内皮素在肝外型门静脉高压症发病机制中的作用

An experimental study on role of endothelin in pathogenesis of portal hypertension

目的 探讨内皮素在门静脉高压症发病机制中的作用及其可能的机制。方法 参照Benoit方法建立大鼠门静脉高压症模型 ,应用放射免疫学方法分别测定门静脉高压症组、正常对照组和假手术组大鼠血浆及肝组织中ET 1的含量 ,并观察ET 1和ETA受体拮抗剂对门静脉高压症大鼠FPP以及体外培养的门静脉血管平滑肌细胞 (VSMC)增殖和蛋白质合成的影响。结果 ①门静脉高压症大鼠血浆和肝组织ET 1含量显著高于正常对照组和假手术组 (P <0 0 1) ;②静脉注ET 1可以显著提高门静脉高压症大鼠的自由门静脉压 (P =0 0 0 2 ) ,静注ETA受体拮抗剂则可以显著降低门静脉高压症大鼠的FPP (P =0 0 47) ;③ET 1可以显著剂量依赖性地促进门静静脉VSMC对3 H TdR和3 H Leu的掺入 ,这种作用可以被ETA受体拮抗剂所抑制。结论 ①ET 1可以通过ETA受体介导的缩血管作用 ,增加肝内门静脉系统血流阻力的功能性部分 ;②ET 1可以显著促进体外培养的大鼠门静脉血管平滑肌细胞的增殖和蛋白质合成 ,参与门静脉系统的血管增生 血管重构 ,并影响门静脉系统血流阻力的器质性部分 ;③门静脉高压症大鼠体内ET 1的过量表达通过影响门静脉系统血流阻力的功能性部分和器质性部分 ,在门静脉高压症的发病机理中具有重要作用。

Objective To investigate the role of endothelin in pathogenesis of portal hypertension and its possible mechanism. Methods The model of portal hypertension was established in rats according to Benoit's method. The serum and hepatic concentration of ET-1 in normal control, sham-operated and portal hypertentive rats were measured with radioimmunoassay. The effects of ET-1 and ETA receptor antagonist on FPP in portal hypertensive rats and proliferation and protein synthesis of VSMC in vitro were also observed. Results 1) The concentrations of ET-1 in serum and hepatic tissue in portal hypertensive rats were significantly higher than that in normal control and sham-operated ones (P<0.01). 2) Injection of ET-1 could significantly elevate the FPP of portal hypertensive rats (P=0.002) while that of ETA receptor antagonist could markedly reduce it (P=0.047). 3) ET-1 could remarkably increase the intake of 3H-TdR and 3H-Leu of portal vein VSMC in vitro in a dose-dependent manner that could be antagonized by antagonist of ETA receptor. Conclusions 1) ET-1 can significantly elevate the FPP by the vasoconstrictive effect that is induced by ETA receptor in portal hypertensive rats and increase the functional part of intra-hepatic resistance of portal vein system. 2) ET-1 can markedly enhance the proliferation and protein synthesis of cultured portal vein VSMC of rats in vitro and is involved in the proliferation and reconstruction of portal vessel and may influence the structural part of portal resistance. 3) The overexpression of ET-1 in portal hypertensive rats can influence both the functional and structural parts of portal resistance in portal hypertension to play an important role in pathogenesis of portal hypertension.