Department of Pathophysiology, Key Laboratory of Education Ministry of Xinjiang Endemic and Ethnic Diseases, Medical College of Shihezi University, Shihezi, Xinjiang Uygur Autonomous Region 832008, P.R. China.
Mol Med Rep. 2019 Nov;20(5):4433-4448. doi: 10.3892/mmr.2019.10620. Epub 2019 Aug 27.
Hypertension is a cardiovascular disease that severely impairs human health; however, its specific etiology and pathogenesis are complex. The present study investigated the effects of the calcium sensing receptor (CaSR) on vascular tone in spontaneously hypertensive rats (SHRs), and clarified the role and mechanism of CaSR in regulating this property with respect to the phospholipase C (PLC)‑inositol 1,4,5‑triphosphate (IP3)/adenylate cyclase‑V(AC‑V)/cyclic adenosine monophosphate (cAMP)/renin‑angiotensin system (RAS) pathway in these animals. CaSR protein expression in the mesenteric artery (MA) of rats and CaSR protein expression in SHRs were significantly reduced. Based on wire myography studies, vasoconstriction was significantly augmented and vasodilatation was attenuated in SHRs, and this effect was endothelium‑independent. The CaSR calcimimetic NPSR568 and inhibitor NPS2143 reduced vasoconstriction and enhanced vasodilation in SHRs. Furthermore, pretreatment with PLC‑IP3/AC‑V/cAMP/RAS pathway blockers significantly reduced the vasoconstriction response and enhanced the vasodilator response in SHRs and Wistar‑Kyoto rats (WKY), and these effects were partially dependent on the endothelium. Additionally, pretreatment with CaSR inhibitors were determined to cooperate with the PLC‑IP3/AC‑V/cAMP/RAS pathway inhibitors to significantly reduce vasoconstriction and enhance vasodilation in SHRs and WKY. Our results demonstrated that CaSR is functionally expressed in the MA of SHRs, and that CaSR expression is decreased in SHRs. Additionally, vasoconstriction was enhanced while vasodilatation was attenuated in SHRs; these processes were determined to be endothelium‑independent. CaSR is involved in the regulation of blood pressure and vascular tension in SHRs and WKYs. In association with mechanistic differences, this effect was proposed to be partially endothelium‑dependent and mediated by the PLC‑IP3/AC‑V/cAMP/RAS pathway.
高血压是一种严重损害人类健康的心血管疾病，但具体的病因和发病机制十分复杂。本研究探讨了钙敏感受体（CaSR）对自发性高血压大鼠（SHR）血管张力的影响，并阐明了 CaSR 在调节血管张力方面的作用和机制，以及该作用与磷脂酶 C（PLC）-肌醇 1,4,5-三磷酸（IP3）/腺苷酸环化酶-V（AC-V）/环腺苷酸（cAMP）/肾素-血管紧张素系统（RAS）通路之间的关系。大鼠肠系膜动脉（MA）中的 CaSR 蛋白表达和 SHR 中的 CaSR 蛋白表达均显著降低。基于wire myography 研究，SHR 的血管收缩显著增强，血管舒张减弱，且该作用是内皮非依赖性的。CaSR 钙敏感受体激动剂 NPSR568 和抑制剂 NPS2143 降低了 SHR 的血管收缩，增强了血管舒张。此外，PLC-IP3/AC-V/cAMP/RAS 通路阻滞剂预处理显著降低了 SHR 和 Wistar-Kyoto 大鼠（WKY）的血管收缩反应，增强了其血管舒张反应，且这些作用部分依赖于内皮。此外，CaSR 抑制剂预处理与 PLC-IP3/AC-V/cAMP/RAS 通路抑制剂共同作用，可显著降低 SHR 和 WKY 的血管收缩，增强其血管舒张。我们的结果表明，CaSR 在 SHR 的 MA 中具有功能性表达，且 SHR 中的 CaSR 表达降低。此外，SHR 的血管收缩增强，血管舒张减弱，这些过程被确定为内皮非依赖性。CaSR 参与 SHR 和 WKY 的血压和血管张力调节。与机制差异相关，该作用部分依赖于内皮，由 PLC-IP3/AC-V/cAMP/RAS 通路介导。
