Weston Arthur H, Absi Mais, Ward Donald T, Ohanian Jacqueline, Dodd Robert H, Dauban Philippe, Petrel Christophe, Ruat Martial, Edwards Gillian
Faculty of Life Sciences, University of Manchester, UK.
Circ Res. 2005 Aug 19;97(4):391-8. doi: 10.1161/01.RES.0000178787.59594.a0. Epub 2005 Jul 21.
Small increases in extracellular Ca2+ dilate isolated blood vessels. In the present study, the possibility that a vascular, extracellular Ca2+-sensing receptor (CaSR) could mediate these vasodilator actions was investigated. Novel ligands that interact with the CaSR were used in microelectrode recordings from rat isolated mesenteric and porcine coronary arteries. The major findings were that (1) raising extracellular Ca2+ or adding calindol, a CaSR agonist, produced concentration-dependent hyperpolarizations of vascular myocytes, actions attenuated by Calhex 231, a negative allosteric modulator of CaSR. (2) Calindol-induced hyperpolarizations were inhibited by the intermediate conductance, Ca2+-sensitive K+ (IKCa) channel inhibitors, TRAM-34, and TRAM-39. (3) The effects of calindol were not observed in the absence of endothelium. (4) CaSR mRNA and protein were present in rat mesenteric arteries and in porcine coronary artery endothelial cells. (5) CaSR and IKCa proteins were restricted to caveolin-poor membrane fractions. We conclude that activation of vascular endothelial CaSRs opens endothelial cell IKCa channels with subsequent myocyte hyperpolarization. The endothelial cell CaSR may have a physiological role in the control of arterial blood pressure.
细胞外钙离子（Ca2+）的小幅增加可使离体血管扩张。在本研究中，我们探讨了血管细胞外钙敏感受体（CaSR）介导这些血管舒张作用的可能性。我们使用了与CaSR相互作用的新型配体，对大鼠离体肠系膜动脉和猪冠状动脉进行微电极记录。主要发现如下：（1）提高细胞外Ca2+浓度或添加CaSR激动剂卡林多，可使血管平滑肌细胞产生浓度依赖性超极化，这种作用可被CaSR负性变构调节剂Calhex 231减弱。（2）卡林多诱导的超极化可被中电导、Ca2+敏感钾通道（IKCa）抑制剂TRAM - 34和TRAM - 39抑制。（3）在内皮细胞缺失的情况下未观察到卡林多的作用。（4）大鼠肠系膜动脉和猪冠状动脉内皮细胞中存在CaSR mRNA和蛋白。（5）CaSR和IKCa蛋白局限于富含小窝蛋白的膜组分中。我们得出结论，血管内皮CaSR的激活可打开内皮细胞的IKCa通道，随后使平滑肌细胞超极化。内皮细胞CaSR可能在动脉血压控制中具有生理作用。
