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首页> 外文期刊>Acta Pharmacologica Sinica >CPU 86017, p-chlorobenzyltetrahydroberberine chloride, attenuates monocrotaline-induced pulmonary hypertension by suppressing endothelin pathway
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CPU 86017, p-chlorobenzyltetrahydroberberine chloride, attenuates monocrotaline-induced pulmonary hypertension by suppressing endothelin pathway

机译：CPU 86017，对氯苄基四氢小ber碱氯化物，通过抑制内皮素途径减轻单克尿林诱导的肺动脉高压

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Aim: To elucidate the involvement of the endothelin (ET) pathway in the patho-genesis of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and the therapeutic effect of CPU 86017 (p-chlorobenzyltetrahydroberberine chloride) in rats. Methods: 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. Results: 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. Conclusion: 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.
机译：目的：阐明内皮素（ET）途径参与单crotaline（MCT）诱发的肺动脉高压（PAH）的致病作用以及CPU 86017（对氯苄基四氢小ber碱氯化物）的治疗作用。方法：给大鼠注射单剂量（60 mg / kg，sc）的MCT，并给予CPU 86017（20,40和80 mg·kg〜（-1）·d〜（-1），口服）或生理盐水28天评价了血流动力学，mRNA表达和血管活性。结果：PAH模型中右心室收缩压和中心静脉压显着升高，CPU 86017降低。PAH组中，血清和肺中的内皮素-1（ET-1）显着升高了54％（79.9 pg） / mL，P <0.01）和93％（166.2 pg / mL，P <0.01），preproET-1，eNOS和iNOS的mRNA水平与对照组相比也显着增加。与PAH组相比，CPU 86017将肺组织中ET-1的含量降低至正常水平，但对血清的作用较弱。在80和40 mg·kg〜（-1）·d〜（-1）组中，CPU 86017中的NO水平显着增加，而血清中的差异不显着。在所有三个CPU 86017组中，均观察到MDA产生显着减少，血清和肺中SOD活性增加。 CPU 86017 po 80 mg·kg〜（-1）·d〜（-1）po使cNOS活性提高33％（P <0.01）。在3个CPU 86017组中，MCT诱导的eNOS和iNOS mRNA水平的上调被显着逆转，在CPU 86017 80 mg·kg〜（-1）·d〜（-1）中，preproET-1 mRNA的丰度也明显降低。 ）组与PAH组。 PAH组在无钙培养基中KCl诱导的血管收缩明显降低，但在CPU 86017干预后部分恢复。 CPU 86017不能改善Ca〜（2+）存在下的收缩。PAH组中去氧肾上腺素诱导的无钙培养基中的血管收缩明显降低，但在CPU 86017干预后并未恢复。在存在Ca〜（2+）的情况下，CPU 86017干预后，颈缩完全恢复正常。结论：CPU 86017主要通过间接抑制ET-1系统来抑制MCT诱导的PAH，而ET-1系统与疾病的发病机制有关。

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