Novel Roles for Kv7 Channels in Shaping Histamine-Induced Contractions and Bradykinin-Dependent Relaxations in Pig Coronary Arteries.
Novel Roles for Kv7 Channels in Shaping Histamine-Induced Contractions and Bradykinin-Dependent Relaxations in Pig Coronary Arteries.
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DOI：
10.1371/journal.pone.0148569
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Obukhov AG
中科院分区：
文献类型：
--
作者：
Chen X;Li W;Hiett SC;Obukhov AG
电压门控 Kv7 通道受到 Gq 蛋白偶联受体激动剂（例如组胺）的抑制。最近的研究提供了证据表明抑制血管 Kv7 通道可能会引发血管收缩。在这项研究中，我们研究了 Kv7 活性如何调节“健康”和代谢综合征 (MetS) 猪右冠状动脉 (CA) 中组胺诱导的收缩。我们对家养、瘦肉 Ossabaw 猪和 MetS Ossabaw 猪 CA 进行了等长张力和免疫组织化学研究。我们发现 Kv7.2/Kv7.4/Kv7.5 激活剂 ML213 和通用 Kv7 抑制剂 XE991 都不会改变预载环下 CA 环的张力，表明血管 Kv7 通道可能在预载环中不活跃。相反，ML213 有效扩张组胺预收缩的 CA，表明 Kv7 通道在组胺应用过程中被激活，但被组胺部分抑制。免疫组织化学分析显示，CA 壁内侧和内膜层的 Kv7.4 免疫染色强度较强，而内膜层的 Kv7.5 免疫染色强度较强，而内侧层的免疫染色强度较弱。与精益 Ossabaw 或国内 CA 相比，MetS Ossabaw CA 中的内侧 Kv7 免疫染色明显较弱。一致地，组胺预收缩的 MetS Ossabaw CA 表现出减弱的 ML213 依赖性扩张。在家猪 CA 中，内侧 Kv7 免疫染色强度较强，组胺诱导的收缩在 4 分钟内自发衰减至峰值幅度的约 31%。相反，在 Ossabaw CA 中，Kv7 免疫染色强度较弱，组胺诱导的收缩更加持续。 XE991 预处理显着减缓了国内 CA 中组胺诱导的收缩的衰减速率，支持了 Kv7 活性增加与组胺诱导的收缩衰减速率加快相关的假设。或者，XE991 显着降低了收缩前 CA 中缓激肽依赖性扩张的幅度。我们认为，在 CA 中，Kv7 通道表达减少或功能丧失可能导致组胺诱导的持续收缩和内皮依赖性舒张减少，这都是冠状动脉痉挛的危险因素。
Voltage-gated Kv7 channels are inhibited by agonists of Gq-protein-coupled receptors, such as histamine. Recent works have provided evidence that inhibition of vascular Kv7 channels may trigger vessel contractions. In this study, we investigated how Kv7 activity modulates the histamine-induced contractions in “healthy” and metabolic syndrome (MetS) pig right coronary arteries (CAs). We performed isometric tension and immunohistochemical studies with domestic, lean Ossabaw, and MetS Ossabaw pig CAs. We found that neither the Kv7.2/Kv7.4/Kv7.5 activator ML213 nor the general Kv7 inhibitor XE991 altered the tension of CA rings under preload, indicating that vascular Kv7 channels are likely inactive in the preloaded rings. Conversely, ML213 potently dilated histamine-pre-contracted CAs, suggesting that Kv7 channels are activated during histamine applications and yet partially inhibited by histamine. Immunohistochemistry analysis revealed strong Kv7.4 immunostaining in the medial and intimal layers of the CA wall, whereas Kv7.5 immunostaining intensity was strong in the intimal but weak in the medial layers. The medial Kv7 immunostaining was significantly weaker in MetS Ossabaw CAs as compared to lean Ossabaw or domestic CAs. Consistently, histamine-pre-contracted MetS Ossabaw CAs exhibited attenuated ML213-dependent dilations. In domestic pig CAs, where medial Kv7 immunostaining intensity was stronger, histamine-induced contractions spontaneously decayed to ~31% of the peak amplitude within 4 minutes. Oppositely, in Ossabaw CAs, where Kv7 immunostaining intensity was weaker, the histamine-induced contractions were more sustained. XE991 pretreatment significantly slowed the decay rate of histamine-induced contractions in domestic CAs, supporting the hypothesis that increased Kv7 activity correlates with a faster rate of histamine-induced contraction decay. Alternatively, XE991 significantly decreased the amplitude of bradykinin-dependent dilations in pre-contracted CAs. We propose that in CAs, a decreased expression or a loss of function of Kv7 channels may lead to sustained histamine-induced contractions and reduced endothelium-dependent relaxation, both risk factors for coronary spasm.