Zhang Tian-tai, Cui Bing, Dai De-zai, Su Wei
Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
Acta Pharmacol Sin. 2005 Nov;26(11):1309-16. doi: 10.1111/j.1745-7254.2005.00214.x.
To elucidate the involvement of the endothelin (ET) pathway in the pathogenesis of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and the therapeutic effect of CPU 86017 (p-chlorobenzyltetrahydroberberine chloride) in rats.
Rats were injected with a single dose (60 mg/kg, sc) of MCT and given CPU 86017 (20, 40, and 80 mg/kg-1/d-1, po) or saline for 28 d. The hemodynamics, mRNA expression, and vascular activity were evaluated.
Right ventricular systolic pressure and central venous pressures were elevated markedly in the PAH model and decreased by CPU 86017. In the PAH group, the endothelin-1 (ET-1) in serum and lungs was dramatically increased by 54% (79.9 pg/mL, P<0.01) and 93% (166.2 pg/mL, P<0.01), and mRNA levels of preproET-1, eNOS, and iNOS also increased dramatically compared with control. Compared with PAH group, CPU 86017 decreased the content of ET-1 to the normal level in lung tissue, but was less effective in serum. The level of NO was significantly increased in CPU 86017 at 80 and 40 mg/kg-1/d-1 groups in tissue, whereas the difference in serum was not significant. A significant reduction in MDA production and an increase in the SOD activity in the serum and lungs was observed in all three CPU 86017 groups. CPU 86017 80 mg/kg-1/d-1 po increased the activity of cNOS by 33% (P<0.01). The up-regulation of eNOS and iNOS mRNA levels induced by MCT was significantly reversed in 3 CPU 86017 groups, and preproET-1 mRNA abundance was also reduced notably in CPU 86017 80 mg/kg-1/d-1 group vs the PAH group. The KCl-induced vasoconstrictions in the calcium-free medium decreased markedly in PAH group but recovered partially after CPU 86017 intervention. The constrictions in the presence of Ca(2+) was not improved by CPU 86017. The phenylephrine-induced vasoconstrictions in the calcium-free medium decreased markedly in PAH group but not recovered after CPU 86017 intervention. The constrictions in the presence of Ca(2+) completely returned to the normal after CPU 86017 intervention.
CPU 86017 suppressed MCT-induced PAH mainly through an indirect suppression of the ET-1 system, which was involved in the pathogenesis of the disease.
阐明内皮素（ET）途径在野百合碱（MCT）诱导的肺动脉高压（PAH）发病机制中的作用以及氯化对氯苄基四氢小檗碱（CPU 86017）对大鼠的治疗效果。
大鼠单次皮下注射60 mg/kg的MCT，并给予CPU 86017（20、40和80 mg/kg-1/d-1，口服）或生理盐水，持续28天。评估血流动力学、mRNA表达和血管活性。
PAH模型中右心室收缩压和中心静脉压显著升高，CPU 86017使其降低。在PAH组中，血清和肺组织中的内皮素-1（ET-1）分别显著增加54%（79.9 pg/mL，P<0.01）和93%（166.2 pg/mL，P<0.01），与对照组相比，前内皮素原-1、内皮型一氧化氮合酶（eNOS）和诱导型一氧化氮合酶（iNOS）的mRNA水平也显著增加。与PAH组相比，CPU 86017使肺组织中ET-1含量降至正常水平，但对血清中的作用较小。在80和40 mg/kg-1/d-1的CPU 86017组中，组织中NO水平显著升高，而血清中差异不显著。在所有三个CPU 86017组中，均观察到血清和肺组织中丙二醛（MDA）生成显著减少，超氧化物歧化酶（SOD）活性增加。口服80 mg/kg-1/d-1的CPU 86017使cNOS活性增加33%（P<0.01）。在三个CPU 86017组中，MCT诱导的eNOS和iNOS mRNA水平上调得到显著逆转，与PAH组相比，80 mg/kg-1/d-1的CPU 86017组中前内皮素原-1 mRNA丰度也显著降低。在无钙培养基中，PAH组氯化钾诱导的血管收缩显著降低，但在CPU 86017干预后部分恢复。在有Ca(2+)存在的情况下，CPU 86017并未改善血管收缩。在无钙培养基中，PAH组去氧肾上腺素诱导的血管收缩显著降低，但在CPU 86017干预后未恢复。在有Ca(2+)存在的情况下，CPU 86017干预后血管收缩完全恢复正常。
CPU 86017主要通过间接抑制ET-1系统来抑制MCT诱导的PAH，ET-1系统参与了该疾病的发病机制。
