Document Detail


CPU 86017, p-chlorobenzyltetrahydroberberine chloride, attenuates monocrotaline-induced pulmonary hypertension by suppressing endothelin pathway.
MedLine Citation:
PMID:  16225752     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Tian-tai Zhang; Bing Cui; De-zai Dai; Wei Su
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Acta pharmacologica Sinica     Volume:  26     ISSN:  1671-4083     ISO Abbreviation:  Acta Pharmacol. Sin.     Publication Date:  2005 Nov 
Date Detail:
Created Date:  2005-10-17     Completed Date:  2007-05-09     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100956087     Medline TA:  Acta Pharmacol Sin     Country:  China    
Other Details:
Languages:  eng     Pagination:  1309-16     Citation Subset:  IM    
Affiliation:
Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
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MeSH Terms
Descriptor/Qualifier:
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:
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

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