Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels generate electrical rhythmicity in various tissues although primarily heart, retina and brain. The HCN channel blocker compound, Ivabradine (Corlanor), is approved by the US Food and Drug Administration (FDA) as a medication to lower heart rate by blocking hyperpolarization activated inward current in the sinoatrial node. In addition, a growing body of evidence suggests a role for HCN channels in regulation of sleep/wake behavior. Zebrafish larvae are ideal model organisms for high throughput drug screening, drug repurposing and behavioral phenotyping studies. We leveraged this model system to investigate effects of three HCN channel blockers (Ivabradine, Zatebradine Hydrochloride and ZD7288) at multiple doses on sleep/wake behavior in wild type zebrafish. Results of interest included shorter latency to daytime sleep at 0.1 μM dose of Ivabradine (ANOVA, p: 0.02), moderate reduction in average activity at 30 μM dose of Zatebradine Hydrochloride (ANOVA, p: 0.024) in daytime, and increased nighttime sleep at 4.5 μM dose of ZD7288 (ANOVA, p: 0.036). Taken together, shorter latency to daytime sleep, decrease in daytime activity and increased nighttime sleep indicate that different HCN channel antagonists affected different parameters of sleep and activity.

中文翻译：

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HCN通道阻滞剂对斑马鱼睡眠/觉醒行为的筛选作用

超极化激活的环核苷酸门控 (HCN) 离子通道在各种组织中产生电节律，但主要是心脏、视网膜和大脑。 HCN 通道阻滞剂化合物 Ivabradine (Corlanor) 经美国食品和药物管理局 (FDA) 批准作为一种药物，通过阻断窦房结中超极化激活的内向电流来降低心率。此外，越来越多的证据表明 HCN 通道在调节睡眠/觉醒行为中发挥着作用。斑马鱼幼虫是高通量药物筛选、药物再利用和行为表型研究的理想模型生物。我们利用该模型系统研究了多种剂量的三种 HCN 通道阻滞剂（伊伐布雷定、盐酸扎特布雷定和 ZD7288）对野生型斑马鱼睡眠/觉醒行为的影响。感兴趣的结果包括 0.1 μM 剂量的伊伐布雷定缩短了白天睡眠潜伏期（方差分析，p：0.02），30 μM 剂量的盐酸扎特布雷定（方差分析，p：0.024）白天平均活动适度减少，以及夜间睡眠增加4.5 μM 剂量的 ZD7288（方差分析，p：0.036）。总而言之，白天睡眠潜伏期较短、白天活动减少和夜间睡眠增加表明不同的 HCN 通道拮抗剂影响不同的睡眠和活动参数。