Vasorelaxant effects of novel Kv7.4 channel enhancers ML213 and NS15370
Vasorelaxant effects of novel Kv7.4 channel enhancers ML213 and NS15370
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DOI：
10.1111/bph.12805
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发表时间：
2014-10-01
影响因子：
7.3
通讯作者：
Greenwood, I. A.
中科院分区：
文献类型：
--
作者：
Jepps, T. A.;Bentzen, B. H.;Greenwood, I. A.
背景和目的KCNQ编码的电压门控钾通道家族（K（v）7.1-K（v）7.5）是平滑肌收缩的主要调节因子，其中K（v）7.4和K（v）7.5占优势。已经开发了各种K（v）7.2-7.5通道增强剂，其已经显示在啮齿动物和人血管中引起血管舒张。最近，已经鉴定了两种新的K（v）7通道增强剂，ML 213和NS 15370，其显示出增加的效力，特别是对K（v）7.4通道。本研究的目的是表征这些新型增强剂在不同大鼠血管中的作用，并将其与先前描述的K（v）7增强剂（S-1，BMS 204352，瑞替加滨）进行比较。我们还试图确定新的K（V）7 enhancers.Key ResultsBoth ML 213和NS 15370放松大鼠胸主动脉，肾动脉和肠系膜动脉的浓度依赖性的方式段的结合位点。在肠系膜动脉中，ML 213和NS 15370显示的EC（50）远低于测试的其他K（v）7增强剂。电流钳实验表明，这两种新的增强剂，在低浓度下，引起显着的超极化肠系膜动脉平滑肌细胞。此外，我们确定这些增强剂的刺激作用依赖于位于S5结构域的色氨酸残基，这是本研究中测试的其他K（v）7增强剂的相同结合位点。从而突出了这些新化合物作为各种平滑肌疾病的潜在治疗剂。
Background and PurposeThe KCNQ-encoded voltage-gated potassium channel family (K(v)7.1-K(v)7.5) are established regulators of smooth muscle contractility, where K(v)7.4 and K(v)7.5 predominate. Various K(v)7.2-7.5 channel enhancers have been developed that have been shown to cause a vasorelaxation in both rodent and human blood vessels. Recently, two novel K(v)7 channel enhancers have been identified, ML213 and NS15370, that show increased potency, particularly on K(v)7.4 channels. The aim of this study was to characterize the effects of these novel enhancers in different rat blood vessels and compare them with K(v)7 enhancers (S-1, BMS204352, retigabine) described previously. We also sought to determine the binding sites of the new K(v)7 enhancers.Key ResultsBoth ML213 and NS15370 relaxed segments of rat thoracic aorta, renal artery and mesenteric artery in a concentration-dependent manner. In the mesenteric artery ML213 and NS15370 displayed EC(50)s that were far lower than other K(v)7 enhancers tested. Current-clamp experiments revealed that both novel enhancers, at low concentrations, caused significant hyperpolarization in mesenteric artery smooth muscle cells. In addition, we determined that the stimulatory effect of these enhancers relied on a tryptophan residue located in the S5 domain, which is the same binding site for the other K(v)7 enhancers tested in this study.Conclusions and ImplicationsThis study has identified and characterized ML213 and NS15370 as potent vasorelaxants in different blood vessels, thereby highlighting these new compounds as potential therapeutics for various smooth muscle disorders.