| CPU 86017, p-chlorobenzyltetrahydroberberine chloride, attenuates monocrotaline-induced pulmonary hypertension by suppressing endothelin pathway. | |
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MedLine Citation:
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PMID: 16225752 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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 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. |
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Authors:
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Tian-tai Zhang; Bing Cui; De-zai Dai; Wei Su |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Acta pharmacologica Sinica Volume: 26 ISSN: 1671-4083 ISO Abbreviation: Acta Pharmacol. Sin. Publication Date: 2005 Nov |
Date Detail:
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Created Date: 2005-10-17 Completed Date: 2007-05-09 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100956087 Medline TA: Acta Pharmacol Sin Country: China |
Other Details:
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Languages: eng Pagination: 1309-16 Citation Subset: IM |
Affiliation:
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Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Berberine / analogs & derivatives*, pharmacology Blood Pressure / drug effects Calcium Channel Blockers / pharmacology* Endothelin-1 / biosynthesis*, blood, genetics Hypertension, Pulmonary / chemically induced, metabolism*, pathology Lung / metabolism* Male Monocrotaline Nitric Oxide / blood, metabolism Nitric Oxide Synthase Type II / biosynthesis, genetics Nitric Oxide Synthase Type III / biosynthesis, genetics RNA, Messenger / biosynthesis, genetics Rats Rats, Sprague-Dawley Vasoconstriction / drug effects |
| Chemical | |
Reg. No./Substance:
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0/4-chlorobenzyltetrahydroberberine; 0/Calcium Channel Blockers; 0/Endothelin-1; 0/RNA, Messenger; 10102-43-9/Nitric Oxide; 2086-83-1/Berberine; 315-22-0/Monocrotaline; EC 1.14.13.39/Nitric Oxide Synthase Type II; EC 1.14.13.39/Nitric Oxide Synthase Type III |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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