Original Articles

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

Authors: Tian-tai Zhang, Bing Cui, De-zai Dai, Wei Su

Abstract

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 MCT and given CPU 86017 (20, 40, and 80 mgdotkg-1dotd-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 mgdotkg-1dotd-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 mgdotkg-1dotd-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 mgdotkg-1dotd-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 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 86017 intervention. The constrictions in the presence of Ca2+ 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.
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