CaSR抑制剂Calhex231通过PTH-AR途径参与创伤失血性休克大鼠血管低反应性的调节

CaSR inhibitor Calhex231 regulates vascular hyporeactivity after trau⁃matic hemorrhagic shock in rats through PTH-AR pathway

目的:探讨钙敏感性受体(CaSR)抑制剂Calhex231(Cal)是否通过甲状旁腺素(PTH)-肾上腺素受体(AR)途径参与创伤失血性休克大鼠血管低反应性的调节。方法:检测Cal对创伤失血性休克大鼠血PTH水平的影响,并观察外源给予PTH对正常和休克大鼠血压的影响;Western blot法检测Cal对大鼠肠系膜上动脉(SMA)以及外源给予PTH对大鼠原代血管平滑肌细胞(VSMC)中2种AR亚型(α1-AR和β1-AR)蛋白表达水平的影响。结果:创伤失血性休克后大鼠血PTH水平显著升高,Cal治疗能够显著降低血PTH水平(P<0.01)。外源给予PTH能显著降低正常大鼠血压。在组织水平上,Cal能提高创伤失血性休克大鼠SMA中α1-AR蛋白表达水平(P<0.05);在细胞水平上,外源给予PTH能使大鼠原代VSMC中α1-AR蛋白表达水平降低,Cal能拮抗PTH降低α1-AR蛋白表达的作用(P<0.05)。结论:CaSR抑制剂Cal可通过降低血PTH水平、上调血管α1-AR蛋白表达水平而发挥改善休克后血管低反应性的作用。

AIM:To determine whether parathyroid hormone(PTH)and adrenergic receptor(AR)contribute to the effects of calcium-sensing receptor(CaSR)inhibitor Calhex231(Cal)on vascular hyporeactivity after traumatic hemorrhagic shock in rats.METHODS:The effect of Cal on blood PTH level in traumatic hemorrhagic shock rats and the effect of exogenous PTH on the blood pressure in normal and shock rats were observed.The protein expression levels of 2 subtypes of AR,includingα1-AR andβ1-AR,in superior mesenteric artery(SMA)and vascular smooth muscle cells(VSMC)were measured by Western blot.RESULTS:The blood level of PTH was significantly increased after traumatic hemorrhagic shock,while Cal significantly decreased the level of PTH(P<0.01).Exogenous PTH treatment significantly lowered blood pressure in normal rats.Treatment with Cal increased the expression ofα1-AR in SMA after shock(P<0.05).Exogenous PTH treatment significantly reduced the expression ofα1-AR in VSMC,while Cal antagonized this effect of PTH(P<0.05).CONCLUSION:The CaSR inhibitor Cal improves the vascular hyporeactivity after traumatic hemorrhagic shock in rats through decreasing blood PTH level and up-regulating vascularα1-AR expression.