Department of Cardiology, Guangdong Cardiovascular Institute, Guangzhou, China.
Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou, China.
Clin Exp Pharmacol Physiol. 2019 Jul;46(7):643-651. doi: 10.1111/1440-1681.13087. Epub 2019 Apr 17.
Thromboxane A (TXA ) has been implicated in the pathogenesis of vascular complications, but the underlying mechanism remains unclear. The contraction of renal arterial rings in mice was measured by a Multi Myograph System. The intracellular calcium concentration ([Ca ] ) in vascular smooth muscle cells (VSMCs) was obtained by using a fluo-4/AM dye and a confocal laser scanning microscopy. The results show that the U46619-induced vasoconstriction of renal artery was completely blocked by a TXA receptor antagonist GR32191, significantly inhibited by a selective phospholipase C (PI-PLC) inhibitor U73122 at 10 μmol/L and partially inhibited by a Phosphatidylcholine - specific phospholipase C (PC-PLC) inhibitor D609 at 50 μmol/L. Moreover, the U46619-induced vasoconstriction was inhibited by a general protein kinase C (PKC) inhibitor chelerythrine at 10 μmol/L, and a selective PKCδ inhibitor rottlerin at 10 μmol/L. In addition, the PKC-induced vasoconstriction was partially inhibited by a Rho-kinase inhibitor Y-27632 at 10 μmol/L and was further completely inhibited together with a putative IP receptor antagonist and store-operated Ca (SOC) entry inhibitor 2-APB at 100 μmol/L. On the other hand, U46619-induced vasoconstriction was partially inhibited by L-type calcium channel (Cav1.2) inhibitor nifedipine at 1 μmol/L and 2-APB at 50 and 100 μmol/L. Last, U46619-induced vasoconstriction was partially inhibited by a cell membrane Ca activated C1 channel blocker 5-Nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) at 50 and 100 μmol/L. Our results suggest that the U46619-induced contraction of mouse intrarenal arteries is mediated by Cav1.2 and SOC channel, through the activation of thromboxane-prostanoid receptors and its downstream signaling pathway.
血栓素 A（TXA）已被牵连到血管并发症的发病机制中，但潜在的机制仍不清楚。通过多肌描记系统测量小鼠肾动脉环的收缩。通过使用荧光素-4/AM 染料和共聚焦激光扫描显微镜获得血管平滑肌细胞（VSMCs）中的细胞内钙浓度([Ca2+])。结果表明，TXA 受体拮抗剂 GR32191 完全阻断 U46619 诱导的肾动脉收缩，10 μmol/L 的选择性磷脂酶 C（PI-PLC）抑制剂 U73122 显著抑制，50 μmol/L 的磷脂酰胆碱特异性磷脂酶 C（PC-PLC）抑制剂 D609 部分抑制。此外，U46619 诱导的收缩被 10 μmol/L 的一般蛋白激酶 C（PKC）抑制剂Chelerythrine 抑制，10 μmol/L 的选择性 PKCδ抑制剂 Rottlerin 抑制。此外，Rho-kinase 抑制剂 Y-27632 部分抑制 PKC 诱导的收缩，100 μmol/L 的假定 IP 受体拮抗剂和储存操作钙（SOC）进入抑制剂 2-APB 完全抑制。另一方面，U46619 诱导的收缩被 1 μmol/L 的 L 型钙通道（Cav1.2）抑制剂硝苯地平部分抑制，50 μmol/L 和 100 μmol/L 的 2-APB 部分抑制。最后，U46619 诱导的收缩被细胞膜钙激活 C1 通道阻滞剂 5-硝基-2-（3-苯丙基氨基）苯甲酸（NPPB）部分抑制，50 μmol/L 和 100 μmol/L。我们的结果表明，U46619 诱导的小鼠肾内动脉收缩是通过 Cav1.2 和 SOC 通道介导的，通过血栓素-前列腺素受体及其下游信号通路的激活。
