Journal
ACTA PHARMACOLOGICA SINICA
Volume 26, Issue 11, Pages 1309-1316Publisher
NATURE PUBLISHING GROUP
DOI: 10.1111/j.1745-7254.2005.00214.x
Keywords
pulmonary artery; hypertension; endothelin-1; nitric-oxide synthase; reactive oxygen species; monocrotaline; CPU 86017
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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 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 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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