Julius L. Chambers Biomedical and Biotechnology Research Institute (L.E.B., C.L.W., E.M.A.) and Department of Biological and Biomedical Sciences (E.M.A.), North Carolina Central University, Durham, North Carolina; and Department of Physiology and Pharmacology and Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston Salem, North Carolina (E.M.A.).
Julius L. Chambers Biomedical and Biotechnology Research Institute (L.E.B., C.L.W., E.M.A.) and Department of Biological and Biomedical Sciences (E.M.A.), North Carolina Central University, Durham, North Carolina; and Department of Physiology and Pharmacology and Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston Salem, North Carolina (E.M.A.)
J Pharmacol Exp Ther. 2022 May;381(2):120-128. doi: 10.1124/jpet.121.001034. Epub 2022 Mar 19.
High Ca lowers blood pressure in hypertension, but the mechanism is not clear. The missing link may be the perivascular sensory nerve Ca-sensing receptor (CaSR) that mediates a vasodilator system after activation by interstitial Ca Our results show that high salt increased CaSR expression in mesenteric arteries as well as Ca relaxation of contracted mesenteric arteries from salt-sensitive (SS) rats. The CaSR was expressed as a doublet (≈120-150 kDa) in arteries from animals fed a high-salt diet for 1-4 weeks. The higher molecular weight glycosylated protein increased in arteries from SS animals; however, expression of the low molecular mass high-mannose protein decreased over 4 weeks of feeding the diet. In tissues from salt-resistant (SR) rats, the diet decreased CaSR expression after 4 weeks. Ca relaxation of mesenteric arteries under phenylephrine tone increased in SS rats but decreased in arteries from SR rats fed the high-salt diet. Ca-activated K channels have a larger role in Ca relaxation of arteries in SR than SS rats. The data suggest that high salt epigenetically regulates the receptor at the translational level in vivo and that the in vitro effect of Ca is on receptor trafficking and signaling. In conclusion, upregulated expression of the CaSR in salt sensitivity increased receptor-mediated vascular relaxation. These findings show that CaSR signaling may compensate for changes in the vasculature in salt-sensitive hypertension. SIGNIFICANCE STATEMENT: The perivascular sensory nerve Ca-sensing receptor (CaSR) mediates Ca relaxation of isolated mesenteric arteries under tension. This receptor may therefore play a significant role in relaxation of resistance arteries in vivo, thus explaining the blood pressure-lowering effect of dietary Ca. The present studies describe the effect of high salt-induced upregulation of the CaSR in salt-sensitive rats and the roles played by Ca-activated K channels and nitric oxide in Ca responses.
高钙可降低高血压患者的血压，但机制尚不清楚。缺失的环节可能是血管周围感觉神经钙敏感受体（CaSR），它在激活后介导血管舒张系统间质钙。我们的结果表明，高盐增加了肠系膜动脉中 CaSR 的表达，并舒张了来自盐敏感（SS）大鼠的收缩性肠系膜动脉。在 1-4 周高盐饮食喂养的动物动脉中，CaSR 表现为二聚体（≈120-150 kDa）。高盐饮食喂养 4 周后，SS 动物动脉中增加了较高分子量的糖基化蛋白，而低分子量高甘露糖蛋白的表达减少。在盐抵抗（SR）大鼠的组织中，高盐饮食 4 周后降低了 CaSR 的表达。SS 大鼠的 phenylephrine 张力下肠系膜动脉的 Ca 舒张增加，但高盐饮食喂养的 SR 大鼠的动脉舒张减少。在 SR 大鼠的动脉中，Ca 激活的 K 通道在 Ca 舒张中起更大的作用。数据表明，高盐在体内通过翻译水平上表观遗传调节受体，而 Ca 的体外作用是受体的运输和信号转导。总之，盐敏感性中 CaSR 的上调增加了受体介导的血管舒张。这些发现表明，CaSR 信号可能补偿盐敏感型高血压中血管的变化。意义陈述：血管周围感觉神经钙敏感受体（CaSR）介导张力下分离的肠系膜动脉的 Ca 舒张。因此，该受体在体内阻力动脉的舒张中可能起重要作用，从而解释了膳食 Ca 的降压作用。本研究描述了高盐诱导的 CaSR 在盐敏感型大鼠中的上调作用以及 Ca 激活的 K 通道和一氧化氮在 Ca 反应中的作用。
