Stimulation of calcium-sensing receptors induces endothelium-dependent vasorelaxations via nitric oxide production and activation of IKCa channels.
Stimulation of calcium-sensing receptors induces endothelium-dependent vasorelaxations via nitric oxide production and activation of IKCa channels.
复制标题
DOI：
10.1016/j.vph.2016.01.001
复制
发表时间：
2016-05
影响因子：
4
通讯作者：
Albert AP
中科院分区：
文献类型：
--
作者：
Greenberg HZ;Shi J;Jahan KS;Martinucci MC;Gilbert SJ;Vanessa Ho WS;Albert AP
据报道，刺激血管钙敏感受体(CaSR)既能引起收缩也能引起松弛。然而，参与这些反应的细胞机制仍不清楚。本研究探讨了刺激血管收缩因子对血管收缩的影响，并着重探讨了血管内皮细胞、一氧化氮(NO)和K+通道在这些反应中的作用。在丝状肌图研究中，将[Ca2+]o从1 mM增加到6 mM，可诱导甲氧胺预收缩的兔肠系膜动脉的浓度依赖性松弛。[Ca2+]o诱导的松弛依赖于功能内皮，并被负变构CaSR调节剂Calhex-231抑制。在应用NO荧光指示剂DAF-FM的实验中，CaSR的激活也诱导新鲜分离的内皮细胞(ECs)产生NO。[Ca2+]o引起的松弛可被内皮型一氧化氮合酶、鸟苷环化酶和蛋白激酶G的抑制剂抑制。用大(BKCa)和中(IKCa)钙激活的K+通道(硫杆菌毒素和轮藻毒素)和KV7通道(利诺匹定)的抑制剂预处理也能降低[Ca~(2+)]o引起的血管松弛。增加[Ca~(2+)]_o也可激活肠系膜动脉内皮细胞穿孔-贴片记录的IKCa电流。这些结果表明，刺激CaSRs诱导内皮依赖性血管松弛，这是由两条独立的途径介导的，涉及NO的产生和IKCa通道的激活。NO刺激PKG导致血管平滑肌细胞BKCa激活，而IKCa活性参与内皮源性超极化。
Stimulation of vascular calcium-sensing receptors (CaSRs) is reported to induce both constrictions and relaxations. However, cellular mechanisms involved in these responses remain unclear. The present study investigates the effect of stimulating CaSRs on vascular contractility and focuses on the role of the endothelium, nitric oxide (NO) and K+ channels in these responses. In wire myography studies, increasing [Ca2 +]o from 1 mM to 6 mM induced concentration-dependent relaxations of methoxamine pre-contracted rabbit mesenteric arteries. [Ca2 +]o-induced relaxations were dependent on a functional endothelium, and were inhibited by the negative allosteric CaSR modulator Calhex-231. [Ca2 +]o-induced relaxations were reduced by inhibitors of endothelial NO synthase, guanylate cyclase, and protein kinase G. CaSR activation also induced NO production in freshly isolated endothelial cells (ECs) in experiments using the fluorescent NO indicator DAF-FM. Pre-treatment with inhibitors of large (BKCa) and intermediate (IKCa) Ca2 +-activated K+ channels (iberiotoxin and charybdotoxin), and Kv7 channels (linopirdine) also reduced [Ca2 +]o-induced vasorelaxations. Increasing [Ca2 +]o also activated IKCa currents in perforated-patch recordings of isolated mesenteric artery ECs. These findings indicate that stimulation of CaSRs induces endothelium-dependent vasorelaxations which are mediated by two separate pathways involving production of NO and activation of IKCa channels. NO stimulates PKG leading to BKCa activation in vascular smooth muscle cells, whereas IKCa activity contributes to endothelium-derived hyperpolarisations.