左旋精氨酸恢复eNOS和iNOS平衡并抑制肺动脉高压的研究

L-arginine inhibits pulmonary hypertension by restoring the balance between endothelial nitric oxide synthase and inducible nitric oxide synthase

目的探讨诱导型一氧化氮合酶（iNOS）在中、晚期肺动脉高压（PH）发病中的作用机制及左旋精氨酸（L—Arg）对其产生的影响。方法30只雄性sD大鼠随机均分为5组，对照组（C组）、MCT3组（M3组）、MCT5组（M5组）、L—Arg3／MCT3组（L3组）、L-Arg5／MCT5组（L5组）。除C组外其他组大鼠均用野百合碱一次性腹腔注射诱导PH模型。此后L3组和L5组分别连续每天腹腔注射L—Arg3周和5周，M3组和M5组分别连续每天腹腔注射与L—Arg等量的生理盐水3周和5周，C组连续每天腹腔注射与L—Arg等量的生理盐水共5周。实验周期结束则用右心导管法测定右心室收缩压（RVSP），间接反映肺动脉压力，然后取大鼠肺组织做免疫组化，检测各组iNOS、内皮一氧化氮合酶（eNOS）和弹性蛋白（elastin）的表达变化。结果M3和M5组中iNOS和elastin的表达明显高于C组，而eNOS表达明显少于C组；L3和L5组iNOS和elastin的表达少于相应M3和M5组，但L5组两种蛋白表达仍高于C组，L3和L5组eNOS的减少明显比相应M3和M5组少，但不及C组。结论PH形成的中、晚期，肺组织中eNOS表达减少，而此时iNOS的表达增高可能产生大量一氧化氮（NO），但并没有改善PH的病情，而L-Arg能够恢复eNOS和iNOS之间的平衡并有效抑制PH的进展。

Objective To investigate the role of iNOS in the middle and late stage of pulmonary hypertension （PH） and the effect of L-Arginine（L-Arg） on these stage. Methods Thirty healthy male SD rats were randomly divided into five groups. All rats except those in control group were injected intraperitoneally （ip） with a single dose （50 mg/kg） of MCT to induce PH. Then the L3 and L5 groups were injected ip with 500 mg/kg L-Arg daily for3 weeks and 5weeks respectively, the M3 and M5 groups received a daily ip injection of the same amount of saline as L-Arg for 3 weeks and 5 weeks respectively; the same amount of saline was injected ip daily in control group for 5 weeks. Right ventricular systolic pressure（RVSP） was measured before lungs were excised for immunohistochemistry at the end of experiments. Results The expressions of iNOS and elastin in M3 and M5 were higher compared to the control group, but L-Arg partly reduced the expressions of iNOS and elastin both at 3 weeks and 5 weeks post-MCT. The reduction of eNOS expression in L3 and L5 groups were lower compared to M3 and M5 groups, hut the eNOS expression in L3 and L5 groups were still lower than control group. Conclusion During the middle and late stage of PH, the expression of eNOS was decreased. The expression of iNOS was induced, which would produce numerous NO. However, these NO had no benefit on the development of PH. L-Arg could restore the balance of eNOS and iNOS, and could inhibit the development of PH, which mac provide a new clues to exolore the oathogenesis and treatment of PH.