NS 11021 is a highly potent and selective activator of large-conductance calcium-activated potassium channels (BKCa/KCa1.1)[1]. BKCa channels are present in various tissues such as neurons, smooth muscle, and mitochondria. They open in response to changes in membrane voltage and increases in intracellular calcium, facilitating rapid efflux of potassium (K+), which is crucial for regulating cellular excitability, muscle contraction, and neurotransmission[2,3]. NS 11021 is commonly used to investigate the physiological and pathological roles of BK channels in disease models related to cardiovascular regulation, neuronal excitability, and erectile dysfunction[4].
In vitro, pretreatment of primary hippocampal neurons from Fmr1 KO rats with NS 11021 (10µM) for 2min, followed by a 10-second 40-Hz stimulation, significantly restored the uptake of TMR-dextran and corrected deficits in activity-dependent bulk endocytosis (ADBE)[5]. Pretreatment of IGR39, Panc-1, and IGR37 cells with NS 11021 (20µM) for 72h markedly reduced cell viability and inhibited cell proliferation[6].
In vivo, a single intraperitoneal injection of NS 11021 (0.5mg/kg) in 1-month-old Atoh1-Pex5-/- mice significantly reduced auditory brainstem response thresholds and improved both the amplitude and latency of auditory brainstem response (ABR) wave I within 24h, effectively restoring hearing loss caused by peroxisome deficiency[7]. A single intravenous injection of NS 11021 (0.1mg/kg and 1mg/kg) in anesthetized Wistar rats significantly enhanced erectile responses induced by electrical stimulation of the cavernous nerve, an effect that was abolished by the administration of tetraethylammonium (TEA, 6mg/kg)[8].
References:
[1] KIRÁLY I, PATARICZA J, BAJORY Z, et al. Involvement of large-conductance Ca2+-activated K+ channels in both nitric oxide and endothelium-derived hyperpolarization-type relaxation in human penile small arteries[J]. Basic & Clinical Pharmacology & Toxicology, 2013, 113(1): 19-24.
[2] CHEN Y C, SHIH C L, WU C L, et al. Exploring the impact of BKCa channel function in cellular membranes on cardiac electrical activity[J]. International Journal of Molecular Sciences, 2024, 25(3): 1537.
[3] SINGH H, STEFANI E, TORO L. Intracellular BKCa (iBKCa) channels[J]. The Journal of Physiology, 2012, 590(23): 5937-5947.
[4] LAYNE J J, NAUSCH B, OLESEN S P, et al. BK channel activation by NS11021 decreases excitability and contractility of urinary bladder smooth muscle[J]. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2010, 298(2): R378-R384.
[5] BONNYCASTLE K, KIND P C, COUSIN M A. FMRP sustains presynaptic function via control of activity-dependent bulk endocytosis[J]. Journal of Neuroscience, 2022, 42(8): 1618-1628.
[6] REMIGANTE A, ZUCCOLINI P, BARBIERI R, et al. NS-11021 modulates cancer-associated processes independently of BK channels in melanoma and pancreatic duct adenocarcinoma cell lines[J]. Cancers, 2021, 13(23): 6144.
[7] FU X, WAN P, LU L, et al. Peroxisome deficiency in cochlear hair cells causes hearing loss by deregulating BK channels[J]. Advanced Science, 2023, 10(20): 2300402.
[8] KUN A, MATCHKOV V V, STANKEVICIUS E, et al. NS11021, a novel opener of large-conductance Ca2+-activated K+ channels, enhances erectile responses in rats[J]. British Journal of Pharmacology, 2009, 158(6): 1465-1476.
NS 11021是一种具有高效选择性的大电导钙激活钾通道（BKCa/KCa1.1）激活剂[1]。BKCa存在于神经元、平滑肌和线粒体等多种组织中，可根据细胞膜电压的变化和细胞内钙的增加而打开，从而快速释放钾（K+），这对于调节细胞兴奋性、肌肉收缩和神经传递至关重要[2,3]。NS 11021通常用于心血管舒缩功能、神经元兴奋性调控以及勃起功能障碍等相关疾病模型中BK通道的生理与病理机制研究[4]。
在体外，NS 11021（10μM）预处理Fmr1 KO大鼠原代海马神经元2min，随后进行10s的40-Hz刺激，显著恢复了神经元中TMR-dextran的摄取并纠正了活动依赖的批量内吞（ADBE）功能缺陷[5]。NS 11021（20μM）预处理IGR39、Panc-1和IGR37细胞72h，显著降低了细胞活力并抑制了细胞增殖[6]。
在体内，NS 11021（0.5mg/kg）单次腹腔注射处理1月龄Atoh1-Pex5-/-小鼠，24h后可显著降低其听觉脑干反应阈值，并改善听性脑干反应（ABR）波I的振幅和潜伏期，有效恢复因过氧化物酶体缺陷导致的听力损失[7]。NS 11021（0.1mg/kg和1mg/kg）单次静脉注射给药麻醉的Wistar大鼠，可显著增强海绵体神经电刺激诱导的勃起反应，但该效应可被四乙胺（TEA, 6mg/kg）消除[8]。