CPU 86017, p-chlorobenzyltetrahydroberberine chloride, attenuates monocrotaline-induced pulmonary hypertension by suppressing endothelin pathway

• 来源期刊: 中国药理学报（英文版）
• 关键词: pulmonary artery hypertension endothelin-1 nitric-oxide synthase reactive oxygen species monocrotaline CPU 86017
• 年，卷（期）: 2005,（11）
• 页码范围: 1309-1316
• 页数: 8页
• 语种: 英文

摘要

Aim: 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. Methods: Rats were injected with a single dose (60 mg/kg, sc) of 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 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 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-1the PAH group. The KCl-induced vasoconstrictions in the calcium-free medium decreased markedly in PAH group but recovered partially after CPU 86017intervention. The constrictions in the presence of Ca2+ 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 86017intervention. The constrictions in the presence of Ca2+ completely returned to the normal after CPU 86017 intervention. Conclusion: CPU 86017 suppressed MCTinduced PAH mainly through an indirect suppression of the ET-1 system, which was involved in the pathogenesis of the disease.