced arrhythmogenicity. SMTC caused abbreviations and enhanced the spatial dispersion of APD, which was reversed by apamin. By contrast, conduction velocity and other parameters associated with CaT were not affected by SMTC or apamin administration. Apamin reduced the frequency of SMTC-induced ATA. In summary, nNOS inhibition abbreviates APD by modifying the SK channels. A specific SK channel blocker, apamin, mitigated APD abbreviation without alteration of CaT, implying an underlying mechanism of posttranslational modification of SK channels. We demonstrated that pharmacological nNOS inhibition increased the atrial arrhythmia inducibility and a specific small-conductance Ca-activated K channel blocker, apamin, reversed the enhanced atrial arrhythmia inducibility. Apamin mitigated APD abbreviation without alteration of Ca transient, implying an underlying mechanism of posttranslational modification of SK channels.
心房颤动（AF）与促进AF维持的基质的电重构过程相关。尽管小电导钙激活钾（SK）通道是心房电重构的关键因素，但其激活机制仍不清楚。神经元型一氧化氮合酶（nNOS）产生的局部一氧化氮（NO）参与心房电重构。在本研究中，对灌注大鼠心脏进行了房性快速心律失常（ATA）诱导和光学标测。nNOS可被甲基硫代瓜氨酸（SMTC）药理学抑制。使用特异性通道抑制剂蜂毒明肽（APA）研究SK通道的影响。使用电压和钙光学标测评估动作电位时程（APD）、传导速度和钙瞬变（CaT）等参数。在AF动力学分析中检测主导频率。SMTC（100 nM）增加了ATA的诱导率，蜂毒明肽（100 nM）减轻了nNOS抑制诱导的致心律失常性。SMTC导致APD缩短并增强了其空间离散度，这被蜂毒明肽逆转。相比之下，传导速度和与CaT相关的其他参数不受SMTC或蜂毒明肽给药的影响。蜂毒明肽降低了SMTC诱导的ATA频率。总之，nNOS抑制通过修饰SK通道缩短APD。特异性SK通道阻滞剂蜂毒明肽减轻了APD缩短，而不改变CaT，这意味着SK通道存在翻译后修饰的潜在机制。我们证明药理学上抑制nNOS增加了心房心律失常的诱导率，而特异性小电导钙激活钾通道阻滞剂蜂毒明肽逆转了增强的心房心律失常诱导率。蜂毒明肽减轻了APD缩短，而不改变钙瞬变，这意味着SK通道存在翻译后修饰的潜在机制。
